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Consciousness	if it is able to produce judgments on all problematic properties of consciousness (such as qualia or binding) having no innate (preloaded) philosophical knowledge on these issues, no philosophical discussions while learning, and no informational models of other creatures in its memory (such models may implicitly or explicitly contain knowledge about these creatures consciousness). However, this test can be used only to detect, but not refute the existence of consciousness. A positive result proves that machine is conscious but a negative result proves nothing. For example, absence of philosophical judgments may be caused by lack of the machines intellect, not by absence of consciousness. Scientific study For many decades, consciousness as a research topic was avoided by the majority of mainstream scientists, because of a general feeling that a phenomenon defined in subjective terms could not properly be studied using objective experimental methods. In 1975 George Mandler published an influential psychological study which distinguished between slow, serial, and limited conscious processes and fast, parallel and extensive unconscious ones. The Science and Religion Forum 1984 annual conference, From Artificial Intelligence to Human Consciousness identified the nature of consciousness as a matter for investigation; Donald Michie was a keynote speaker. Starting in the 1980s, an expanding community of neuroscientists and psychologists have associated themselves with a field called Consciousness Studies, giving rise to a stream of experimental work published in books, journals such as Consciousness and Cognition, Frontiers in Consciousness Research, Psyche, and the Journal of Consciousness Studies, along with regular conferences organized by groups such as the Association for the Scientific Study of Consciousness and the Society for Consciousness Studies. Modern medical and psychological investigations into consciousness are based on psychological experiments (including, for example, the investigation of priming effects using subliminal stimuli), and on case studies of alterations in consciousness produced by trauma, illness, or drugs. Broadly viewed, scientific approaches are based on two core concepts. The first identifies the content of consciousness with the experiences that are reported by human subjects; the second makes use of the concept of consciousness that has been developed by neurologists and other medical professionals who deal with patients whose behavior is impaired. In either case, the ultimate goals are to develop techniques for assessing consciousness objectively in humans as well as other animals, and to understand the neural and psychological mechanisms that underlie it.A study in 2016 looked at lesions in specific areas of the brainstem that were associated with coma and vegetative states. A small region of the rostral dorsolateral pontine tegmentum in the brainstem was suggested to drive consciousness through functional connectivity with two cortical regions, the left ventral anterior insular cortex, and the pregenual anterior cingulate cortex. These three regions may work together as a triad to maintain consciousness. Measurement Experimental research on consciousness presents special difficulties, due to the lack of a universally accepted operational definition. In the majority of experiments that are specifically about consciousness, the subjects are human, and the criterion used is verbal report: in other words, subjects are asked to describe their experiences, and their descriptions are treated as observations of the contents of consciousness. For example, subjects who stare continuously at a Necker cube usually report that they experience it "flipping" between two 3D configurations, even though the stimulus itself remains the same. The objective is to understand the relationship between the conscious awareness of stimuli (as indicated by verbal report) and the effects the stimuli have on brain activity and behavior. In several paradigms, such as the technique of response priming, the behavior of subjects is clearly influenced by stimuli for which they report no awareness, and suitable experimental manipulations can lead to increasing priming effects despite decreasing prime identification (double dissociation).Verbal report is widely considered to be the most reliable indicator of consciousness, but it raises a number of issues. For one thing, if verbal reports are treated as observations, akin to observations in other branches of science, then the possibility arises that they may contain errors—but it is difficult to make sense of the idea that subjects could be wrong about their own experiences, and even more difficult to see how such an error could be detected. Daniel Dennett has argued for an approach he calls heterophenomenology, which means treating verbal reports as stories that may or may not be true, but his ideas about how to do this have not been widely adopted. Another issue with verbal report as a criterion is that it restricts the field of study to humans who have language: this approach cannot be used to study consciousness in other species, pre-linguistic children, or people with types of brain damage that impair language. As a third issue, philosophers who dispute the validity of the Turing test may feel that it is possible, at least in principle, for verbal report to be dissociated from consciousness entirely: a philosophical zombie may give detailed verbal reports of awareness in the absence of any genuine awareness.Although verbal report is in practice the "gold standard" for ascribing consciousness, it is not the only possible criterion. In medicine, consciousness is assessed as a combination of verbal behavior, arousal, brain activity and purposeful movement. The last three of these can be used as indicators of consciousness when verbal behavior is absent. The scientific literature regarding the neural bases of arousal and purposeful movement is very extensive. Their reliability as indicators of consciousness is disputed, however, due to numerous studies showing that alert human subjects can be induced to behave purposefully in a variety of ways in spite of reporting a complete lack of awareness. Studies of the neuroscience of free will have also shown that the experiences that people report when they behave purposefully sometimes do not correspond to their actual behaviors or to the patterns of electrical activity recorded from their brains.Another approach applies specifically to the study of self-awareness, that is, the ability to distinguish oneself from others. In the 1970s Gordon Gallup developed an operational test for self-awareness, known as the mirror test. The test examines whether animals are able to differentiate between seeing themselves in a mirror versus seeing other animals. The classic example involves placing a spot of coloring on the skin or fur near the individuals forehead and seeing if they attempt to remove it or at least touch the spot, thus indicating that they recognize that the individual they are seeing in the mirror is themselves. Humans (older than 18 months) and other great apes, bottlenose dolphins, orcas, pigeons, European magpies and elephants have all been observed to pass this test. Neural correlates A major part of the scientific literature on consciousness consists of studies that examine the relationship between the experiences reported by subjects and the activity that simultaneously takes place in their brains—that is, studies of the neural correlates of consciousness. The hope is to find that activity in a particular part of the brain, or a particular pattern of global brain activity, which will be strongly predictive of conscious awareness. Several brain imaging techniques, such as EEG and fMRI, have been used for physical measures of brain activity in these studies.Another idea that has drawn attention for several decades is that consciousness is associated with high-frequency (gamma band) oscillations in brain activity. This idea arose from proposals in the 1980s, by Christof von der Malsburg and Wolf Singer, that gamma oscillations could solve the so-called binding problem, by linking information represented in different parts of the brain into a unified experience. Rodolfo Llinás, for example, proposed that consciousness results from recurrent thalamo-cortical resonance where the specific thalamocortical systems (content) and the non-specific (centromedial thalamus) thalamocortical systems (context) interact in the gamma band frequency via synchronous oscillations.A number of studies have shown that activity in primary sensory areas of the brain is not sufficient to produce consciousness: it is possible for subjects to report a lack of awareness even when areas such as the primary visual cortex (V1) show clear electrical responses to a stimulus. Higher brain areas are seen as more promising, especially the prefrontal cortex, which is involved in a range of higher cognitive functions collectively known as executive functions. There is substantial evidence that a "top-down" flow of neural activity (i.e., activity propagating from the frontal cortex to sensory areas) is more predictive of conscious awareness than a "bottom-up" flow of activity. The prefrontal cortex is not the only candidate area, however: studies by Nikos Logothetis and his colleagues have shown, for example, that visually responsive neurons in parts of the temporal lobe reflect the visual perception in the situation when conflicting visual images are presented to different eyes (i.e., bistable percepts during binocular rivalry). Furthermore, top-down feedback from higher to lower visual brain areas may be weaker or absent in the peripheral visual field, as suggested by some experimental data and theoretical arguments; nevertheless humans can perceive visual inputs in the peripheral visual field arising from bottom-up V1 neural activities. Meanwhile, bottom-up V1 activities for the central visual fields can be vetoed, and thus made invisible to perception, by the top-down feedback, when these bottom-up signals are inconsistent with brains internal model of the visual world.Modulation of neural responses may correlate with phenomenal experiences. In contrast to the raw electrical responses that do not correlate with consciousness, the modulation of these responses by other stimuli correlates surprisingly well with an important aspect of consciousness: namely with the phenomenal experience of stimulus intensity (brightness, contrast). In the research group of Danko Nikolić it has been shown that some of the changes in the subjectively perceived brightness correlated with the modulation of firing rates while others correlated with the modulation of neural synchrony. An fMRI investigation suggested that these findings were strictly limited to the primary visual areas. This indicates that, in the primary visual areas, changes in firing rates and synchrony can be considered as neural correlates of qualia—at least for some type of qualia. In 2011, Graziano and Kastner proposed the "attention schema" theory of awareness. In that theory, specific cortical areas, notably in the superior temporal sulcus and the temporo-parietal junction, are used to build the construct of awareness and attribute it to other people. The same cortical machinery is also used to attribute awareness to oneself. Damage to these cortical regions can lead to deficits in consciousness such as hemispatial neglect. In the attention schema theory, the value of explaining the feature of awareness and attributing it to a person is to gain a useful predictive model of that persons attentional processing. Attention is a style of information processing in which a brain focuses its resources on a limited set of interrelated signals. Awareness, in this theory, is a useful, simplified schema that represents attentional states. To be aware of X is explained by constructing a model of ones attentional focus on X. In 2013, the perturbational complexity index (PCI) was proposed, a measure of the algorithmic complexity of the electrophysiological response of the cortex to transcranial magnetic stimulation. This measure was shown to be higher in individuals that are awake, in REM sleep or in a locked-in state than in those who are in deep sleep or in a vegetative state, making it potentially useful as a quantitative assessment of consciousness states. In 2017, work by David Rudrauf and colleagues, including Karl Friston, applied the active inference paradigm to consciousness, a model of how sensory data is integrated with priors in a process of projective transformation. The authors argue that, while their model identifies a key relationship between computation and phenomenology, it does not completely solve the hard problem of consciousness or completely close the explanatory gap.Assuming that not only humans but even some non-mammalian species are conscious, a number of evolutionary approaches to the problem of neural correlates of consciousness open up. For example, assuming that birds are conscious—a common assumption among neuroscientists and ethologists due to the extensive cognitive repertoire of birds—there are comparative neuroanatomical ways to validate some of the principal, currently competing, mammalian consciousness–brain theories. The rationale for such a comparative study is that the avian brain deviates structurally from the mammalian brain. So how similar are they? What homologues can be identified? The general conclusion from the study by Butler, et al., is that some of the major theories for the mammalian brain also appear to be valid for the avian brain. The structures assumed to be critical for consciousness in mammalian brains have homologous counterparts in avian brains. Thus the main portions of the theories of Crick and Koch, Edelman and Tononi, and Cotterill seem to be compatible with the assumption that birds are conscious. Edelman also differentiates between what he calls primary consciousness (which is a trait shared by humans and non-human animals) and higher-order consciousness as it appears in humans alone along with human language capacity. Certain aspects of the three theories, however, seem less easy to apply to the hypothesis of avian consciousness. For instance, the suggestion by Crick and Koch that layer 5 neurons of the mammalian brain have a special role, seems difficult to apply to the avian brain, since the avian homologues have a different morphology. Likewise, the theory of Eccles seems incompatible, since a structural homologue/analogue to the dendron has not been found in avian brains. The assumption of an avian consciousness also brings the reptilian brain into focus. The reason is the structural continuity between avian and reptilian brains, meaning that the phylogenetic origin of consciousness may be earlier than suggested by many leading neuroscientists. Joaquin Fuster of UCLA has advocated the position of the importance of the prefrontal cortex in humans, along with the areas of Wernicke and Broca, as being of particular importance to the development of human language capacities neuro-anatomically necessary for the emergence of higher-order consciousness in humans. Biological function and evolution Opinions are divided as to where in biological evolution consciousness emerged and about whether or not consciousness has any survival value. Some argue that consciousness is a byproduct of evolution. It has been argued that consciousness emerged (i) exclusively with the first humans, (ii) exclusively with the first mammals, (iii) independently in mammals and birds, or (iv) with the first reptiles. Other authors date the origins of consciousness to the first animals with nervous systems or early vertebrates in the Cambrian over 500 million years ago. Donald Griffin suggests in his book Animal Minds a gradual evolution of consciousness. Each of these scenarios raises the question of the possible survival value of consciousness. Thomas Henry Huxley defends in an essay titled On the Hypothesis that Animals are Automata, and its History an epiphenomenalist theory of consciousness according to which consciousness is a causally inert effect of neural activity—"as the steam-whistle which accompanies the work of a locomotive engine is without influence upon its machinery". To this William James objects in his essay Are We Automata? by stating an evolutionary argument for mind-brain interaction implying that if the preservation and development of consciousness in the biological evolution is a result of natural selection, it is plausible that consciousness has not only been influenced by neural processes, but has had a survival value itself; and it could only have had this if it had been efficacious. Karl Popper develops in the book The Self and Its Brain a similar evolutionary argument.Regarding the primary function of conscious processing, a recurring idea in recent theories is that phenomenal states somehow integrate neural activities and information-processing that would otherwise be independent. This has been called the integration consensus. Another example has been proposed by Gerald Edelman called dynamic core hypothesis which puts emphasis on reentrant connections that reciprocally link areas of the brain in a massively parallel manner. Edelman also stresses the importance of the evolutionary emergence of higher-order consciousness in humans from the historically older trait of primary consciousness which humans share with non-human animals (see Neural correlates section above). These theories of integrative function present solutions to two classic problems associated with consciousness: differentiation and unity. They show how our conscious experience can discriminate between a virtually unlimited number of different possible scenes and details (differentiation) because it integrates those details from our sensory systems, while the integrative nature of consciousness in this view easily explains how our experience can seem unified as one whole despite all of these individual parts. However, it remains unspecified which kinds of information are integrated in a conscious manner and which kinds can be integrated without consciousness. Nor is it explained what specific causal role conscious integration plays, nor why the same functionality cannot be achieved without consciousness. Obviously not all kinds of information are capable of being disseminated consciously (e.g., neural activity related to vegetative functions, reflexes, unconscious motor programs, low-level perceptual analyses, etc.) and many kinds of information can be disseminated and combined with other kinds without consciousness, as in intersensory interactions such as the ventriloquism effect. Hence it remains unclear why any of it is conscious. For a review of the differences between conscious and unconscious integrations, see the article of Ezequiel Morsella.As noted earlier, even among writers who consider consciousness to be a well-defined thing, there is widespread dispute about which animals other than humans can be said to possess it. Edelman has described this distinction as that of humans possessing higher-order consciousness while sharing the trait of primary consciousness with non-human animals (see previous paragraph). Thus, any examination of the evolution of consciousness is faced with great difficulties. Nevertheless, some writers have argued that consciousness can be viewed from the standpoint of evolutionary biology as an adaptation in the sense of a trait that increases fitness. In his article "Evolution of consciousness", John Eccles argued that special anatomical and physical properties of the mammalian cerebral cortex gave rise to consciousness ("[a] psychon... linked to [a] dendron through quantum physics"). Bernard Baars proposed that once in place, this "recursive" circuitry may have provided a basis for the subsequent development of many of the functions that consciousness facilitates in higher organisms. Peter Carruthers has put forth one such potential adaptive advantage gained by conscious creatures by suggesting that consciousness allows an individual to make distinctions between appearance and reality. This ability would enable a creature to recognize the likelihood that their perceptions are deceiving them (e.g. that water in the distance may be a mirage) and behave accordingly, and it could also facilitate the manipulation of others by recognizing how things appear to them for both cooperative and devious ends. Other philosophers, however, have suggested that consciousness would not be necessary for any functional advantage in evolutionary processes. No one has given a causal explanation, they argue, of why it would not be possible for a functionally equivalent non-conscious organism (i.e., a philosophical zombie) to achieve the very same survival advantages as a conscious organism. If evolutionary processes are blind to the difference between function F being performed by conscious organism O and non-conscious organism O*, it is unclear what adaptive advantage consciousness could provide. As a result, an exaptive explanation of consciousness has gained favor with some theorists that posit consciousness did not evolve as an adaptation but was an exaptation arising as a consequence of other developments such as increases in brain size or cortical rearrangement. Consciousness in this sense has been compared to the blind spot in the retina where it is not an adaption of the retina, but instead just a by-product of the way the retinal axons were wired. Several scholars including Pinker, Chomsky, Edelman, and Luria have indicated the importance of the emergence of human language as an important regulative mechanism of learning and memory in the context of the development of higher-order consciousness (see Neural correlates section above). Another idea suggested where consciousness originates from a cell that has nestled itself in a blood capillary in the brain where the blood flow determines whether or not one is conscious. States of consciousness There are some brain states in which consciousness seems to be absent, including dreamless sleep or coma. There are also a variety of circumstances that can change the relationship between the mind and the world in less drastic ways, producing what are known as altered states of consciousness. Some altered states occur naturally; others can be produced by drugs or brain damage. Altered states can be accompanied by changes in thinking, disturbances in the sense of time, feelings of loss of control, changes in emotional expression, alternations in body image and changes in meaning or significance.The two most widely accepted altered states are sleep and dreaming. Although dream sleep and non-dream sleep appear very similar to an outside observer, each is associated with a distinct pattern of brain activity, metabolic activity, and eye movement; each is also associated with a distinct pattern of experience and cognition. During ordinary non-dream sleep, people who are awakened report only vague and sketchy thoughts, and their experiences do not cohere into a continuous narrative. During dream sleep, in contrast, people who are awakened report rich and detailed experiences in which events form a continuous progression, which may however be interrupted by bizarre or fantastic intrusions. Thought processes during the dream state frequently show a high level of irrationality. Both dream and non-dream states are associated with severe disruption of memory: it usually disappears in seconds during the non-dream state, and in minutes after awakening from a dream unless actively refreshed.Research conducted on the effects of partial epileptic seizures on consciousness found that patients who have partial epileptic seizures experience altered states of consciousness. In partial epileptic seizures, consciousness is impaired or lost while some aspects of consciousness, often automated behaviors, remain intact. Studies found that when measuring the qualitative features during partial epileptic seizures, patients exhibited an increase in arousal and became absorbed in the experience of the seizure, followed by difficulty in focusing and shifting attention. A variety of psychoactive drugs, including alcohol, have notable effects on consciousness. These range from a simple dulling of awareness produced by sedatives, to increases in the intensity of sensory qualities produced by stimulants, cannabis, empathogens–entactogens such as MDMA ("Ecstasy"), or most notably by the class of drugs known as psychedelics. LSD, mescaline, psilocybin, dimethyltryptamine, and others in this group can produce major distortions of perception, including hallucinations; some users even describe their drug-induced experiences as mystical or spiritual in quality. The brain mechanisms underlying these effects are not as well understood as those induced by use of alcohol, but there is substantial evidence that alterations in the brain system that uses the chemical neurotransmitter serotonin play an essential role.There has been some research into physiological changes in yogis and people who practise various techniques of meditation. Some research with brain waves during meditation has reported differences between those corresponding to ordinary relaxation and those corresponding to meditation. It has been disputed, however, whether there is enough evidence to count these as physiologically distinct states of consciousness.The most extensive study of the characteristics of altered states of consciousness was made by psychologist Charles Tart in the 1960s and 1970s. Tart analyzed a state of consciousness as made up of a number of component processes, including exteroception (sensing the external world); interoception (sensing the body); input-processing (seeing meaning); emotions; memory; time sense; sense of identity; evaluation and cognitive processing; motor output; and interaction with the environment. Each of these, in his view, could be altered in multiple ways by drugs or other manipulations. The components that Tart identified have not, however, been validated by empirical studies. Research in this area has not yet reached firm conclusions, but a recent questionnaire-based study identified eleven significant factors contributing to drug-induced states of consciousness: experience of unity; spiritual experience; blissful state; insightfulness; disembodiment; impaired control and cognition; anxiety; complex imagery; elementary imagery; audio-visual synesthesia; and changed meaning of percepts. Entropic brain The entropic brain is a theory of conscious states informed by neuroimaging research with psychedelic drugs. The theory suggests that the brain in primary states such as rapid eye movement (REM) sleep, early psychosis and under the influence of psychedelic drugs, is in a disordered state; normal waking consciousness constrains some of this freedom and makes possible metacognitive functions such as internal self-administered reality testing and self-awareness. Criticism has included questioning whether the theory has been adequately tested. Theories of origin The origin and mechanism of subjective experience within the brain remains unknown, although several scientific theories have been proposed. Roger Penrose has said that there are four such current theories.Integrated information theory (IIT) postulates that consciousness resides in the information being processed and arises once the information reaches a certain level of complexity. Orchestrated objective reduction (Orch OR) postulates that consciousness originates at the quantum level inside neurons. The mechanism is held to be a quantum process called objective reduction that is orchestrated by cellular structures called microtubules. However the details of the mechanism would go beyond current quantum theory. Medical aspects The medical approach to consciousness is scientifically oriented. It derives from a need to treat people whose brain function has been impaired as a result of disease, brain damage, toxins, or drugs. In medicine, conceptual distinctions are considered useful to the degree that they can help to guide treatments. The medical approach focuses mostly on the amount of consciousness a person has: in medicine, consciousness is assessed as a "level" ranging from coma and brain death at the low end, to full alertness and purposeful responsiveness at the high end.Consciousness is of concern to patients and physicians, especially neurologists and anesthesiologists. Patients may have disorders of consciousness or may need to be anesthetized for a surgical procedure. Physicians may perform consciousness-related interventions such as instructing the patient to sleep, administering general anesthesia, or inducing medical coma. Also, bioethicists may be concerned with the ethical implications of consciousness in medical cases of patients such as the Karen Ann Quinlan case, while neuroscientists may study patients with impaired consciousness in hopes of gaining information about how the brain works. Assessment In medicine, consciousness is examined using a set of procedures known as neuropsychological assessment. There are two commonly used methods for assessing the level of consciousness of a patient: a simple procedure that requires minimal training, and a more complex procedure that requires substantial expertise. The simple procedure begins by asking whether the patient is able to move and react to physical stimuli. If so, the next question is whether the patient can respond in a meaningful way to questions and commands. If so, the patient is asked for name, current location, and current day and time. A patient who can answer all of these questions is said to be "alert and oriented times four" (sometimes denoted "A&Ox4" on a medical chart), and is usually considered fully conscious.The more complex procedure is known as a neurological examination, and is usually carried out by a neurologist in a hospital setting. A formal neurological examination runs through a precisely delineated series of tests, beginning with tests for basic sensorimotor reflexes, and culminating with tests for sophisticated use of language. The outcome may be summarized using the Glasgow Coma Scale, which yields a number in the range 3–15, with a score of 3 to 8 indicating coma, and 15 indicating full consciousness. The Glasgow Coma Scale has three subscales, measuring the best motor response (ranging from "no motor response" to "obeys commands"), the best eye response (ranging from "no eye opening" to "eyes opening spontaneously") and the best verbal response (ranging from "no verbal response" to "fully oriented"). There is also a simpler pediatric version of the scale, for children too young to be able to use language.In 2013, an experimental procedure was developed to measure degrees of consciousness, the procedure involving stimulating the brain with a magnetic pulse, measuring resulting waves of electrical activity, and developing a consciousness score based on the complexity of the brain activity. Disorders of consciousness Medical conditions that inhibit consciousness are considered disorders of consciousness. This category generally includes minimally conscious state and persistent vegetative state, but sometimes also includes the less severe locked-in syndrome and more severe chronic coma. Differential diagnosis of these disorders is an active area of biomedical research. Finally, brain death results in possible irreversible disruption of consciousness. While other conditions may cause a moderate deterioration (e.g., dementia and delirium) or transient interruption (e.g., grand mal and petit mal seizures) of consciousness, they are not included in this category. Anosognosia One of the most striking disorders of consciousness goes by the name anosognosia, a Greek-derived term meaning unawareness of disease. This is a condition in which patients are disabled in some way, most commonly as a result of a stroke, but either misunderstand the nature of the problem or deny that there is anything wrong with them. The most frequently occurring form is seen in people who have experienced a stroke damaging the parietal lobe in the right hemisphere of the brain, giving rise to a syndrome known as
Consciousness	hemispatial neglect, characterized by an inability to direct action or attention toward objects located to the left with respect to their bodies. Patients with hemispatial neglect are often paralyzed on the left side of the body, but sometimes deny being unable to move. When questioned about the obvious problem, the patient may avoid giving a direct answer, or may give an explanation that doesnt make sense. Patients with hemispatial neglect may also fail to recognize paralyzed parts of their bodies: one frequently mentioned case is of a man who repeatedly tried to throw his own paralyzed right leg out of the bed he was lying in, and when asked what he was doing, complained that somebody had put a dead leg into the bed with him. An even more striking type of anosognosia is Anton–Babinski syndrome, a rarely occurring condition in which patients become blind but claim to be able to see normally, and persist in this claim in spite of all evidence to the contrary. Stream of consciousness William James is usually credited with popularizing the idea that human consciousness flows like a stream, in his Principles of Psychology of 1890. According to James, the "stream of thought" is governed by five characteristics: Every thought tends to be part of a personal consciousness. Within each personal consciousness thought is always changing. Within each personal consciousness thought is sensibly continuous. It always appears to deal with objects independent of itself. It is interested in some parts of these objects to the exclusion of others.A similar concept appears in Buddhist philosophy, expressed by the Sanskrit term Citta-saṃtāna, which is usually translated as mindstream or "mental continuum". Buddhist teachings describe that consciousness manifests moment to moment as sense impressions and mental phenomena that are continuously changing. The teachings list six triggers that can result in the generation of different mental events. These triggers are input from the five senses (seeing, hearing, smelling, tasting or touch sensations), or a thought (relating to the past, present or the future) that happen to arise in the mind. The mental events generated as a result of these triggers are: feelings, perceptions and intentions/behaviour. The moment-by-moment manifestation of the mind-stream is said to happen in every person all the time. It even happens in a scientist who analyses various phenomena in the world, or analyses the material body including the organ brain. The manifestation of the mindstream is also described as being influenced by physical laws, biological laws, psychological laws, volitional laws, and universal laws. The purpose of the Buddhist practice of mindfulness is to understand the inherent nature of the consciousness and its characteristics. Narrative form In the West, the primary impact of the idea has been on literature rather than science: "stream of consciousness as a narrative mode" means writing in a way that attempts to portray the moment-to-moment thoughts and experiences of a character. This technique perhaps had its beginnings in the monologues of Shakespeares plays and reached its fullest development in the novels of James Joyce and Virginia Woolf, although it has also been used by many other noted writers.Here, for example, is a passage from Joyces Ulysses about the thoughts of Molly Bloom: Yes because he never did a thing like that before as ask to get his breakfast in bed with a couple of eggs since the City Arms hotel when he used to be pretending to be laid up with a sick voice doing his highness to make himself interesting for that old faggot Mrs Riordan that he thought he had a great leg of and she never left us a farthing all for masses for herself and her soul greatest miser ever was actually afraid to lay out 4d for her methylated spirit telling me all her ailments she had too much old chat in her about politics and earthquakes and the end of the world let us have a bit of fun first God help the world if all the women were her sort down on bathingsuits and lownecks of course nobody wanted her to wear them I suppose she was pious because no man would look at her twice I hope Ill never be like her a wonder she didnt want us to cover our faces but she was a welleducated woman certainly and her gabby talk about Mr Riordan here and Mr Riordan there I suppose he was glad to get shut of her. Spiritual approaches To most philosophers, the word "consciousness" connotes the relationship between the mind and the world. To writers on spiritual or religious topics, it frequently connotes the relationship between the mind and God, or the relationship between the mind and deeper truths that are thought to be more fundamental than the physical world. The mystical psychiatrist Richard Maurice Bucke, author of the 1901 book Cosmic Consciousness: A Study in the Evolution of the Human Mind, distinguished between three types of consciousness: Simple Consciousness, awareness of the body, possessed by many animals; Self Consciousness, awareness of being aware, possessed only by humans; and Cosmic Consciousness, awareness of the life and order of the universe, possessed only by humans who are enlightened. Many more examples could be given, such as the various levels of spiritual consciousness presented by Prem Saran Satsangi and Stuart Hameroff.Another thorough account of the spiritual approach is Ken Wilbers 1977 book The Spectrum of Consciousness, a comparison of western and eastern ways of thinking about the mind. Wilber described consciousness as a spectrum with ordinary awareness at one end, and more profound types of awareness at higher levels. See also References Further reading External links The dictionary definition of consciousness at Wiktionary Consciousness Studies at Wikibooks Gulick, Robert Van. "Consciousness". In Zalta, Edward N. (ed.). Stanford Encyclopedia of Philosophy. "Consciousness". Internet Encyclopedia of Philosophy.
Back pain	Back pain is pain felt in the back. It may be classified as neck pain (cervical), middle back pain (thoracic), lower back pain (lumbar) or coccydynia (tailbone or sacral pain) based on the segment affected. The lumbar area is the most common area affected. An episode of back pain may be acute, subacute or chronic depending on the duration. The pain may be characterized as a dull ache, shooting or piercing pain or a burning sensation. Discomfort can radiate to the arms and hands as well as the legs or feet, and may include numbness or weakness in the legs and arms. The majority of back pain is nonspecific and idiopathic. Common underlying mechanisms include degenerative or traumatic changes to the discs and facet joints, which can then cause secondary pain in the muscles and nerves and referred pain to the bones, joints and extremities. Diseases and inflammation of the gallbladder, pancreas, aorta and kidneys may also cause referred pain in the back. Tumors of the vertebrae, neural tissues and adjacent structures can also manifest as back pain. Back pain is common; approximately nine of ten adults experiencing it at some point in their lives, and five of ten working adults experience back pain each year. Some estimate that as many of 95% of people will experience back pain at some point in their lifetime. It is the most common cause of chronic pain and is a major contributor to missed work and disability. For most individuals, back pain is self-limiting. Most people with back pain do not experience chronic severe pain but rather persistent or intermittent pain that is mild or moderate. In most cases of herniated disks and stenosis, rest, injections or surgery have similar general pain-resolution outcomes on average after one year. In the United States, acute low back pain is the fifth most common reason for physician visits and causes 40% of missed work days. It is the single leading cause of disability worldwide. Classification Back pain is classified in terms of duration of symptoms. Acute back pain lasts <6 weeks Subacute back pain lasts between 6 and 12 weeks. Chronic back pain lasts for greater than 12 weeks. Causes There are many causes of back pain, including blood vessels, internal organs, infections, mechanical and autoimmune causes. Approximately 90 percent of people with back pain are diagnosed with nonspecific, idiopathic acute pain with no identifiable underlying pathology. In approximately 10 percent of people, a cause can be identified through diagnostic imaging. Fewer than two percent of cases are attributed to secondary factors, with metastatic cancers and serious infections, such as spinal osteomyelitis and epidural abscesses, accounting for approximately one percent. Nonspecific In as many as 90 percent of cases, no physiological causes or abnormalities on diagnostic tests can be found. Nonspecific back pain can result from back strain or sprains, which can cause peripheral injury to muscle or ligaments. Many patients cannot identify the events or activities that may have caused the strain. The pain can present acutely but in some cases can persist, leading to chronic pain. Chronic back pain in people with otherwise normal scans can result from central sensitization, in which an initial injury causes a longer-lasting state of heightened sensitivity to pain. This persistent state maintains pain even after the initial injury has healed. Treatment of sensitization may involve low doses of antidepressants and directed rehabilitation such as physical therapy. Spinal disc disease Spinal disc disease occurs when the nucleus pulposus, a gel-like material in the inner core of the vertebral disc, ruptures. Rupturing of the nucleus pulposus can lead to compression of nerve roots. Symptoms may be unilateral or bilateral, and correlate to the region of the spine affected. The most common region for spinal disk disease is at L4–L5 or L5–S1. The risk for lumbar disc disease is increased in overweight individuals because of the increased compressive force on the nucleus pulposus, and is twice as likely to occur in men. A 2002 study found that lifestyle factors such as night-shift work and lack of physical activity can also increase the risk of lumbar disc disease. Severe spinal-cord compression is considered a surgical emergency and requires decompression to preserve motor and sensory function. Cauda equina syndrome involves severe compression of the cauda equina and presents initially with pain followed by motor and sensory. Bladder incontinence is seen in later stages of cauda equina syndrome. Degenerative disease Spondylosis, or degenerative arthritis of the spine, occurs when the intervertebral disc undergoes degenerative changes, causing the disc to fail at cushioning the vertebrae. There is an association between intervertebral disc space narrowing and lumbar spine pain. The space between the vertebrae becomes more narrow, resulting in compression and irritation of the nerves.Spondylolithesis is the anterior shift of one vertebra compared to the neighboring vertebra. It is associated with age-related degenerative changes as well as trauma and congenital anomalies. Spinal stenosis can occur in cases of severe spondylosis, spondylotheisis and age-associated thickening of the ligamentum flavum. Spinal stenosis involves narrowing of the spinal canal and typically presents in patients greater than 60 years of age. Neurogenic claudication can occur in cases of severe lumbar spinal stenosis and presents with symptoms of pain in the lower back, buttock or leg that is worsened by standing and relieved by sitting. Vertebral compression fractures occur in four percent of patients presenting with lower back pain. Risk factors include age, female gender, history of osteoporosis, and chronic glucocorticoid use. Fractures can occur as a result of trauma but in many cases can be asymptomatic. Infection Common infectious causes of back pain include osteomyelitis, septic discitis, paraspinal abscess and epidural abscess. Infectious causes that lead to back pain involve various structures surrounding the spine.Osteomyelitis is the bacterial infection of the bone. Vertebral osteomyelitis is most commonly caused by staphylococci. Risk factors include skin infection, urinary tract infection, IV catheter use, IV drug use, previous endocarditis and lung disease. Spinal epidural abscess is commonly caused by severe infection with bacteremia. Risk factors include recent administration of epidurals, IV drug use or recent infection. Cancer Spread of cancer to the bone or spinal cord can lead to back pain. Bone is one of the most common sites of metastatic lesions. Patients typically have a history of malignancy. Common types of cancer that present with back pain include multiple myeloma, lymphoma, leukemia, spinal cord tumors, primary vertebral tumors and prostate cancer. Back pain is present in 29% of patients with systemic cancer. Unlike other causes of back pain that commonly affect the lumbar spine, the thoracic spine is most commonly affected. The pain can be associated with systemic symptoms such as weight loss, chills, fever, nausea and vomiting. Unlike other causes of back pain, neoplasm-associated back pain is constant, dull, poorly localized and worsens with rest. Metastasis to the bone also increases the risk of spinal-cord compression or vertebral fractures that require emergency surgical treatment. Autoimmune Inflammatory arthritides such as ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and systemic lupus erythematosus can all cause varying levels of joint destruction. Among the inflammatory arthritides, ankylosing spondylitis is most closely associated with back pain because of the inflammatory destruction of the bony components of the spine. Ankylosing spondylitis is common in young men and presents with a range of possible symptoms such as uveitis, psoriasis and inflammatory bowel disease. Referred pain Back pain can also be referred from another source. Referred pain occurs when pain is felt at a location different than the source of the pain. Disease processes that can present with back pain include pancreatitis, kidney stones, severe urinary tract infections and abdominal aortic aneurysms. Risk factors Heavy lifting, obesity, sedentary lifestyle and lack of exercise can increase the risk of back pain. Cigarette smokers are more likely to experience back pain than are nonsmokers. Poor posture and weight gain in pregnancy are also risk factors for back pain. In general, fatigue can worsen pain.A few studies suggest that psychosocial factors such as work-related stress and dysfunctional family relationships may correlate more closely with back pain than do structural abnormalities revealed in X-rays and other medical imaging scans. While back pain physical effects can range from muscle aching to a shooting, burning, or stabbing sensation. It can radiate pain down the legs and have pain increased by bending, twisting, lifting, standing, or walking. While the physical effects of back pain are always at the forefront back pain also has other psychological effects. Back Pain has been linked to depression, anxiety, stress, and avoidance behaviors due to mentally not being able to cope with the physical pain. “Both acute and chronic back pain can be associated with psychological distress in the form of anxiety (worries, stress) or depression (sadness, discouragement). Psychological distress is a common reaction to the suffering aspects of acute back pain, even when symptoms are short-term and not medically serious [35]’( (IASP, 2021) Diagnosis Initial assessment of back pain consists of a history and physical examination. Important characterizing features of back pain include location, duration, severity, history of prior back pain and possible trauma. Other important components of the patient history include age, physical trauma, prior history of cancer, fever, weight loss, urinary incontinence, progressive weakness or expanding sensory changes, which can indicate a medically urgent condition.Physical examination of the back should assess for posture and deformities. Pain elicited by palpating certain structures may be helpful in localizing the affected area. A neurologic exam is needed to assess for changes in gait, sensation and motor function. Determining if there are radicular symptoms, such as pain, numbness or weakness that radiate down limbs, is important for differentiating between central and peripheral causes of back pain. The straight leg test is a maneuver used to determine the presence of lumbosacral radiculopathy, which occurs when there is irritation in the nerve root that causes neurologic symptoms such as numbness and tingling. Non-radicular back pain is most commonly caused by injury to the spinal muscles or ligaments, degenerative spinal disease or a herniated disc. Disc herniation and foraminal stenosis are the most common causes of radiculopathy.Imaging of the spine and laboratory tests is not recommended during the acute phase. This assumes that there is no reason to expect that the patient has an underlying problem. In most cases, the pain subsides naturally after several weeks. People who seek diagnosis through imaging are typically less likely to receive a better outcome than are those who wait for the condition to resolve. Imaging Magnetic resonance imaging (MRI) is the preferred modality for the evaluation of back pain and visualization of bone, soft tissue, nerves and ligaments. X-rays are a less costly initial option offered to patients with a low clinical suspicion of infection or malignancy, and they are combined with laboratory studies for interpretation. Imaging is not needed for the majority of patients with back pain. In cases of acute back pain, MRI is recommended for those with major risk factors or clinical suspicion of cancer, spinal infection or severe progressive neurological deficits. For patients with subacute to chronic back pain, MRI is recommended if minor risk factors exist for cancer, ankylosing spondylitis or vertebral compression fracture, or if significant trauma or symptomatic spinal stenosis is present.Early imaging studies during the acute phase do not improve care or prognosis. Imaging findings are not correlated with severity or outcome. Laboratory studies Laboratory studies are employed when there are suspicions of autoimmune causes, infection or malignancy. Laboratory testing may include white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Elevated ESR could indicate infection, malignancy, chronic disease, inflammation, trauma or tissue ischemia. Elevated CRP levels are associated with infection. Red flags Imaging is not typically needed in the initial diagnosis or treatment of back pain. However, if there are certain "red flag" symptoms present, plain radiographs (X-ray), CT scan or magnetic resonance imaging may be recommended. These red flags include: History of cancer Unexplained weight loss Immunosuppression Urinary infection Intravenous drug use Prolonged use of corticosteroids Back pain not improved with conservative management History of significant trauma Minor fall or heavy lift in a potentially osteoporotic or elderly individual Acute onset of urinary retention, overflow incontinence, loss of anal sphincter tone, or fecal incontinence Saddle anesthesia Global or progressive motor weakness in the lower limbs Prevention Moderate-quality evidence exists that suggests that the combination of education and exercise may reduce an individuals risk of developing an episode of low back pain. Lesser-quality evidence points to exercise alone as a possible deterrent to the risk of the condition. Management Nonspecific pain Patients with uncomplicated back pain should be encouraged to remain active and to return to normal activities. The management goals when treating back pain are to achieve maximal reduction in pain intensity as rapidly as possible, to restore the individuals ability to function in everyday activities, to help the patient cope with residual pain, to assess for side effects of therapy and to facilitate the patients passage through the legal and socioeconomic impediments to recovery. For many, the goal is to keep the pain at a manageable level to progress with rehabilitation, which then can lead to long-term pain relief. Also, for some people the goal is to use nonsurgical therapies to manage the pain and avoid major surgery, while for others surgery may represent the quickest path to pain relief.Not all treatments work for all conditions or for all individuals with the same condition, and many must try several treatment options to determine what works best for them. The present stage of the condition (acute or chronic) is also a determining factor in the choice of treatment. Only a minority of people with back pain (most estimates are 1–10%) require surgery. Nonmedical Back pain is generally first treated with nonpharmacological therapy, as it typically resolves without the use of medication. Superficial heat and massage, acupuncture and spinal manipulation therapy may be recommended. Heat therapy is useful for back spasms or other conditions. A review concluded that heat therapy can reduce symptoms of acute and subacute low-back pain. Regular activity and gentle stretching exercises is encouraged in uncomplicated back pain and is associated with better long-term outcomes. Physical therapy to strengthen the muscles in the abdomen and around the spine may also be recommended. These exercises are associated with better patient satisfaction, although they have not been shown to provide functional improvement. However, one review found that exercise is effective for chronic back pain but not for acute pain. Exercise should be performed under the supervision of a healthcare professional. Massage therapy may provide short-term pain relief, but not functional improvement, for those with acute lower back pain. It may also offer short-term pain relief and functional improvement for those with long-term (chronic) and subacute lower pack pain, but this benefit does not appear to be sustained after six months of treatment. There do not appear to be any serious adverse effects associated with massage. Acupuncture may provide some relief for back pain. However, further research with stronger evidence is needed. Spinal manipulation appears similar to other recommended treatments. "Back school" is an intervention that consists of both education and physical exercises. There is no strong evidence supporting the use of back school for treating acute, subacute, or chronic non-specific back pain. Insoles appear to be an ineffective treatment intervention. While traction for back pain is often used in combination with other approaches, there appears to be little or no impact on pain intensity, functional status, global improvement or return to work. Medication If nonpharmacological measures are ineffective, medication may be administered. Non-steroidal anti-inflammatory drugs (NSAIDs) are typically attempted first. NSAIDs have been proven more effective than placebo, and are usually more effective than paracetamol (acetaminophen). Long-term use of opioids has not been tested to determine whether it is effective or safe for treating chronic lower back pain. For severe back pain not relieved by NSAIDs or acetaminophen, opioids may be used. Opioids may not be better than NSAIDs or antidepressants for chronic back pain with regard to pain relief and gain of function. Skeletal muscle relaxers may also be used. Their short-term use has been proven effective in the relief of acute back pain. However, the evidence of this effect has been disputed, and these medications do have negative side effects. For patients with nerve root pain and acute radiculopathy, there is evidence that a single dose of steroids, such as dexamethasone, may provide pain relief. Epidural corticosteroid injection (ESI) is a procedure in which steroid medications are injected into the epidural space. The steroid medications reduce inflammation and thus decrease pain and improve function. ESI has long been used to both diagnose and treat back pain, although recent studies have shown a lack of efficacy in treating low back pain. Surgery Surgery for back pain is typically used as a last resort, when serious neurological deficit is evident. A 2009 systematic review of back surgery studies found that, for certain diagnoses, surgery is moderately better than other common treatments, but the benefits of surgery often decline in the long term.Surgery may sometimes be appropriate for people with severe myelopathy or cauda equina syndrome. Causes of neurological deficits can include spinal disc herniation, spinal stenosis, degenerative disc disease, tumor, infection, and spinal hematomas, all of which can impinge on the nerve roots around the spinal cord. There are multiple surgical options to treat back pain, and these options vary depending on the cause of the pain. When a herniated disc is compressing the nerve roots, hemi- or partial- laminectomy or discectomy may be performed, in which the material compressing on the nerve is removed. A mutli-level laminectomy can be done to widen the spinal canal in the case of spinal stenosis. A foraminotomy or foraminectomy may also be necessary, if the vertebrae are causing significant nerve root compression. A discectomy is performed when the intervertebral disc has herniated or torn. It involves removing the protruding disc, either a portion of it or all of it, that is placing pressure on the nerve root. Total disc replacement can also be performed, in which the source of the pain (the damaged disc) is removed and replaced, while maintaining spinal mobility. When an entire disc is removed (as in discectomy), or when the vertebrae are unstable, spinal fusion surgery may be performed. Spinal fusion is a procedure in which bone grafts and metal hardware is used to fix together two or more vertebrae, thus preventing the bones of the spinal column from compressing on the spinal cord or nerve roots.If infection, such as a spinal epidural abscess, is the source of the back pain, surgery may be indicated when a trial of antibiotics is ineffective. Surgical evacuation of spinal hematoma can also be attempted, if the blood products fail to break down on their own. Pregnancy About 50% of women experience low back pain during pregnancy. Some studies have suggested that women who have experienced back pain before pregnancy are at a higher risk of experiencing back pain during pregnancy. It may be severe enough to cause significant pain and disability in as many as one third of pregnant women. Back pain typically begins at approximately 18 weeks of gestation and peaks between 24 and 36 weeks. Approximately 16% of women who experience back pain during pregnancy report continued back pain years after pregnancy, indicating that those with significant back pain are at greater risk of back pain following pregnancy.Biomechanical factors of pregnancy shown to be associated with back pain include increased curvature of the lower back, or lumbar lordosis, to support the added weight on the abdomen. Also, the hormone relaxin is released during pregnancy, which softens the structural tissues in the pelvis and lower back to prepare for vaginal delivery. This softening and increased flexibility of the ligaments and joints in the lower back can result in pain. Back pain in pregnancy is often accompanied by radicular symptoms, suggested to be caused by the baby pressing on the sacral plexus and lumbar plexus in the pelvis.Typical factors aggravating the back pain of pregnancy include standing, sitting, forward bending, lifting and walking. Back pain in pregnancy may also be characterized by pain radiating into the thigh and buttocks, nighttime pain severe enough to wake the patient, pain that is increased at night or pain that is increased during the daytime.Local heat, acetaminophen (paracetamol) and massage can be used to help relieve pain. Avoiding standing for prolonged periods of time is also suggested. Economics Although back pain does not typically cause permanent disability, it is a significant contributor to physician visits and missed work days in the United States, and is the single leading cause of disability worldwide. The American Academy of Orthopaedic Surgeons report approximately 12 million visits to doctors offices each year are due to back pain. Missed work and disability related to low back pain costs over $50 billion each year in the United States. In the United Kingdom in 1998, approximately £1.6 billion per year was spent on expenses related to disability from back pain. References External links Back and spine at Curlie Handout on Health: Back Pain at National Institute of Arthritis and Musculoskeletal and Skin Diseases Qaseem A, Wilt TJ, McLean RM, Forciea MA (April 2017). "Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians". Annals of Internal Medicine. 166 (7): 514–30. doi:10.7326/M16-2367. PMID 28192789. Non-specific Back Pain Guidelines 2017 – Kaiser Foundation Health Plan of Washington Archived
Arrhythmia	Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults – is called tachycardia, and a resting heart rate that is too slow – below 60 beats per minute – is called bradycardia. Some types of arrhythmias have no symptoms. Symptoms, when present, may include palpitations or feeling a pause between heartbeats. In more serious cases, there may be lightheadedness, passing out, shortness of breath or chest pain. While most cases of arrhythmia are not serious, some predispose a person to complications such as stroke or heart failure. Others may result in sudden death.Arrhythmias are often categorized into four groups: extra beats, supraventricular tachycardias, ventricular arrhythmias and bradyarrhythmias. Extra beats include premature atrial contractions, premature ventricular contractions and premature junctional contractions. Supraventricular tachycardias include atrial fibrillation, atrial flutter and paroxysmal supraventricular tachycardia. Ventricular arrhythmias include ventricular fibrillation and ventricular tachycardia. Bradyarrhythmias are due to sinus node dysfunction or atrioventricular conduction disturbances. Arrhythmias are due to problems with the electrical conduction system of the heart. A number of tests can help with diagnosis, including an electrocardiogram (ECG) and Holter monitor.Many arrhythmias can be effectively treated. Treatments may include medications, medical procedures such as inserting a pacemaker, and surgery. Medications for a fast heart rate may include beta blockers, or antiarrhythmic agents such as procainamide, which attempt to restore a normal heart rhythm. This latter group may have more significant side effects, especially if taken for a long period of time. Pacemakers are often used for slow heart rates. Those with an irregular heartbeat are often treated with blood thinners to reduce the risk of complications. Those who have severe symptoms from an arrhythmia or are medically unstable may receive urgent treatment with a controlled electric shock in the form of cardioversion or defibrillation.Arrhythmia affects millions of people. In Europe and North America, as of 2014, atrial fibrillation affects about 2% to 3% of the population. Atrial fibrillation and atrial flutter resulted in 112,000 deaths in 2013, up from 29,000 in 1990. However, in most recent cases concerning the SARS-CoV‑2 pandemic, cardiac arrhythmias are commonly developed and associated with high morbidity and mortality among patients hospitalized with the COVID-19 infection, due to the infections ability to cause myocardial injury. Sudden cardiac death is the cause of about half of deaths due to cardiovascular disease and about 15% of all deaths globally. About 80% of sudden cardiac death is the result of ventricular arrhythmias. Arrhythmias may occur at any age but are more common among older people. Arrhythmias may also occur in children; however, the normal range for the heart rate varies with age. Classification Arrhythmia may be classified by rate (tachycardia, bradycardia), mechanism (automaticity, re-entry, triggered) or duration (isolated premature beats; couplets; runs, that is 3 or more beats; non-sustained = less than 30 seconds or sustained= over 30 seconds).Arrhythmias are also classified by site of origin: Atrial arrhythmia Sinus bradycardia Sinus arrhythmia Sinus tachycardia Premature atrial contractions (PACs) Wandering atrial pacemaker Atrial tachycardia Multifocal atrial tachycardia Supraventricular tachycardia (SVT) Atrial flutter Atrial fibrillation (Afib) AV nodal reentrant tachycardia Junctional arrhythmia AV nodal reentrant tachycardia Junctional rhythm Junctional tachycardia Premature junctional contraction Ventricular arrhythmia Premature ventricular contractions (PVCs), sometimes called ventricular extra beats (VEBs) Premature ventricular beats occurring after every normal beat are termed ventricular bigeminy PVCs that occur at intervals of 2 normal beats to 1 PVC, or 1 normal beat to 2 PVCs, are termed "PVCs in trigeminy" Groups of three premature ventricular beats are called triplets and are considered a brief run of non-sustained ventricular tachycardia (NSVT); if the grouping lasts for more than 30 seconds, it is considered sustained ventricular tachycardia (VT). Accelerated idioventricular rhythm Monomorphic ventricular tachycardia Polymorphic ventricular tachycardia Ventricular fibrillation Torsades de pointes Arrhythmogenic right ventricular dysplasia Re-entry ventricular arrhythmia Heart blocks These are also known as AV blocks, because the vast majority of them arise from pathology at the atrioventricular node. They are the most common causes of bradycardia: First-degree heart block, which manifests as PR prolongation Second-degree heart block Type 1 Second degree heart block, also known as Mobitz I or Wenckebach Type 2 Second degree heart block, also known as Mobitz II Third-degree heart block, also known as complete heart blockFirst, second, and third-degree blocks also can occur at the level of the sinoatrial junction. This is referred to as sinoatrial block typically manifesting with various degrees and patterns of sinus bradycardia. Sudden arrhythmic death syndrome Sudden arrhythmic death syndrome (SADS), is a term used as part of sudden unexpected death syndrome to describe sudden death because of cardiac arrest occasioned by an arrhythmia in the presence or absence of any structural heart disease on autopsy. The most common cause of sudden death in the US is coronary artery disease specifically because of poor oxygenation of the heart muscle, that is myocardial ischemia or a heart attack Approximately 180,000 to 250,000 people die suddenly of this cause every year in the US. SADS may occur from other causes. There are many inherited conditions and heart diseases that can affect young people which can subsequently cause sudden death without advance symptoms.Causes of SADS in young people include viral myocarditis, long QT syndrome, Brugada syndrome, Catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia. Fetal arrhythmia Arrhythmias may also occur in the fetus. The normal heart rate of the fetus is between 110 and 160 beats per minute. Any rhythm beyond these limits is abnormal and classed as a fetal arrhythmia. These are mainly the result of premature atrial contractions, usually give no symptoms, and have little consequence. However, around one percent of these will be the result of significant structural damage to the heart. Signs and symptoms The term cardiac arrhythmia covers a very large number of very different conditions.The most common symptom of arrhythmia is an awareness of an abnormal heartbeat, called palpitations. These may be infrequent, frequent, or continuous. Some of these arrhythmias are harmless (though distracting for patients) but some of them predispose to adverse outcomes.Some arrhythmias do not cause symptoms and are not associated with increased mortality. However, some asymptomatic arrhythmias are associated with adverse events. Examples include a higher risk of blood clotting within the heart and a higher risk of insufficient blood being transported to the heart because of a weak heartbeat. Other increased risks are of embolization and stroke, heart failure, and sudden cardiac death.If an arrhythmia results in a heartbeat that is too fast, too slow, or too weak to supply the bodys needs, this manifests as lower blood pressure and may cause lightheadedness, dizziness, syncope or brain death due to insufficient supply of blood to the brain.Some types of arrhythmia result in cardiac arrest, or sudden death.Medical assessment of the abnormality using an electrocardiogram is one way to diagnose and assess the risk of any given arrhythmia. Mechanism Cardiac arrhythmia are caused by one of two major mechanism. The first of arrhythmia is a result of enhanced or abnormal impulse formation originating at the pacemaker or the His-Purkinje network. The second is due to reentry conduction disturbances. Diagnostic Cardiac arrhythmia is often first detected by simple but nonspecific means: auscultation of the heartbeat with a stethoscope, or feeling for peripheral pulses. These cannot usually diagnose specific arrhythmia but can give a general indication of the heart rate and whether it is regular or irregular. Not all the electrical impulses of the heart produce audible or palpable beats; in many cardiac arrhythmias, the premature or abnormal beats do not produce an effective pumping action and are experienced as "skipped" beats.The simplest specific diagnostic test for assessment of heart rhythm is the electrocardiogram (abbreviated ECG or EKG). A Holter monitor is an EKG recorded over a 24-hour period, to detect arrhythmias that may happen briefly and unpredictably throughout the day.A more advanced study of the hearts electrical activity can be performed to assess the source of the aberrant heart beats. This can be accomplished in an electrophysiology study, an endovascular procedure that uses a catheter to "listen" to the electrical activity from within the heart, additionally if the source of the arrhythmias is found, often the abnormal cells can be ablated and the arrhythmia can be permanently corrected. Transesophageal atrial stimulation (TAS) instead uses an electrode inserted through the esophagus to a part where the distance to the posterior wall of the left atrium is only approximately 5–6 mm (remaining constant in people of different age and weight). Transesophageal atrial stimulation can differentiate between atrial flutter, AV nodal reentrant tachycardia and orthodromic atrioventricular reentrant tachycardia. It can also evaluate the risk in people with Wolff–Parkinson–White syndrome, as well as terminate supraventricular tachycardia caused by re-entry. Differential diagnosis Normal electrical activity Each heartbeat originates as an electrical impulse from a small area of tissue in the right atrium of the heart called the sinus node or sinoatrial node (SA node). The impulse initially causes both atria to contract, then activates the atrioventricular node (AV node), which is normally the only electrical connection between the atria and the ventricles (main pumping chambers). The impulse then spreads through both ventricles via the bundle of His and the Purkinje fibers causing a synchronized contraction of the heart muscle and, thus, the pulse.In adults, the normal resting heart rate ranges from 60 to 90 beats per minute. The resting heart rate in children is much faster. In athletes, however, the resting heart rate can be as slow as 40 beats per minute, and be considered normal.The term sinus arrhythmia refers to a normal phenomenon of alternating mild acceleration and slowing of the heart rate that occurs with breathing in and out respectively. It is usually quite pronounced in children and steadily decreases with age. This can also be present during meditation breathing exercises that involve deep inhaling and breath holding patterns. Bradycardias A slow rhythm (less than 60 beats/min) is labelled bradycardia. This may be caused by a slowed signal from the sinus node (sinus bradycardia), by a pause in the normal activity of the sinus node (sinus arrest), or by blocking of the electrical impulse on its way from the atria to the ventricles (AV block or heart block). Heart block comes in varying degrees and severity. It may be caused by reversible poisoning of the AV node (with drugs that impair conduction) or by irreversible damage to the node. Bradycardias may also be present in the normally functioning heart of endurance athletes or other well-conditioned persons. Bradycardia may also occur in some types of seizures. Tachycardias In adults and children over 15, resting heart rate faster than 100 beats per minute is labeled tachycardia. Tachycardia may result in palpitation; however, tachycardia is not necessarily an arrhythmia. Increased heart rate is a normal response to physical exercise or emotional stress. This is mediated by the sympathetic nervous system on the sinus node and called sinus tachycardia. Other conditions that increase sympathetic nervous system activity in the heart include ingested or injected substances, such as caffeine or amphetamines, and an overactive thyroid gland (hyperthyroidism) or anemia.Tachycardia that is not sinus tachycardia usually results from the addition of abnormal impulses to the normal cardiac cycle. Abnormal impulses can begin by one of three mechanisms: automaticity, re-entry, or triggered activity. A specialized form of re-entry which is both common and problematic is termed fibrillation.Although the term "tachycardia" has been known for over 160 years, bases for the classification of arrhythmias are still being discussed. Heart defects Congenital heart defects are structural or electrical pathway problems in the heart that are present at birth. Anyone can be affected by this because overall health does not play a role in the problem. Problems with the electrical pathway of the heart can cause very fast or even deadly arrhythmias. Wolff–Parkinson–White syndrome is due to an extra pathway in the heart that is made up of electrical muscle tissue. This tissue allows the electrical impulse, which stimulates the heartbeat, to happen very rapidly. Right ventricular outflow tract tachycardia is the most common type of ventricular tachycardia in otherwise healthy individuals. This defect is due to an electrical node in the right ventricle just before the pulmonary artery. When the node is stimulated, the patient will go into ventricular tachycardia, which does not allow the heart to fill with blood before beating again. Long QT syndrome is another complex problem in the heart and has been labeled as an independent factor in mortality. There are multiple methods of treatment for these including cardiac ablations, medication treatment, or lifestyle changes to have less stress and exercise. Automaticity Automaticity refers to a cardiac muscle cell firing off an impulse on its own. All of the cells in the heart have the ability to initiate an action potential; however, only some of these cells are designed to routinely trigger heartbeats. These cells are found in the conduction system of the heart and include the SA node, AV node, Bundle of His, and Purkinje fibers. The sinoatrial node is a single specialized location in the atrium that has a higher automaticity (a faster pacemaker) than the rest of the heart and, therefore, is usually responsible for setting the heart rate and initiating each heartbeat.Any part of the heart that initiates an impulse without waiting for the sinoatrial node is called an ectopic focus and is, by definition, a pathological phenomenon. This may cause a single premature beat now and then, or, if the ectopic focus fires more often than the sinoatrial node, it can produce a sustained abnormal rhythm. Rhythms produced by an ectopic focus in the atria, or by the atrioventricular node, are the least dangerous dysrhythmias; but they can still produce a decrease in the hearts pumping efficiency because the signal reaches the various parts of the heart muscle with different timing than usual and can be responsible for poorly coordinated contraction.Conditions that increase automaticity include sympathetic nervous system stimulation and hypoxia. The resulting heart rhythm depends on where the first signal begins: If it is the sinoatrial node, the rhythm remains normal but rapid; if it is an ectopic focus, many types of dysrhythmia may ensue. Re-entry Re-entrant arrhythmias occur when an electrical impulse recurrently travels in a tight circle within the heart, rather than moving from one end of the heart to the other and then stopping.Every cardiac cell can transmit impulses of excitation in every direction but will do so only once within a short time. Normally, the action potential impulse will spread through the heart quickly enough that each cell will respond only once. However, if there is some essential heterogeneity of refractory period or if conduction is abnormally slow in some areas (for example in heart damage) so the myocardial cells are unable to activate the fast sodium channel, part of the impulse will arrive late and potentially be treated as a new impulse. Depending on the timing, this can produce a sustained abnormal circuit rhythm. As a sort of re-entry, vortices of excitation in the myocardium (autowave vortices) are considered to be the main mechanism of life-threatening cardiac arrhythmias. In particular, the autowave reverberator is common in the thin walls of the atria, sometimes resulting in atrial flutter. Re-entry is also responsible for most paroxysmal supraventricular tachycardia, and dangerous ventricular tachycardia. These types of re-entry circuits are different from WPW syndromes, which utilize abnormal conduction pathways. Although omega-3 fatty acids from fish oil can be protective against arrhythmias, they can facilitate re-entrant arrhythmias. Fibrillation When an entire chamber of the heart is involved in multiple micro-reentry circuits and is, therefore, quivering with chaotic electrical impulses, it is said to be in fibrillation. Fibrillation can affect the atrium (atrial fibrillation) or the ventricle (ventricular fibrillation): ventricular fibrillation is imminently life-threatening. Atrial fibrillation affects the upper chambers of the heart, known as the atria. Atrial fibrillation may be due to serious underlying medical conditions and should be evaluated by a physician. It is not typically a medical emergency. Ventricular fibrillation occurs in the ventricles (lower chambers) of the heart; it is always a medical emergency. If left untreated, ventricular fibrillation (VF, or V-fib) can lead to death within minutes. When a heart goes into V-fib, effective pumping of the blood stops. V-fib is considered a form of cardiac arrest. An affected individual will not survive unless cardiopulmonary resuscitation (CPR) and defibrillation are provided immediately.CPR can prolong the survival of the brain in the lack of a normal pulse, but defibrillation is the only intervention that can restore a healthy heart rhythm. Defibrillation is performed by applying an electric shock to the heart, which resets the cells, permitting a normal beat to re-establish itself. Triggered beats Triggered beats occur when problems at the level of the ion channels in individual heart cells result in abnormal propagation of electrical activity and can lead to a sustained abnormal rhythm. They are relatively rare and can result from the action of anti-arrhythmic drugs, or after depolarizations. Management The method of cardiac rhythm management depends firstly on whether the affected person is stable or unstable. Treatments may include physical maneuvers, medications, electricity conversion, or electro- or cryo-cautery.In the United States, people admitted to the hospital with cardiac arrhythmia and conduction disorders with and without complications were admitted to the intensive care unit more than half the time in 2011. Physical maneuvers Several physical acts can increase parasympathetic nervous supply to the heart, resulting in blocking of electrical conduction through the AV node. This can slow down or stop several arrhythmias that originate above or at the AV node (see main article: supraventricular tachycardias). Parasympathetic nervous supply to the heart is via the vagus nerve, and these maneuvers are collectively known as vagal maneuvers. Antiarrhythmic drugs There are many classes of antiarrhythmic medications, with different mechanisms of action and many different individual drugs within these classes. Although the goal of drug therapy is to prevent arrhythmia, nearly every antiarrhythmic drug has the potential to act as a pro-arrhythmic, and so must be carefully selected and used under medical supervision. Other drugs Several groups of drugs slow conduction through the heart, without actually preventing an arrhythmia. These drugs can be used to "rate control" a fast rhythm and make it physically tolerable for the patient.Some arrhythmias promote blood clotting within the heart and increase the risk of embolus and stroke. Anticoagulant medications such as warfarin and heparins, and anti-platelet drugs such as aspirin can reduce the risk of clotting. Electricity Arrhythmias may also be treated electrically, by applying a shock across the heart – either externally to the chest wall, or internally to the heart via implanted electrodes.Cardioversion is either achieved pharmacologically or via the application of a shock synchronized to the underlying heartbeat. It is used for the treatment of supraventricular tachycardias. In elective cardioversion, the recipient is usually sedated or lightly anesthetized for the procedure. Defibrillation differs in that the shock is not synchronized. It is needed for the chaotic rhythm of ventricular fibrillation and is also used for pulseless ventricular tachycardia. Often, more electricity is required for defibrillation than for cardioversion. In most defibrillation, the recipient has lost consciousness so there is no need for sedation. Defibrillation or cardioversion may be accomplished by an implantable cardioverter-defibrillator (ICD). Electrical treatment of arrhythmias also includes cardiac pacing. Temporary pacing may be necessary for reversible causes of very slow heartbeats, or bradycardia (for example, from drug overdose or myocardial infarction). A permanent pacemaker may be placed in situations where the bradycardia is not expected to recover. Electrical cautery Some cardiologists further sub-specialize into electrophysiology. In specialized catheter laboratories, they use fine probes inserted through the blood vessels to map electrical activity from within the heart. This allows abnormal areas of conduction to be located very accurately and subsequently destroyed by heat, cold, electrical, or laser probes in a process called catheter ablation. This procedure may be completely curative for some forms of arrhythmia, but for others, the success rate remains disappointing. AV nodal reentrant tachycardia is often curable by ablating one of the pathways in the AV node (usually the slow pathway). Atrial fibrillation can also be treated, by performing a pulmonary vein isolation, but the results are less reliable. Research Arrhythmias due to medications have been reported since the 1920s with the use of quinine. In the 1960s and 1970s problems with antihistamines and antipsychotics were discovered. It was not until the 1980s that the underlying issue, QTc prolongation was determined. See also Pre-excitation syndrome Holiday heart syndrome References External links Arrhythmia at Curlie
Urethra	The urethra (from Greek οὐρήθρα – ourḗthrā) is a tube that connects the urinary bladder to the urinary meatus for the removal of urine from the body of both females and males. In human females and other primates, the urethra connects to the urinary meatus above the vagina, whereas in marsupials, the females urethra empties into the urogenital sinus.Females use their urethra only for urinating, but males use their urethra for both urination and ejaculation. The external urethral sphincter is a striated muscle that allows voluntary control over urination. The internal sphincter, formed by the involuntary smooth muscles lining the bladder neck and urethra, receives its nerve supply by the sympathetic division of the autonomic nervous system. The internal sphincter is present both in males and females. Structure The urethra is a fibrous and muscular tube which connects the urinary bladder to the external urethral meatus. Its length differs between the sexes, because it passes through the penis in males. Male In the human male, the urethra is on average 18 to 20 centimeters (7.1 to 7.9 inches) long and opens at the end of the external urethral meatus.The urethra is divided into four parts in men, named after the location: There is inadequate data for the typical length of the male urethra; however, a study of 109 men showed an average length of 22.3 cm (SD = 2.4 cm), ranging from 15 cm to 29 cm. Female In the human female, the urethra is about 4 cm long, and exits the body between the clitoris and the vagina, extending from the internal to the external urethral orifice. The meatus is located below the clitoris. It is placed behind the symphysis pubis, embedded in the anterior wall of the vagina, and its direction is obliquely downward and forward; it is slightly curved with the concavity directed forward. The proximal two-thirds of the urethra is lined by transitional epithelial cells, while the distal third is lined by stratified squamous epithelial cells.Between the superior and inferior fascia of the urogenital diaphragm, the female urethra is surrounded by the urethral sphincter. Microanatomy The cells lining the urethra (the epithelium) start off as transitional cells as it exits the bladder, which are variable layers of flat to cuboidal cells that change shape depending on whether they are compressed by the contents of the urethra. Further along the urethra there are pseudostratified columnar and stratified columnar epithelia. The lining becomes multiple layers of flat cells near the end of the urethra, which is the same as the external skin around it.There are small mucus-secreting urethral glands, as well as bulbo-urethral glands of Cowper, that secret mucous acting to lubricate the urethra.The urethra consists of three coats: muscular, erectile, and mucous, the muscular layer being a continuation of that of the bladder. Blood and nerve supply and lymphatics Somatic (conscious) innervation of the external urethral sphincter is supplied by the pudendal nerve. Development In the developing embryo, at the hind end lies a cloaca. This, over the fourth to the seventh week, divides into a urogenital sinus and the beginnings of the anal canal, with a wall forming between these two inpouchings called the urorectal septum. The urogenital sinus divides into three parts, with the middle part forming the urethra; the upper part is largest and becomes the urinary bladder, and the lower part then changes depending on the biological sex of the embryo. The cells lining the urethra (the epithelium) come from endoderm, whereas the connective tissue and smooth muscle parts are derived from mesoderm.After the third month, urethra also contributes to the development of associated structures depending on the biological sex of the embryo. In the male, the epithelium multiples to form the prostate. In the female, the upper part of the urethra forms the urethra and paraurethral glands. Function Urination The urethra is the vessel through which urine passes after leaving the bladder. During urination, the smooth muscle lining the urethra relaxes in concert with bladder contraction(s) to forcefully expel the urine in a pressurized stream. Following this, the urethra re-establishes muscle tone by contracting the smooth muscle layer, and the bladder returns to a relaxed, quiescent state. Urethral smooth muscle cells are mechanically coupled to each other to coordinate mechanical force and electrical signaling in an organized, unitary fashion. Ejaculation The male urethra is the conduit for semen during sexual intercourse. Urine is removed before ejaculation by pre-ejaculate fluid – called Cowpers fluid – from the bulbourethral gland. Clinical significance Infection of the urethra is urethritis, which often causes purulent urethral discharge. It is most often due to a sexually transmitted infection such as gonorrhoea or chlamydia, and less commonly due to other bacteria such as ureaplasma or mycoplasma; trichomonas vaginalis; or the viruses herpes simplex virus and adenovirus. Investigations such as a gram stain of the discharge might reveal the cause; nucleic acid testing based on the first urine sample passed in a day, or a swab of the urethra sent for bacterial culture and sensitivity may also be used. Treatment usually involves antibiotics that treat both gonorrhoea and chlamydia, as these often occur together. A person being treated for urethritis should not have sex until the infection is treated, so that they do not spread the infection to others. Because of this spread, which may occur during an incubation period before a person gets symptoms, there is often contact tracing so that sexual partners of an affected person can be found and treatment offered.Cancer can also develop in the lining of the urethra. When cancer is present, the most common symptom in an affected person is blood in the urine; a physical medical examination may be otherwise normal, except in late disease. Cancer of the urethra is most often due to cancer of the cells lining the urethra, called transitional cell carcinoma, although it can more rarely occur as a squamous cell carcinoma if the type of cells lining the urethra have changed, such as due to a chronic schistosomiasis infection. Investigations performed usually include collecting a sample of urine for an inspection for malignant cells under a microscope, called cytology, as well as examination with a flexible camera through the urethra, called urethroscopy. If a malignancy is found, a biopsy will be taken, and a CT scan will be performed of other body parts (a CT scan of the chest, abdomen and pelvis) to look for additional metastatic lesions. After the cancer is staged, treatment may involve chemotherapy. Injury Passage of kidney stones through the urethra can be painful. Damage to the urethra, such as by kidney stones, chronic infection, cancer, or from catheterisation, can lead to narrowing, called a urethral stricture. The location and structure of the narrowing can be investigated with a medical imaging scan in which dye is injected through the urinary meatus into the urethra, called a retrograde urethrogram. Additional forms of imaging, such as ultrasound, computed tomography and magnetic resonance imaging may also be used to provide further details.Injuries to the urethra (e.g., from a pelvic fracture) Foreign bodies in the urethra are uncommon, but there have been medical case reports of self-inflicted injuries, a result of insertion of foreign bodies into the urethra such as an electrical wire. Other Hypospadias and epispadias are forms of abnormal development of the urethra in the male, where the meatus is not located at the distal end of the penis (it occurs lower than normal with hypospadias, and higher with epispadias). In a severe chordee, the urethra can develop between the penis and the scrotum. Catheterisation A tube called a catheter can be inserted through the urethra to drain urine from the bladder, called an indwelling urinary catheter; or, to bypass the urethra, a catheter may be directly inserted through the abdominal wall into the bladder, called a suprapubic catheter. This may be to relieve or bypass an obstruction, to monitor how much urine someone produces, or because a person has difficulty urinating, for example due to a neurological cause such as multiple sclerosis. Complications that are associated with catheter insertion can include catheter-associated infections, injury to the urethra or nearby structures, or pain. Other animals History The word "urethra" comes from the Ancient Greek stem "uro" relating to urination, with the structure described as early as the time of Hippocrates. Confusingly however, at the time it was called "ureter". Thereafter, terms "ureter" and "urethra" were variably used to refer to each other thereafter for more than a millennia. It was only in the 1550s that anatomists such as Bartolomeo Eustacchio and Jacques Dubois began to use the terms to specifically and consistently refer to what is in modern English called the ureter and the urethra. Following this, in the 19th and 20th centuries multiple terms relating to the structures such as urethritis and urethrography, were coined.Kidney stones have been identified and recorded about as long as written historical records exist. The urinary tract as well as its function to drain urine from the kidneys, has been described by Galen in the second century AD. Surgery to the urethra to remove kidney stones has been described since at least the first century AD by Aulus Cornelius Celsus. Additional images See also Perineal urethra Vulvovaginal health Urethral glands Urethral sponge Sexual stimulation: Urethral sounding and Urethral intercourse Urethrorrhagia Urethrotomy Internal urethral orifice References External links Histology at KUMC epithel-epith07 "Male Urethra"
Neonatal adrenoleukodystrophy	Neonatal adrenoleukodystrophy is an inborn error of peroxisome biogenesis. It is part of the Zellweger spectrum. It has been linked with multiple genes (at least five) associated with peroxisome biogenesis, and has an autosomal recessive pattern of inheritance. References == External links ==
Oligospermia	Terms oligospermia, oligozoospermia, and low sperm count refer to semen with a low concentration of sperm and is a common finding in male infertility. Often semen with a decreased sperm concentration may also show significant abnormalities in sperm morphology and motility (technically oligoasthenoteratozoospermia). There has been interest in replacing the descriptive terms used in semen analysis with more quantitative information. Diagnosis The diagnosis of oligozoospermia is based on one low count in a semen analysis performed on two occasions. For many decades sperm concentrations of less than 20 million sperm/ml were considered low or oligospermic, recently, however, the WHO reassessed sperm criteria and established a lower reference point, less than 15 million sperm/ml, consistent with the 5th percentile for fertile men. Sperm concentrations fluctuate and oligospermia may be temporary or permanent. Sources usually classify oligospermia in 3 classes: Mild: concentrations 10 million – 15 million sperm/mL Moderate: concentrations 5 million – 10 million sperm/mL Severe: concentrations less than 5 million sperm/mLThe diagnosis of oligozoospermia requires a work-up via semen analysis (listed in Male infertility). Causes There are many causes for oligospermia including: Pre-testicular causes Pre-testicular factors refer to conditions that impede adequate support of the testes and include situations of poor hormonal support and poor general health including: Hypogonadism due to various causes Drugs, alcohol, smoking Strenuous riding (bicycle riding, horseback riding) Medications, including androgens. Testicular factors Testicular factors refer to conditions where the testes produces semen of poor quality despite adequate hormonal support and include: Age Genetic defects on the Y chromosome Y chromosome microdeletions Abnormal set of chromosomes Klinefelter syndrome Neoplasm, e.g. seminoma Cryptorchidism Varicocele (14% in one study) Trauma Hydrocele Mumps Malaria Defects in USP26 enzyme in some casesMast cells releasing inflammatory mediators appear to directly suppress sperm motility in a potentially reversible manner, and may be a common pathophysiological mechanism for several of the above-mentioned factors. Post-testicular causes Post-testicular factors decrease male fertility due to conditions that affect the male genital system after testicular sperm production and include defects of the genital tract as well as problems in ejaculation: Vas deferens obstruction Lack of Vas deferens, often related to genetic markers for cystic fibrosis Infection, e.g. prostatitis Ejaculatory duct obstruction Idiopathic oligospermia (oligoasthenoteratozoospermia) In about 30% of infertile men no causative factor is found for their decrease in sperm concentration or quality by common clinical, instrumental, or laboratory means, and the condition is termed "idiopathic" (unexplained). A number of factors may be involved in the genesis of this condition, including age, infectious agents ( such as Chlamydia trachomatis), Y chromosome microdeletions, mitochondrial changes, environmental pollutants, and "subtle" hormonal changes.A review in 2013 came to the result that oligospermia and azoospermia are significantly associated with being overweight (odds ratio 1.1), obese (odds ratio 1.3) and morbidly obese (odds ratio 2.0), but the cause of this is unknown. It found no significant relation between oligospermia and being underweight. DNA damage The human breast cancer susceptibility gene 2 (BRCA2) is employed in homologous recombinational repair of DNA damages during meiosis. A common single-nucleotide polymorphism of BRCA2 is associated with severe oligospermia.Men with mild oligospermia (semen concentration of 15 million to 20 million sperm/ml) were studied for an association of sperm DNA damage with life style factors. A significant association was found between sperm DNA damage and factors such as age, obesity and occupational stress. Treatment Treatment takes place within the context of infertility management and needs also to consider the fecundity of the female partner. Thus the choices can be complex. In a number of situations direct medical or surgical intervention can improve the sperm concentration, examples are use of FSH in men with pituitary hypogonadism, antibiotics in case of infections, or operative corrections of a hydrocele, varicocele, or vas deferens obstruction. In most cases of oligospermia including its idiopathic form there is no direct medical or surgical intervention agreed to be effective. Empirically many medical approaches have been tried including clomiphene citrate, tamoxifen, HMG, FSH, HCG, testosterone, Vitamin E, Vitamin C, anti-oxidants, carnitine, acetyl-L-carnitine, zinc, high-protein diets. In a number of pilot studies some positive results have been obtained. Clomiphene citrate has been used with modest success. The combination of tamoxifen plus testosterone was reported to improve the sperm situation.The use of carnitine showed some promise in a controlled trial in selected cases of male infertility improving sperm quality and further studies are needed.In many situations, intrauterine inseminations are performed with success. In more severe cases IVF, or IVF - ICSI is done and is often the best option, specifically if time is a factor or fertility problems coexist on the female side. The Low dose Estrogen Testosterone Combination Therapy may improve sperm count and motility in some men including severe oligospermia. Fertility Achieving a pregnancy naturally may be a challenge if the male has a low sperm count. However, chances are good if the female partner is fertile; many couples with this problem have been successful. Prognosis is more limited if there is a combination of factors that include sperm dysfunction and reduced ovarian reserve. See also Conception device Male infertility Semen quality Vasectomy == References ==
Onset	Onset may refer to: Onset (audio), the beginning of a musical note or sound Onset, Massachusetts, village in the United States Onset Island (Massachusetts), a small island located at the western end of the Cape Cod Canal Interonset interval, a term in music Syllable onset, a term in phonetics and phonology The Onset, Liverpool indie rock group formed by Mike Badger of the Las The Onset (album), a 2005 album by the band USS Onset (SP-1224), a United States Navy patrol boat in commission from 1917 to 1918 "Onset", a 2019 song by Haiku Hands See also Offset (disambiguation)
Epilepsy	Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical activity in the brain. These episodes can result in physical injuries, either directly such as broken bones or through causing accidents. In epilepsy, seizures tend to recur and may have no immediate underlying cause. Isolated seizures that are provoked by a specific cause such as poisoning are not deemed to represent epilepsy. People with epilepsy may be treated differently in various areas of the world and experience varying degrees of social stigma due to the alarming nature of their symptoms.The underlying mechanism of epileptic seizures is excessive and abnormal neuronal activity in the cortex of the brain which can be observed in the electroencephalogram (EEG) of an individual. The reason this occurs in most cases of epilepsy is unknown (idiopathic); some cases occur as the result of brain injury, stroke, brain tumors, infections of the brain, or birth defects through a process known as epileptogenesis. Known genetic mutations are directly linked to a small proportion of cases. The diagnosis involves ruling out other conditions that might cause similar symptoms, such as fainting, and determining if another cause of seizures is present, such as alcohol withdrawal or electrolyte problems. This may be partly done by imaging the brain and performing blood tests. Epilepsy can often be confirmed with an EEG, but a normal test does not rule out the condition.Epilepsy that occurs as a result of other issues may be preventable. Seizures are controllable with medication in about 69% of cases; inexpensive anti-seizure medications are often available. In those whose seizures do not respond to medication; surgery, neurostimulation or dietary changes may then be considered. Not all cases of epilepsy are lifelong, and many people improve to the point that treatment is no longer needed.As of 2020, about 50 million people have epilepsy. Nearly 80% of cases occur in the developing world. In 2015, it resulted in 125,000 deaths, an increase from 112,000 in 1990. Epilepsy is more common in older people. In the developed world, onset of new cases occurs most frequently in babies and the elderly. In the developing world, onset is more common in older children and young adults due to differences in the frequency of the underlying causes. About 5–10% of people will have an unprovoked seizure by the age of 80, with the chance of experiencing a second seizure rising to between 40% and 50%. In many areas of the world, those with epilepsy either have restrictions placed on their ability to drive or are not permitted to drive until they are free of seizures for a specific length of time. The word epilepsy is from Ancient Greek ἐπιλαμβάνειν, "to seize, possess, or afflict". Signs and symptoms Epilepsy is characterized by a long-term risk of recurrent epileptic seizures. These seizures may present in several ways depending on the parts of the brain involved and the persons age. Seizures The most common type (60%) of seizures are convulsive which involve involuntary muscle contractions. Of these, one-third begin as generalized seizures from the start, affecting both hemispheres of the brain and impairing consciousness. Two-thirds begin as focal seizures (which affect one hemisphere of the brain) which may progress to generalized seizures. The remaining 40% of seizures are non-convulsive. An example of this type is the absence seizure, which presents as a decreased level of consciousness and usually lasts about 10 seconds.Certain experiences, known as auras often precede focal seizures. The seizures can include sensory (visual, hearing, or smell), psychic, autonomic, and motor phenomena depending on which part of the brain is involved. Muscle jerks may start in a specific muscle group and spread to surrounding muscle groups in which case it is known as a Jacksonian march. Automatisms may occur, which are non-consciously generated activities and mostly simple repetitive movements like smacking the lips or more complex activities such as attempts to pick up something.There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. They all involve loss of consciousness and typically happen without warning. Tonic-clonic seizures occur with a contraction of the limbs followed by their extension and arching of the back which lasts 10–30 seconds (the tonic phase). A cry may be heard due to contraction of the chest muscles, followed by a shaking of the limbs in unison (clonic phase). Tonic seizures produce constant contractions of the muscles. A person often turns blue as breathing is stopped. In clonic seizures there is shaking of the limbs in unison. After the shaking has stopped it may take 10–30 minutes for the person to return to normal; this period is called the "postictal state" or "postictal phase." Loss of bowel or bladder control may occur during a seizure. People experiencing a seizure may bite their tongue, either the tip or on the sides; in tonic-clonic seizure, bites to the sides are more common. Tongue bites are also relatively common in psychogenic non-epileptic seizures.Myoclonic seizures involve very brief spasms of muscles in either a few areas or all over. These sometimes cause the person to fall, which can cause injury. Absence seizures can be subtle with only a slight turn of the head or eye blinking with impaired consciousness; typically, the person does not fall over and returns to normal right after it ends. Atonic seizures involve losing muscle activity for greater than one second, typically occurring on both sides of the body. Rarer seizure types can cause involuntary unnatural laughter (gelastic), crying (dyscrastic), or more complex experiences such as déjà vu.About 6% of those with epilepsy have seizures that are often triggered by specific events and are known as reflex seizures. Those with reflex epilepsy have seizures that are only triggered by specific stimuli. Common triggers include flashing lights and sudden noises. In certain types of epilepsy, seizures happen more often during sleep, and in other types they occur almost only when sleeping. Seizure clusters Patients with epilepsy may experience seizure clusters which may be broadly defined as an acute deterioration in seizure control. The prevalence of seizure clusters is uncertain given that studies have used different definitions to define them. However, estimates suggest that the prevalence may range from 5% to 50% of epilepsy patients. Refractory epilepsy patients who have a high seizure frequency are at the greatest risk for having seizure clusters. Seizure clusters are associated with increased healthcare utilization, worse quality of life, impaired psychosocial functioning, and possibly increased mortality. Benzodiazepines are used as an acute treatment for seizure clusters. Post-ictal After the active portion of a seizure (the ictal state) there is typically a period of recovery during which there is confusion, referred to as the postictal period, before a normal level of consciousness returns. It usually lasts 3 to 15 minutes but may last for hours. Other common symptoms include feeling tired, headache, difficulty speaking, and abnormal behavior. Psychosis after a seizure is relatively common, occurring in 6–10% of people. Often people do not remember what happened during this time. Localized weakness, known as Todds paralysis, may also occur after a focal seizure. It would typically last for seconds to minutes but may rarely last for a day or two. Psychosocial Epilepsy can have adverse effects on social and psychological well-being. These effects may include social isolation, stigmatization, or disability. They may result in lower educational achievement and worse employment outcomes. Learning disabilities are common in those with the condition, and especially among children with epilepsy. The stigma of epilepsy can also affect the families of those with the disorder.Certain disorders occur more often in people with epilepsy, depending partly on the epilepsy syndrome present. These include depression, anxiety, obsessive–compulsive disorder (OCD), and migraine. Attention deficit hyperactivity disorder (ADHD) affects three to five times more children with epilepsy than children without the condition. ADHD and epilepsy have significant consequences on a childs behavioral, learning, and social development. Epilepsy is also more common in children with autism.Approximately, one-in-three people with epilepsy have a lifetime history of a psychiatric disorder. There are believed to be multiple causes for this including pathophysiological changes related to the epilepsy itself as well as adverse experiences related to living with epilepsy (e.g., stigma, discrimination). In addition, it is thought that the relationship between epilepsy and psychiatric disorders is not unilateral but rather bidirectional. For example, patients with depression have an increased risk for developing new-onset epilepsy.The presence of comorbid depression or anxiety in patients with epilepsy is associated with a poorer quality of life, increased mortality, increased healthcare utilization and a worse response to treatment (including surgical). Anxiety disorders and depression may explain more variability in quality of life than seizure type or frequency. There is evidence that both depression and anxiety disorders are underdiagnosed and undertreated in patients with epilepsy. Causes Epilepsy can have both genetic and acquired causes, with the interaction of these factors in many cases. Established acquired causes include serious brain trauma, stroke, tumours, and brain problems resulting from a previous infection. In about 60% of cases, the cause is unknown. Epilepsies caused by genetic, congenital, or developmental conditions are more common among younger people, while brain tumors and strokes are more likely in older people.Seizures may also occur as a consequence of other health problems; if they occur right around a specific cause, such as a stroke, head injury, toxic ingestion, or metabolic problem, they are known as acute symptomatic seizures and are in the broader classification of seizure-related disorders rather than epilepsy itself. Genetics Genetics is believed to be involved in the majority of cases, either directly or indirectly. Some epilepsies are due to a single gene defect (1–2%); most are due to the interaction of multiple genes and environmental factors. Each of the single gene defects is rare, with more than 200 in all described. Most genes involved affect ion channels, either directly or indirectly. These include genes for ion channels themselves, enzymes, GABA, and G protein-coupled receptors.In identical twins, if one is affected, there is a 50–60% chance that the other will also be affected. In non-identical twins, the risk is 15%. These risks are greater in those with generalized rather than focal seizures. If both twins are affected, most of the time they have the same epileptic syndrome (70–90%). Other close relatives of a person with epilepsy have a risk five times that of the general population. Between 1 and 10% of those with Down syndrome and 90% of those with Angelman syndrome have epilepsy. Phakomatoses Phakomatoses, also known as neurocutaneous disorders, are a group of multisystemic diseases that most prominently affect the skin and central nervous system. They are caused by defective development of the embryonic ectodermal tissue that is most often due to a single genetic mutation. The brain, as well as other neural tissue and the skin, are all derived from the ectoderm and thus defective development may result in epilepsy as well as other manifestations such as autism and intellectual disability. Some types of phakomatoses such as tuberous sclerosis complex and Sturge-Weber syndrome have a higher prevalence of epilepsy relative to others such as neurofibromatosis type 1.Tuberous sclerosis complex is an autosomal dominant disorder that is caused by mutations in either the TSC1 or TSC2 gene and it affects approximately 1 in 6,000-10,000 live births. These mutations result in the upregulation of the mechanistic target of rapamycin (mTOR) pathway which leads to the growth of tumors in many organs including the brain, skin, heart, eyes and kidneys. In addition, abnormal mTOR activity is believed to alter neural excitability. The prevalence of epilepsy is estimated to be 80-90%. The majority of cases of epilepsy present within the first 3 years of life and are medically refractory. Relatively recent developments for the treatment of epilepsy in TSC patients include mTOR inhibitors, cannabidiol and vigabatrin. Epilepsy surgery is often pursued. Sturge-Weber syndrome is caused by an activating somatic mutation in the GNAQ gene and it affects approximately 1 in 20,000-50,000 live births. The mutation results in vascular malformations affecting the brain, skin and eyes. The typical presentation includes a facial port-wine birthmark, ocular angiomas and cerebral vascular malformations which are most often unilateral but are bilateral in 15% of cases. The prevalence of epilepsy is 75-100% and is higher in those with bilateral involvement. Seizures typically occur within the first two years of life and are refractory in nearly half of cases. However, high rates of seizure freedom with surgery have been reported in as many as 83%.Neurofibromatosis type 1 is the most common phakomatoses and occurs in approximately 1 in 3,000 live births. It is caused by autosomal dominant mutations in the Neurofibromin 1 gene. Clinical manifestations are variable but may include hyperpigmented skin marks, hamartomas of the iris called Lisch nodules, neurofibromas, optic pathway gliomas and cognitive impairment. The prevalence of epilepsy is estimated to be 4-7%. Seizures are typically easier to control with anti-seizure medications relative to other phakomatoses but in some refractory cases surgery may need to be pursued. Acquired Epilepsy may occur as a result of several other conditions, including tumors, strokes, head trauma, previous infections of the central nervous system, genetic abnormalities, and as a result of brain damage around the time of birth. Of those with brain tumors, almost 30% have epilepsy, making them the cause of about 4% of cases. The risk is greatest for tumors in the temporal lobe and those that grow slowly. Other mass lesions such as cerebral cavernous malformations and arteriovenous malformations have risks as high as 40–60%. Of those who have had a stroke, 6–10% develop epilepsy. Risk factors for post-stroke epilepsy include stroke severity, cortical involvement, hemorrhage and early seizures. Between 6 and 20% of epilepsy is believed to be due to head trauma. Mild brain injury increases the risk about two-fold while severe brain injury increases the risk seven-fold. In those who have experienced a high-powered gunshot wound to the head, the risk is about 50%.Some evidence links epilepsy and celiac disease and non-celiac gluten sensitivity, while other evidence does not. There appears to be a specific syndrome that includes coeliac disease, epilepsy, and calcifications in the brain. A 2012 review estimates that between 1% and 6% of people with epilepsy have coeliac disease while 1% of the general population has the condition.The risk of epilepsy following meningitis is less than 10%; it more commonly causes seizures during the infection itself. In herpes simplex encephalitis the risk of a seizure is around 50% with a high risk of epilepsy following (up to 25%). A form of an infection with the pork tapeworm (cysticercosis), in the brain, is known as neurocysticercosis, and is the cause of up to half of epilepsy cases in areas of the world where the parasite is common. Epilepsy may also occur after other brain infections such as cerebral malaria, toxoplasmosis, and toxocariasis. Chronic alcohol use increases the risk of epilepsy: those who drink six units of alcohol per day have a 2.5-fold increase in risk. Other risks include Alzheimers disease, multiple sclerosis, tuberous sclerosis, and autoimmune encephalitis. Getting vaccinated does not increase the risk of epilepsy. Malnutrition is a risk factor seen mostly in the developing world, although it is unclear however if it is a direct cause or an association. People with cerebral palsy have an increased risk of epilepsy, with half of people with spastic quadriplegia and spastic hemiplegia having the disease. Mechanism Normally brain electrical activity is non-synchronous, as large numbers of neurons do not normally fire at the same time, but rather fire in order as signals travel throughout the brain. Neuron activity is regulated by various factors both within the cell and the cellular environment. Factors within the neuron include the type, number and distribution of ion channels, changes to receptors and changes of gene expression. Factors around the neuron include ion concentrations, synaptic plasticity and regulation of transmitter breakdown by glial cells. Epilepsy The exact mechanism for epilepsy is unknown, but a little is known about its cellular and network mechanisms. However, it is unknown under which circumstances the brain shifts into the activity of a seizure with its excessive synchronization. Changes in MicroRNAs (miRNAs) levels seems to play a leading role. MicroRNAs (miRNAs) are a family of small non-coding RNAs that control the expression levels of multiple proteins by decreasing mRNA stability and translation, and could therefore be key regulatory mechanisms and therapeutic targets in epilepsy In epilepsy, the resistance of excitatory neurons to fire during this period is decreased. This may occur due to changes in ion channels or inhibitory neurons not functioning properly. This then results in a specific area from which seizures may develop, known as a "seizure focus". Another mechanism of epilepsy may be the up-regulation of excitatory circuits or down-regulation of inhibitory circuits following an injury to the brain. These secondary epilepsies occur through processes known as epileptogenesis. Failure of the blood–brain barrier may also be a causal mechanism as it would allow substances in the blood to enter the brain. Seizures There is evidence that epileptic seizures are usually not a random event. Seizures are often brought on by factors (also known as triggers) such as stress, excessive alcohol use, flickering light, or a lack of sleep, among others. The term seizure threshold is used to indicate the amount of stimulus necessary to bring about a seizure; this threshold is lowered in epilepsy.In epileptic seizures a group of neurons begin firing in an abnormal, excessive, and synchronized manner. This results in a wave of depolarization known as a paroxysmal depolarizing shift. Normally, after an excitatory neuron fires it becomes more resistant to firing for a period of time. This is due in part to the effect of inhibitory neurons, electrical changes within the excitatory neuron, and the negative effects of adenosine.Focal seizures begin in one area of the brain while generalized seizures begin in both hemispheres. Some types of seizures may change brain structure, while others appear to have little effect. Gliosis, neuronal loss, and atrophy of specific areas of the brain are linked to epilepsy but it is unclear if epilepsy causes these changes or if these changes result in epilepsy.The seizures can be described on different scales, from the cellular level to the whole brain. These are several concomitant factor, which on different scale can "drive" the brain to pathological states and trigger a seizure. Diagnosis The diagnosis of epilepsy is typically made based on observation of the seizure onset and the underlying cause. An electroencephalogram (EEG) to look for abnormal patterns of brain waves and neuroimaging (CT scan or MRI) to look at the structure of the brain are also usually part of the initial investigations. While figuring out a specific epileptic syndrome is often attempted, it is not always possible. Video and EEG monitoring may be useful in difficult cases. Definition Epilepsy is a disorder of the brain defined by any of the following conditions: Furthermore, epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past that age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years.This 2014 definition of the International League Against Epilepsy is a clarification of the ILAE 2005 conceptual definition, according to which epilepsy is "a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure."It is, therefore, possible to outgrow epilepsy or to undergo treatment that causes epilepsy to be resolved, but with no guarantee that it will not return. In the definition, epilepsy is now called a disease, rather than a disorder. This was a decision of the executive committee of the ILAE, taken because the word "disorder," while perhaps having less stigma than does "disease," also does not express the degree of seriousness that epilepsy deserves.The definition is practical in nature and is designed for clinical use. In particular, it aims to clarify when an "enduring predisposition" according to the 2005 conceptual definition is present. Researchers, statistically minded epidemiologists, and other specialized groups may choose to use the older definition or a definition of their own devising. The ILAE considers doing so is perfectly allowable, so long as it is clear what definition is being used. Classification In contrast to the classification of seizures which focuses on what happens during a seizure, the classification of epilepsies focuses on the underlying causes. When a person is admitted to hospital after an epileptic seizure the diagnostic workup results preferably in the seizure itself being classified (e.g. tonic-clonic) and in the underlying disease being identified (e.g. hippocampal sclerosis). The name of the diagnosis finally made depends on the available diagnostic results and the applied definitions and classifications (of seizures and epilepsies) and its respective terminology. The International League Against Epilepsy (ILAE) provided a classification of the epilepsies and epileptic syndromes in 1989 as follows: This classification was widely accepted but has also been criticized mainly because the underlying causes of epilepsy (which are a major determinant of clinical course and prognosis) were not covered in detail. In 2010 the ILAE Commission for Classification of the Epilepsies addressed this issue and divided epilepsies into three categories (genetic, structural/metabolic, unknown cause) that were refined in their 2011 recommendation into four categories and a number of subcategories reflecting recent technologic and scientific advances. A revised, operational classification of seizure types has been introduced by the ILAE. It allows more clearly understood terms and clearly defines focal and generalized onset dichotomy, when possible, even without observing the seizures based on description by patient or observers. The essential changes in terminology are that "partial" is called "focal" with awareness used as a classifier for focal seizures -based on description focal seizures are now defined as behavioral arrest, automatisms, cognitive, autonomic, emotional or hyperkinetic variants while atonic, myoclonic, clonic, infantile spasms, and tonic seizures may be either focal or generalized based on their onset. Several terms that were not clear or consistent in description were removed such as dyscognitive, psychic, simple and complex partial, while "secondarily generalized" is replaced by a clearer term "focal to bilateral tonic clonic seizure". New seizure types now believed to be generalized are eyelid myoclonia, myoclonic atonic, myoclonic absence, and myoclonic tonic clonic. Sometimes it is possible to classify seizures as focal or generalized based on presenting features even though onset in not known. This system is based on the 1981 seizure classification modified in 2010 and principally is the same with an effort to improve the flexibility and clarity of use to understand seizures types better in keeping with current knowledge. Syndromes Cases of epilepsy may be organized into epilepsy syndromes by the specific features that are present. These features include the age that seizure begin, the seizure types, EEG findings, among others. Identifying an epilepsy syndrome is useful as it helps determine the underlying causes as well as what anti-seizure medication should be tried.The ability to categorize a case of epilepsy into a specific syndrome occurs more often with children since the onset of seizures is commonly early. Less serious examples are benign rolandic epilepsy (2.8 per 100,000), childhood absence epilepsy (0.8 per 100,000) and juvenile myoclonic epilepsy (0.7 per 100,000). Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as developmental and epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and cognitive dysfunction, for instance Lennox–Gastaut syndrome (1-2% of all persons with epilepsy), Dravet syndrome(1: 15000-40000 worldwide), and West syndrome(1-9: 100000). Genetics is believed to play an important role in epilepsies by a number of mechanisms. Simple and complex modes of inheritance have been identified for some of them. However, extensive screening have failed to identify many single gene variants of large effect. More recent exome and genome sequencing studies have begun to reveal a number of de novo gene mutations that are responsible for some epileptic encephalopathies, including CHD2 and SYNGAP1 and DNM1, GABBR2, FASN and RYR3.Syndromes in which causes are not clearly identified are difficult to match with categories of the current classification of epilepsy. Categorization for these cases was made somewhat arbitrarily. The idiopathic (unknown cause) category of the 2011 classification includes syndromes in which the general clinical features and/or age specificity strongly point to a presumed genetic cause. Some childhood epilepsy syndromes are included in the unknown cause category in which the cause is presumed genetic, for instance benign rolandic epilepsy. Others are included in symptomatic despite a presumed genetic cause (in at least in some cases), for instance Lennox-Gastaut syndrome. Clinical syndromes in which epilepsy is not the main feature (e.g. Angelman syndrome) were categorized symptomatic but it was argued to include these within the category idiopathic. Classification of epilepsies and particularly of epilepsy syndromes will change with advances in research. Tests An electroencephalogram (EEG) can assist in showing brain activity suggestive of an increased risk of seizures. It is only recommended for those who are likely to have had an epileptic seizure on the basis of symptoms. In the diagnosis of epilepsy, electroencephalography may help distinguish the type of seizure or syndrome present. In children it is typically only needed after a second seizure unless specified by a specialist. It cannot be used to rule out the diagnosis and may be falsely positive in those without the disease. In certain situations it may be useful to perform the EEG while the affected individual is sleeping or sleep deprived.Diagnostic imaging by CT scan and MRI is recommended after a first non-febrile seizure to detect structural problems in and around the brain. MRI is generally a better imaging test except when bleeding is suspected, for which CT is more sensitive and more easily available. If someone attends the emergency room with a seizure but returns to normal quickly, imaging tests may be done at a later point. If a person has a previous diagnosis of epilepsy with previous imaging, repeating the imaging is usually not needed even if there are subsequent seizures.For adults, the testing of electrolyte, blood glucose and calcium levels is important to rule out problems with these as causes. An electrocardiogram can rule out problems with the rhythm of the heart. A lumbar puncture may be useful to diagnose a central nervous system infection but is not routinely needed. In children additional tests may be required such as urine biochemistry and blood testing looking for metabolic disorders. Together with EEG and neuroimaging, genetic testing is becoming one of the most important diagnostic technique for epilepsy, as a diagnosis might be achieved in a relevant proportion of cases with severe epilepsies, both in children and adults. For those with negative genetic testing, in some it might be important to repeat or re-analyze previous genetic studies after 2–3 years.A high blood prolactin level within the first 20 minutes following a seizure may be useful to help confirm an epileptic seizure as opposed to psychogenic non-epileptic seizure. Serum prolactin level is less useful for detecting focal seizures. If it is normal an epileptic seizure is still possible and a serum prolactin does not separate epileptic seizures from syncope. It is not recommended as a routine part of the diagnosis of epilepsy. D
Epilepsy	ifferential diagnosis Diagnosis of epilepsy can be difficult. A number of other conditions may present very similar signs and symptoms to seizures, including syncope, hyperventilation, migraines, narcolepsy, panic attacks and psychogenic non-epileptic seizures (PNES). In particular a syncope can be accompanied by a short episode of convulsions. Nocturnal frontal lobe epilepsy, often misdiagnosed as nightmares, was considered to be a parasomnia but later identified to be an epilepsy syndrome. Attacks of the movement disorder paroxysmal dyskinesia may be taken for epileptic seizures. The cause of a drop attack can be, among many others, an atonic seizure.Children may have behaviors that are easily mistaken for epileptic seizures but are not. These include breath-holding spells, bedwetting, night terrors, tics and shudder attacks. Gastroesophageal reflux may cause arching of the back and twisting of the head to the side in infants, which may be mistaken for tonic-clonic seizures.Misdiagnosis is frequent (occurring in about 5 to 30% of cases). Different studies showed that in many cases seizure-like attacks in apparent treatment-resistant epilepsy have a cardiovascular cause. Approximately 20% of the people seen at epilepsy clinics have PNES and of those who have PNES about 10% also have epilepsy; separating the two based on the seizure episode alone without further testing is often difficult. Prevention While many cases are not preventable, efforts to reduce head injuries, provide good care around the time of birth, and reduce environmental parasites such as the pork tapeworm may be effective. Efforts in one part of Central America to decrease rates of pork tapeworm resulted in a 50% decrease in new cases of epilepsy. Complication Epilepsy can be dangerous when seizure occurs at certain times. The possibility of drowning and having car accident is higher. It is also dangerous when seizure occurs during pregnancy. Certain anti-epileptic medications increase the risk of birth defects. It is also found that people with epilepsy are more likely to have psychological problems. Other complications include aspiration pneumonia and difficulty learning. Management Epilepsy is usually treated with daily medication once a second seizure has occurred, while medication may be started after the first seizure in those at high risk for subsequent seizures. Supporting peoples self management of their condition may be useful. In drug-resistant cases different management options may be looked at including a special diet, the implantation of a neurostimulator, or neurosurgery. First aid Rolling people with an active tonic-clonic seizure onto their side and into the recovery position helps prevent fluids from getting into the lungs. Putting fingers, a bite block or tongue depressor in the mouth is not recommended as it might make the person vomit or result in the rescuer being bitten. Efforts should be taken to prevent further self-injury. Spinal precautions are generally not needed.If a seizure lasts longer than 5 minutes or if there are more than two seizures in an hour without a return to a normal level of consciousness between them, it is considered a medical emergency known as status epilepticus. This may require medical help to keep the airway open and protected; a nasopharyngeal airway may be useful for this. At home the recommended initial medication for seizure of a long duration is midazolam placed in the mouth. Diazepam may also be used rectally. In hospital, intravenous lorazepam is preferred. If two doses of benzodiazepines are not effective, other medications such as phenytoin are recommended. Convulsive status epilepticus that does not respond to initial treatment typically requires admission to the intensive care unit and treatment with stronger agents such as thiopentone or propofol. Medications The mainstay treatment of epilepsy is anticonvulsant medications, possibly for the persons entire life. The choice of anticonvulsant is based on seizure type, epilepsy syndrome, other medications used, other health problems, and the persons age and lifestyle. A single medication is recommended initially; if this is not effective, switching to a single other medication is recommended. Two medications at once is recommended only if a single medication does not work. In about half, the first agent is effective; a second single agent helps in about 13% and a third or two agents at the same time may help an additional 4%. About 30% of people continue to have seizures despite anticonvulsant treatment.There are a number of medications available including phenytoin, carbamazepine and valproate. Evidence suggests that phenytoin, carbamazepine, and valproate may be equally effective in both focal and generalized seizures. Controlled release carbamazepine appears to work as well as immediate release carbamazepine, and may have fewer side effects. Recently, Nux vomica and Cicuta virosa have been shown to produce significant anti-epileptic effects and no side effects. This could prove to be very helpful for a large segment of population. In the United Kingdom, carbamazepine or lamotrigine are recommended as first-line treatment for focal seizures, with levetiracetam and valproate as second-line due to issues of cost and side effects. Valproate is recommended first-line for generalized seizures with lamotrigine being second-line. In those with absence seizures, ethosuximide or valproate are recommended; valproate is particularly effective in myoclonic seizures and tonic or atonic seizures. If seizures are well-controlled on a particular treatment, it is not usually necessary to routinely check the medication levels in the blood.The least expensive anticonvulsant is phenobarbital at around US$5 a year. The World Health Organization gives it a first-line recommendation in the developing world and it is commonly used there. Access however may be difficult as some countries label it as a controlled drug.Adverse effects from medications are reported in 10 to 90% of people, depending on how and from whom the data is collected. Most adverse effects are dose-related and mild. Some examples include mood changes, sleepiness, or an unsteadiness in gait. Certain medications have side effects that are not related to dose such as rashes, liver toxicity, or suppression of the bone marrow. Up to a quarter of people stop treatment due to adverse effects. Some medications are associated with birth defects when used in pregnancy. Many of the common used medications, such as valproate, phenytoin, carbamazepine, phenobarbital, and gabapentin have been reported to cause increased risk of birth defects, especially when used during the first trimester. Despite this, treatment is often continued once effective, because the risk of untreated epilepsy is believed to be greater than the risk of the medications. Among the antiepileptic medications, levetiracetam and lamotrigine seem to carry the lowest risk of causing birth defects.Slowly stopping medications may be reasonable in some people who do not have a seizure for two to four years; however, around a third of people have a recurrence, most often during the first six months. Stopping is possible in about 70% of children and 60% of adults. Measuring medication levels is not generally needed in those whose seizures are well controlled. Surgery Epilepsy surgery may be an option for people with focal seizures that remain a problem despite other treatments. These other treatments include at least a trial of two or three medications. The goal of surgery is total control of seizures and this may be achieved in 60–70% of cases. Common procedures include cutting out the hippocampus via an anterior temporal lobe resection, removal of tumors, and removing parts of the neocortex. Some procedures such as a corpus callosotomy are attempted in an effort to decrease the number of seizures rather than cure the condition. Following surgery, medications may be slowly withdrawn in many cases. Neurostimulation Neurostimulation via neuro-cybernetic prosthesis implantation, may be another option in those who are not candidates for surgery, providing chronic, pulsatile electrical stimulation of specific nerve or brain regions, alongside standard care. Three types have been used in those who do not respond to medications: vagus nerve stimulation (VNS), anterior thalamic stimulation, and closed-loop responsive stimulation. Vagus nerve stimulation Non-pharmacological modulation of neurotransmitters via high-level VNS (h-VNS) may reduce seizure frequency in children and adults who do not respond to medical and/or surgical therapy, when compared with low-level VNS (l-VNS). In a 2022 Cochrane review of 4 randomised controlled trials, with moderate certainty of evidence, people receiving h-VNS treatment were 73% more likely (13% more likely to 164% more likely) to experience a reduction in seizure frequency by at least 50% (the minimum threshold defined for individual clinical response). Potentially 249 (163 to 380) per 1000 people with drug-resistant epilepsy may achieve a 50% reduction in seizures following h-VNS, benefiting an additional 105 per 1000 people compared with l-VNS. This outcome was limited by the number of studies available, and the quality of one trial in particular, wherein 3 people received l-VNS in error. A sensitivity analysis suggested that the best case scenario was that the likelihood of clinical response to h-VNS may be 91% (27% to 189%) higher than those receiving l-VNS. In the worst-case scenario, the likelihood of clinical response to h-VNS was still 61% higher (7% higher to 143% higher) than l-VNS. Despite the potential benefit for h-VNS treatment, the Cochrane review also found that the risk of several adverse-effects was greater than those receiving l-VNS. There was moderate certainty of evidence that voice alteration or hoarseness risk may be 2.17(1.49 to 3.17) fold higher than people receiving l-VNS. Dyspnoea risk was also 2.45 (1.07 to 5.60) times that of l-VNS receipients, although the low number of events and studies meant that the certainty of evidence was low. The risk of rebound-withdrawal symptoms, coughing, pain and paraesthesia was unclear. Diet There is promising evidence that a ketogenic diet (high-fat, low-carbohydrate, adequate-protein) decreases the number of seizures and eliminates seizures in some; however, further research is necessary. It is a reasonable option in those who have epilepsy that is not improved with medications and for whom surgery is not an option. About 10% stay on the diet for a few years due to issues of effectiveness and tolerability. Side effects include stomach and intestinal problems in 30%, and there are long-term concerns about heart disease. Less radical diets are easier to tolerate and may be effective. It is unclear why this diet works. In people with coeliac disease or non-celiac gluten sensitivity and occipital calcifications, a gluten-free diet may decrease the frequency of seizures. Other Avoidance therapy consists of minimizing or eliminating triggers. For example, those who are sensitive to light may have success with using a small television, avoiding video games, or wearing dark glasses. Operant-based biofeedback based on the EEG waves has some support in those who do not respond to medications. Psychological methods should not, however, be used to replace medications.Exercise has been proposed as possibly useful for preventing seizures, with some data to support this claim. Some dogs, commonly referred to as seizure dogs, may help during or after a seizure. It is not clear if dogs have the ability to predict seizures before they occur.There is moderate-quality evidence supporting the use of psychological interventions along with other treatments in epilepsy. This can improve quality of life, enhance emotional wellbeing, and reduce fatigue in adults and adolescents. Psychological interventions may also improve seizure control for some individuals by promoting self-management and adherence.As an add-on therapy in those who are not well controlled with other medications, cannabidiol appears to be useful in some children. In 2018 the FDA approved this product for Lennox–Gastaut syndrome and Dravet syndrome.There are a few studies on the use of dexamethasone for the successful treatment of drug-resistant seizures in both adults and children In pregnancy In women of childbearing age, use of antiepileptic drugs is a major concern balancing possible side effects on the fetus against risk from uncontrolled seizures. Use of AEDs entail teratogenic effects including intrauterine growth retardation, major congenital malformations and developmental (neurocognitive) and behavioral issues, that need to be discussed with the patient at the time of starting the AEDs and before they plan pregnancy. Most women with epilepsy receive safe and effective treatment and have normal children, however risks exist. The International League Against Epilepsy created a task force on women and epilepsy which published consensus recommendations to guide therapy decisions until more definitive evidence is available in the future. Alternative medicine Alternative medicine, including acupuncture, routine vitamins, and yoga, have no reliable evidence to support their use in epilepsy. Melatonin, as of 2016, is insufficiently supported by evidence. The trials were of poor methodological quality and it was not possible to draw any definitive conclusions.Several supplements (with varied reliabilities of evidence) have been reported to be helpful for drug-resistant epilepsy. These include high-dose Omega-3, berberine, Manuka honey, Reishi and Lions Mane mushrooms, curcumin, vitamin E, coenzyme Q-10, and resveratrol. The reason these can work(in theory) is that they reduce inflammation or oxidative stress, two of the major mechanism contributing to epilepsy. Prognosis Epilepsy cannot usually be cured, but medication can control seizures effectively in about 70% of cases. Of those with generalized seizures, more than 80% can be well controlled with medications while this is true in only 50% of people with focal seizures. One predictor of long-term outcome is the number of seizures that occur in the first six months. Other factors increasing the risk of a poor outcome include little response to the initial treatment, generalized seizures, a family history of epilepsy, psychiatric problems, and waves on the EEG representing generalized epileptiform activity. In the developing world, 75% of people are either untreated or not appropriately treated. In Africa, 90% do not get treatment. This is partly related to appropriate medications not being available or being too expensive. Mortality People with epilepsy are at an increased risk of death. This increase is between 1.6 and 4.1 fold greater than that of the general population. The greatest increase in mortality from epilepsy is among the elderly. Those with epilepsy due to an unknown cause have little increased risk.Mortality is often related to: the underlying cause of the seizures, status epilepticus, suicide, trauma, and sudden unexpected death in epilepsy (SUDEP). Death from status epilepticus is primarily due to an underlying problem rather than missing doses of medications. The risk of suicide is between 2 and 6 times higher in those with epilepsy; the cause of this is unclear. SUDEP appears to be partly related to the frequency of generalized tonic-clonic seizures and accounts for about 15% of epilepsy-related deaths; it is unclear how to decrease its risk.In the United Kingdom, it is estimated that 40–60% of deaths are possibly preventable. In the developing world, many deaths are due to untreated epilepsy leading to falls or status epilepticus. Epidemiology Epilepsy is one of the most common serious neurological disorders affecting about 39 million people as of 2015. It affects 1% of the population by age 20 and 3% of the population by age 75. It is more common in males than females with the overall difference being small. Most of those with the disorder (80%) are in low income populations or the developing world.The estimated prevalence of active epilepsy (as of 2012) is in the range 3–10 per 1,000, with active epilepsy defined as someone with epilepsy who has had a least one unprovoked seizure in the last five years. Epilepsy begins each year in 40–70 per 100,000 in developed countries and 80–140 per 100,000 in developing countries. Poverty is a risk and includes both being from a poor country and being poor relative to others within ones country. In the developed world epilepsy most commonly starts either in the young or in the old. In the developing world its onset is more common in older children and young adults due to the higher rates of trauma and infectious diseases. In developed countries the number of cases a year has decreased in children and increased among the elderly between the 1970s and 2003. This has been attributed partly to better survival following strokes in the elderly. History The oldest medical records show that epilepsy has been affecting people at least since the beginning of recorded history. Throughout ancient history, the disease was thought to be a spiritual condition. The worlds oldest description of an epileptic seizure comes from a text in Akkadian (a language used in ancient Mesopotamia) and was written around 2000 BC. The person described in the text was diagnosed as being under the influence of a moon god, and underwent an exorcism. Epileptic seizures are listed in the Code of Hammurabi (c. 1790 BC) as reason for which a purchased slave may be returned for a refund, and the Edwin Smith Papyrus (c. 1700 BC) describes cases of individuals with epileptic convulsions.The oldest known detailed record of the disease itself is in the Sakikku, a Babylonian cuneiform medical text from 1067–1046 BC. This text gives signs and symptoms, details treatment and likely outcomes, and describes many features of the different seizure types. As the Babylonians had no biomedical understanding of the nature of disease, they attributed the seizures to possession by evil spirits and called for treating the condition through spiritual means. Around 900 BC, Punarvasu Atreya described epilepsy as loss of consciousness; this definition was carried forward into the Ayurvedic text of Charaka Samhita (about 400 BC).The ancient Greeks had contradictory views of the disease. They thought of epilepsy as a form of spiritual possession, but also associated the condition with genius and the divine. One of the names they gave to it was the sacred disease (ἠ ἱερὰ νόσος). Epilepsy appears within Greek mythology: it is associated with the Moon goddesses Selene and Artemis, who afflicted those who upset them. The Greeks thought that important figures such as Julius Caesar and Hercules had the disease. The notable exception to this divine and spiritual view was that of the school of Hippocrates. In the fifth century BC, Hippocrates rejected the idea that the disease was caused by spirits. In his landmark work On the Sacred Disease, he proposed that epilepsy was not divine in origin and instead was a medically treatable problem originating in the brain. He accused those of attributing a sacred cause to the disease of spreading ignorance through a belief in superstitious magic. Hippocrates proposed that heredity was important as a cause, described worse outcomes if the disease presents at an early age, and made note of the physical characteristics as well as the social shame associated with it. Instead of referring to it as the sacred disease, he used the term great disease, giving rise to the modern term grand mal, used for tonic–clonic seizures. Despite his work detailing the physical origins of the disease, his view was not accepted at the time. Evil spirits continued to be blamed until at least the 17th century.In Ancient Rome people did not eat or drink with the same pottery as that used by someone who was affected. People of the time would spit on their chest believing that this would keep the problem from affecting them. According to Apuleius and other ancient physicians, in order to detect epilepsy, it was common to light a piece of gagates, whose smoke would trigger the seizure. Occasionally a spinning potters wheel was used, perhaps a reference to photosensitive epilepsy.In most cultures, persons with epilepsy have been stigmatized, shunned, or even imprisoned. As late as in the second half of the 20th century, in Tanzania and other parts of Africa epilepsy was associated with possession by evil spirits, witchcraft, or poisoning and was believed by many to be contagious. In the Salpêtrière, the birthplace of modern neurology, Jean-Martin Charcot found people with epilepsy side by side with the mentally ill, those with chronic syphilis, and the criminally insane. In ancient Rome, epilepsy was known as the morbus comitialis (disease of the assembly hall) and was seen as a curse from the gods. In northern Italy, epilepsy was once traditionally known as Saint Valentines malady. In at least the 1840s in the United States of America, epilepsy was known as the falling sickness or the falling fits, and was considered a form of medical insanity. Around the same time period, epilepsy was known in France as the haut-mal (high evil), mal-de terre (earthen sickness), mal de Saint Jean (Saint Johns sickness), mal des enfans (child sickness), and mal-caduc (obsolete sickness). Patients of epilepsy in France were also known as tombeurs, or people who fall, due to the seizures and loss of consciousness in an epileptic episode.In the mid-19th century, the first effective anti-seizure medication, bromide, was introduced. The first modern treatment, phenobarbital, was developed in 1912, with phenytoin coming into use in 1938. Society and culture Stigma Stigma is commonly experienced, around the world, by those with epilepsy. It can affect people economically, socially and culturally. In India and China, epilepsy may be used as justification to deny marriage. People in some areas still believe those with epilepsy to be cursed. In parts of Africa, such as Tanzania and Uganda, epilepsy is claimed to be associated with possession by evil spirits, witchcraft, or poisoning and is incorrectly believed by many to be contagious. Before 1971 in the United Kingdom, epilepsy was considered grounds for the annulment of marriage. The stigma may result in some people with epilepsy denying that they have ever had seizures. Economics Seizures result in direct economic costs of about one billion dollars in the United States. Epilepsy resulted in economic costs in Europe of around 15.5 billion euros in 2004. In India epilepsy is estimated to result in costs of US$1.7 billion or 0.5% of the GDP. It is the cause of about 1% of emergency department visits (2% for emergency departments for children) in the United States. Vehicles Those with epilepsy are at about twice the risk of being involved in a motor vehicular collision and thus in many areas of the world are not allowed to drive or only able to drive if certain conditions are met. Diagnostic delay has been suggested to be a cause of some potentially avoidable motor vehicle collisions since at least one study showed that most motor vehicle accidents occurred in those with undiagnosed nonmotor seizures as opposed to those with motor seizures at epilepsy onset. In some places physicians are required by law to report if a person has had a seizure to the licensing body while in others the requirement is only that they encourage the person in question to report it himself. Countries that require physician reporting include Sweden, Austria, Denmark and Spain. Countries that require the individual to report include the UK and New Zealand, and physicians may report if they believe the individual has not already. In Canada, the United States and Australia the requirements around reporting vary by province or state. If seizures are well controlled most feel allowing driving is reasonable. The amount of time a person must be free from seizures before he can drive varies by country. Many countries require one to three years without seizures. In the United States the time needed without a seizure is determined by each state and is between three months and one year.Those with epilepsy or seizures are typically denied a pilot license. In Canada if an individual has had no more than one seizure, they may be considered after five years for a limited license if all other testing is normal. Those with febrile seizures and drug related seizures may also be considered. In the United States, the Federal Aviation Administration does not allow those with epilepsy to get a commercial pilot license. Rarely, exceptions can be made for persons who have had an isolated seizure or febrile seizures and have remained free of seizures into adulthood without medication. In the United Kingdom, a full national private pilot license requires the same standards as a professional drivers license. This requires a period of ten years without seizures while off medications. Those who do not meet this requirement may acquire a restricted license if free from seizures for five years. Support organizations There are organizations that provide support for people and families affected by epilepsy. The Out of the Shadows campaign, a joint effort by the World Health Organization, the International League Against Epilepsy and the International Bureau for Epilepsy, provides help internationally. In the United States, the Epilepsy Foundation is a national organization that works to increase the acceptance of those with the disorder, their ability to function in society and to promote research for a cure. The Epilepsy Foundation, some hospitals, and some individuals also run support groups in the United States. In Australia, the Epilepsy Foundation provides support, delivers education and training and funds research for people living with epilepsy. International Epilepsy Day (World Epilepsy Day) began in 2015 and occurs on the second Monday in February.Purple Day, a different world-wide epilepsy awareness day for epilepsy, was initiated by a nine-year-old Canadian named Cassidy Megan in 2008, and is every year on March 26. Research Seizure prediction and modeling Seizure prediction refers to attempts to forecast epileptic seizures based on the EEG before they occur. As of 2011, no effective mechanism to predict seizures has been developed. Kindling, where repeated exposures to events that could cause seizures eventually causes seizures more easily, has been used to create animal models of epilepsy. One of the hypotheses present in the literature is based on inflammatory pathways. Studies supporting this mechanism revealed that inflammatory, glycolipid, and oxidative factors are higher in epilepsy patients, especially those with generalized epilepsy. Potential future therapies Gene therapy is being studied in some types of epilepsy. Medications that alter immune function, such as intravenous immunoglobulins, are poorly supported by evidence. Noninvasive stereotactic radiosurgery is, as of 2012, being compared to standard surgery for certain types of epilepsy. Other animals Epilepsy occurs in a number of other animals including dogs and cats; it is in fact the most common brain disorder in dogs. It is typically treated with anticonvulsants such as phenobarbital or bromide in dogs and phenobarbital in cats. Imepitoin is also used in dogs. While generalized seizures in horses are fairly easy to diagnose, it may be more difficult in non-generalized seizures and EEGs may be useful. References Further reading External links Epilepsy at Curlie World Health Organization fact sheet "Epilepsy Basics: An Overview for Behavioral Health Providers". YouTube. Epilepsy Foundation. 30 May 2019. Archived from the original on 11 December 2021. "What To Do If Someone Has A Seizure - First Aid Training - St John Ambulance". YouTube. St John Ambulance. 1 February 2017. Archived from the original on 11 December 2021.
Brother	A brother is a man or boy who shares one or more parents with another; a male sibling. The female counterpart is a sister. Although the term typically refers to a familial relationship, it is sometimes used endearingly to refer to non-familial relationships. A full brother is a first degree relative. Overview The term brother comes from the Proto-Indo-European *bʰréh₂tēr, which becomes Latin frater, of the same meaning. Sibling warmth or affection between male siblings has been correlated to some more negative effects. In pairs of brothers, higher sibling warmth is related to more risk taking behaviour, although risk taking behaviour is not related to sibling warmth in any other type of sibling pair. The cause of this phenomenon in which sibling warmth is only correlated with risk taking behaviours in brother pairs still is unclear. This finding does, however, suggest that although sibling conflict is a risk factor for risk taking behaviour, sibling warmth does not serve as a protective factor. Some studies suggest that girls having an older brother delays the onset of menarche by roughly one year. Research also suggests that the likelihood of being gay increases with the more older brothers a man has. Some analyzers have suggested that a mans attractiveness to a heterosexual woman may increase with the more he resembles her brother, while his unattractiveness may increase the more his likeness diverges from her brother. Females with a twin or very close-in-age brother, sometimes view him as their male alter ego, or what they would have been like, if they had a Y chromosomes. Fraternal relationship The book Nicomachean Ethics, Book VIII written by Aristotle in 350 B.C.E., offers a way in which people should view the relationships between biological brothers. The relationship of brothers is laid out with the following quote: "The friendship of brothers has the characteristics found in that of comrades and in general between people who are like each other, is as much as they belong more to each other and start with a love for each other from their very birth, and in as much as those born to the same parents and brought up together and similarly educated are more akin in character; and the test of time has been applied most fully and convincingly in their case". For these reasons, it is the job of the older brother to influence the ethics of the younger brother by being a person of good action. Aristotle says "by imitating and reenacting the acts of good people, a child becomes habituated to good action". Over time the younger brother will develop the good actions of the older brother as well and be like him. Aristotle also adds this on the matter of retaining the action of doing good once imitated: "Once the habits of ethics or immorality become entrenched, they are difficult to break." The good habits that are created by the influence of the older brother become habit in the life of the younger brother and turn out to be seemingly permanent. It is the role of the older brother to be a positive influence on the development of the younger brothers upbringing when it comes to the education of ethics and good actions. When positive characteristics are properly displayed to the younger brother by the older brother, these habits and characteristics are imitated and foster an influential understanding of good ethics and positive actions. Famous brothers Gracchi, Ancient Roman reformers George Washington Adams, John Adams II, and Charles Francis Adams Sr., politicians Ben Affleck and Casey Affleck, actors The Alexander Brothers; musicians Alec Baldwin, William Baldwin, Stephen Baldwin, Daniel Baldwin, also known as the Baldwin brothers; actors John and Lionel Barrymore, actors Chang and Eng Bunker, the original Siamese twins George W. Bush, Jeb Bush, Neil Bush and Marvin Bush, sons of George H. W. Bush David Carradine, Keith Carradine, and Robert Carradine, American actors Bill Clinton, 42nd President of the United States, and Roger Clinton, Jr., his younger half-brother Joel and Ethan Coen; filmmakers Stephen Curry and Seth Curry; current NBA point guards in the Western Conference Dizzy and Daffy Dean, Major League Baseball pitchers Mark DeBarge, Randy DeBarge, El DeBarge, James DeBarge, and Bobby DeBarge, the male members of the singing group DeBarge Doud Eisenhower and John Eisenhower, sons of Dwight D. Eisenhower Emilio Estevez and Charlie Sheen, actors Isaac Everly and Phil Everly, The Everly Brothers, singers Liam Gallagher and Noel Gallagher, members of Oasis (band) Barry Gibb, Robin Gibb, and Maurice Gibb, members of the Brothers Gibb or "Bee Gees" singing group John Gotti, Eugene "Gene" Gotti, Peter Gotti and Richard V. Gotti, and Vincent Gotti, New York "made men" with the Gambino crime family Frederick Dent Grant, Ulysses S. Grant, and Jesse Root Grant Jacob Grimm and Wilhelm Grimm, known as the Brothers Grimm, German academics and folk tale collectors Matt Hardy and Jeff Hardy, professional wrestlers Herbert Hoover Jr. and Allan Hoover Pau and Marc Gasol, professional basketball players OKelly Isley, Jr., Rudolph Isley, and Ronald Isley, Ernie Isley, Marvin Isley, and Vernon Isley, members of The Isley Brothers singer-songwriting group and band, which also included their brother-in-law, Chris Jasper Jackie Jackson, Tito Jackson, Jermaine Jackson, Marlon Jackson, Michael Jackson and Randy Jackson, members of The Jackson 5 and later The Jacksons Jesse and Frank James, Old West outlaws John, Robert and Ted Kennedy, politicians Edward M. Kennedy Jr. and Patrick J. Kennedy, politicians Terry Labonte and Bobby Labonte, race car drivers Robert Todd Lincoln, Edward Baker Lincoln, William Wallace Lincoln and Tad Lincoln, sons of Abraham Lincoln Loud Brothers, piano designers and manufacturers Eli and Peyton Manning, National Football League quarterbacks Mario and Luigi, video game characters John McCain, U.S. Senator and two-time presidential candidate, and Joe McCain, American stage actor, newspaper reporter Justin, Travis, and Griffin McElroy, podcasters Billy Leon McCrary and Benny Loyd McCrary, wrestlers known as The McGuire Twins Harold Nixon, Richard Nixon, Donald Nixon, Arthur Nixon, and Edward Nixon Alan Osmond, Wayne Osmond, Merrill Osmond, Jay Osmond and Donny Osmond, members of The Osmonds Logan Paul and Jake Paul, YouTubers, internet personalities, and actors Neil and Ronald Reagan Ringling brothers, circus performers, owners, and show runners John D. Rockefeller and William Rockefeller, co-founders of Standard Oil and members of the Rockefeller family Cornelius Roosevelt and James I. Roosevelt Theodore Roosevelt Jr., Kermit Roosevelt, Archibald Bulloch Roosevelt, and Quentin Roosevelt James Roosevelt, Elliot Roosevelt, Franklin Delano Roosevelt Jr., and John Aspinwall Roosevelt Russo brothers, filmmakers, producers, and directors Daniel Sedin and Henrik Sedin, professional hockey players Wallace Shawn and Allen Shawn, writer and composer of The Fever Bobby Shriver, Timothy Shriver, Mark Shriver, and Anthony Shriver Thomas "Tommy" Smothers and Richard "Dick" Smothers, performing artists known as the Smothers Brothers Prabowo Subianto and Hashim Djojohadikusumo, politicians Fred Trump Jr., Donald Trump, and Robert Trump Vincent van Gogh, painter, and Theo van Gogh, art dealer J. J. Watt, T. J. Watt, Derek Watt, National Football League Players Damon Wayans, Dwayne Wayans, Keenan Ivory Wayans, Marlon Wayans, Shawn Wayans, performing artists, directors and producers Bob Weinstein and Harvey Weinstein, film producers Brian Wilson, Dennis Wilson, and Carl Wilson, members of The Beach Boys Marvin Winans, Carvin Winans, Michael Winans, and Ronald Winans, members of The Winans, singers and musicians Orville Wright and Wilbur Wright, known as the Wright brothers, pioneer aviators Agus Harimurti Yudhoyono and Edhie Baskoro Yudhoyono, politicians Other works about brothers In the Bible: Cain and Abel, the sons of Adam and Eve Jacob and Esau, the sons of Isaac and Rebecca Moses and Aaron, prophets Sts. Peter and Andrew, apostles Sts. James and John, apostles My Brother, My Brother, and Me, podcast Saving Private Ryan (1998), film Simon & Simon, television series Supernatural, American television series The Brothers Karamazov, novel The Wayans Bros., television series Bonanza (1959–1973), television series In the Ramayana: Rama, Lakshmana, Bharata, and Shatrughna In the Mahabharata: The Pandavas – Yudhishthira, Arjuna, Bhima, Sahadeva and Nakula The Kauravas – One hundred brothers including Duryodhana, Dushasana and Vikarna, among others See also Sister Brotherhood (disambiguation) Stepsibling References External links The dictionary definition of brother at Wiktionary
Pleural effusion	A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per kilogram weight per hour, and is cleared by lymphatic absorption leaving behind only 5–15 millilitres of fluid, which helps to maintain a functional vacuum between the parietal and visceral pleurae. Excess fluid within the pleural space can impair inspiration by upsetting the functional vacuum and hydrostatically increasing the resistance against lung expansion, resulting in a fully or partially collapsed lung. Various kinds of fluid can accumulate in the pleural space, such as serous fluid (hydrothorax), blood (hemothorax), pus (pyothorax, more commonly known as pleural empyema), chyle (chylothorax), or very rarely urine (urinothorax). When unspecified, the term "pleural effusion" normally refers to hydrothorax. A pleural effusion can also be compounded by a pneumothorax (accumulation of air in the pleural space), leading to a hydropneumothorax. Types Various methods can be used to classify pleural fluid. By the origin of the fluid: Serous fluid (hydrothorax) Blood (haemothorax) Chyle (chylothorax) Pus (pyothorax or empyema) Urine (urinothorax)By pathophysiology: Transudative pleural effusion Exudative pleural effusionBy the underlying cause (see next section). Causes Transudative The most common causes of transudative pleural effusion in the United States are heart failure and cirrhosis. Nephrotic syndrome, leading to the loss of large amounts of albumin in urine and resultant low albumin levels in the blood and reduced colloid osmotic pressure, is another less common cause of pleural effusion. Pulmonary emboli were once thought to cause transudative effusions, but have been recently shown to be exudative. The mechanism for the exudative pleural effusion in pulmonary thromboembolism is probably related to increased permeability of the capillaries in the lung, which results from the release of cytokines or inflammatory mediators (e.g. vascular endothelial growth factor) from the platelet-rich blood clots. The excessive interstitial lung fluid traverses the visceral pleura and accumulates in the pleural space.Conditions associated with transudative pleural effusions include: Congestive heart failure Liver cirrhosis Severe hypoalbuminemia Nephrotic syndrome Acute atelectasis Myxedema Peritoneal dialysis Meigss syndrome Obstructive uropathy End-stage kidney disease Exudative When a pleural effusion has been determined to be exudative, additional evaluation is needed to determine its cause, and amylase, glucose, pH and cell counts should be measured. Red blood cell counts are elevated in cases of bloody effusions (for example after heart surgery or hemothorax from incomplete evacuation of blood). Amylase levels are elevated in cases of esophageal rupture, pancreatic pleural effusion, or cancer. Glucose is decreased with cancer, bacterial infections, or rheumatoid pleuritis. pH is low in empyema (<7.2) and maybe low in cancer. If cancer is suspected, the pleural fluid is sent for cytology. If cytology is negative, and cancer is still suspected, either a thoracoscopy, or needle biopsy of the pleura may be performed. Gram staining and culture should also be done. If tuberculosis is possible, examination for Mycobacterium tuberculosis (either a Ziehl–Neelsen or Kinyoun stain, and mycobacterial cultures) should be done. A polymerase chain reaction for tuberculous DNA may be done, or adenosine deaminase or interferon gamma levels may also be checked.The most common causes of exudative pleural effusions are bacterial pneumonia, cancer (with lung cancer, breast cancer, and lymphoma causing approximately 75% of all malignant pleural effusions), viral infection, and pulmonary embolism. Another common cause is after heart surgery when incompletely drained blood can lead to an inflammatory response that causes exudative pleural fluid. Conditions associated with exudative pleural effusions: Parapneumonic effusion due to pneumonia Malignancy (either lung cancer or metastases to the pleura from elsewhere) Infection (empyema due to bacterial pneumonia) Trauma Pulmonary infarction Pulmonary embolism Autoimmune disorders Pancreatitis Ruptured esophagus (Boerhaaves syndrome) Rheumatoid pleurisy Drug-induced lupus Other/ungrouped Other causes of pleural effusion include tuberculosis (though stains of pleural fluid are only rarely positive for acid-fast bacilli, this is the most common cause of pleural effusions in some developing countries), autoimmune disease such as systemic lupus erythematosus, bleeding (often due to chest trauma), chylothorax (most commonly caused by trauma), and accidental infusion of fluids. Less common causes include esophageal rupture or pancreatic disease, intra-abdominal abscesses, rheumatoid arthritis, asbestos pleural effusion, mesothelioma, Meigss syndrome (ascites and pleural effusion due to a benign ovarian tumor), and ovarian hyperstimulation syndrome.Pleural effusions may also occur through medical or surgical interventions, including the use of medications (pleural fluid is usually eosinophilic), coronary artery bypass surgery, abdominal surgery, endoscopic variceal sclerotherapy, radiation therapy, liver or lung transplantation, insertion of ventricular shunt as a treatment method of hydrocephalus, and intra- or extravascular insertion of central lines. Pathophysiology Pleural fluid is secreted by the parietal layer of the pleura and reabsorbed by the lymphatics in the most dependent parts of the parietal pleura, primarily the diaphragmatic and mediastinal regions. Exudative pleural effusions occur when the pleura is damaged, e.g., by trauma, infection, or malignancy, and transudative pleural effusions develop when there is either excessive production of pleural fluid or the resorption capacity is reduced. Lights criteria can be used to differentiate between exudative and transudative pleural effusions. Diagnosis A pleural effusion is usually diagnosed on the basis of medical history and physical exam, and confirmed by a chest X-ray. Once accumulated fluid is more than 300 mL, there are usually detectable clinical signs, such as decreased movement of the chest on the affected side, dullness to percussion over the fluid, diminished breath sounds on the affected side, decreased vocal resonance and fremitus (though this is an inconsistent and unreliable sign), and pleural friction rub. Above the effusion, where the lung is compressed, there may be bronchial breathing sounds and egophony. A large effusion there may cause tracheal deviation away from the effusion. A systematic review (2009) published as part of the Rational Clinical Examination Series in the Journal of the American Medical Association showed that dullness to conventional percussion was most accurate for diagnosing pleural effusion (summary positive likelihood ratio, 8.7; 95% confidence interval, 2.2–33.8), while the absence of reduced tactile vocal fremitus made pleural effusion less likely (negative likelihood ratio, 0.21; 95% confidence interval, 0.12–0.37). Imaging A pleural effusion appears as an area of whiteness on a standard posteroanterior chest X-ray. Normally, the space between the visceral pleura and the parietal pleura cannot be seen. A pleural effusion infiltrates the space between these layers. Because the pleural effusion has a density similar to water, it can be seen on radiographs. Since the effusion has greater density than the rest of the lung, it gravitates towards the lower portions of the pleural cavity. The pleural effusion behaves according to basic fluid dynamics, conforming to the shape of pleural space, which is determined by the lung and chest wall. If the pleural space contains both air and fluid, then an air-fluid level that is horizontal will be present, instead of conforming to the lung space. Chest radiographs in the lateral decubitus position (with the patient lying on the side of the pleural effusion) are more sensitive and can detect as little as 50 mL of fluid. Between 250 and 600mL of fluid must be present before upright chest X-rays can detect a pleural effusion (e.g., blunted costophrenic angles).Chest computed tomography is more accurate for diagnosis and may be obtained to better characterize the presence, size, and characteristics of a pleural effusion. Lung ultrasound, nearly as accurate as CT and more accurate than chest X-ray, is increasingly being used at the point of care to diagnose pleural effusions, with the advantage that it is a safe, dynamic, and repeatable imaging modality. To increase diagnostic accuracy of detection of pleural effusion sonographically, markers such as boomerang and VIP signs can be utilized. Thoracentesis Once a pleural effusion is diagnosed, its cause must be determined. Pleural fluid is drawn out of the pleural space in a process called thoracentesis, and it should be done in almost all patients who have pleural fluid that is at least 10 mm in thickness on CT, ultrasonography, or lateral decubitus X-ray and that is new or of uncertain etiology. In general, the only patients who do not require thoracentesis are those who have heart failure with symmetric pleural effusions and no chest pain or fever; in these patients, diuresis can be tried, and thoracentesis is avoided unless effusions persist for more than 3 days. In a thoracentesis, a needle is inserted through the back of the chest wall in the sixth, seventh, or eighth intercostal space on the midaxillary line, into the pleural space. The use of ultrasound to guide the procedure is now standard of care as it increases accuracy and decreases complications. After removal, the fluid may then be evaluated for: Chemical composition including protein, lactate dehydrogenase (LDH), albumin, amylase, pH, and glucose Gram stain and culture to identify possible bacterial infections White and red blood cell counts and differential white blood cell counts Cytopathology to identify cancer cells, but may also identify some infective organisms Other tests as suggested by the clinical situation – lipids, fungal culture, viral culture, tuberculosis cultures, lupus cell prep, specific immunoglobulins Lights criteria Definitions of the terms "transudate" and "exudate" are the source of much confusion. Briefly, transudate is produced through pressure filtration without capillary injury while exudate is "inflammatory fluid" leaking between cells.Transudative pleural effusions are defined as effusions that are caused by systemic factors that alter the pleural equilibrium, or Starling forces. The components of the Starling forces – hydrostatic pressure, permeability, and oncotic pressure (effective pressure due to the composition of the pleural fluid and blood) – are altered in many diseases, e.g., left ventricular failure, kidney failure, liver failure, and cirrhosis. Exudative pleural effusions, by contrast, are caused by alterations in local factors that influence the formation and absorption of pleural fluid (e.g., bacterial pneumonia, cancer, pulmonary embolism, and viral infection).An accurate diagnosis of the cause of the effusion, transudate versus exudate, relies on a comparison of the chemistries in the pleural fluid to those in the blood, using Lights criteria. According to Lights criteria (Light, et al. 1972), a pleural effusion is likely exudative if at least one of the following exists: The ratio of pleural fluid protein to serum protein is greater than 0.5 The ratio of pleural fluid LDH and serum LDH is greater than 0.6 Pleural fluid LDH is greater than 0.6 or 2⁄3 times the normal upper limit for serum. Different laboratories have different values for the upper limit of serum LDH, but examples include 200 and 300 IU/l.The sensitivity and specificity of Lights criteria for detection of exudates have been measured in many studies and are usually reported to be around 98% and 80%, respectively. This means that although Lights criteria are relatively accurate, twenty percent of patients that are identified by Lights criteria as having exudative pleural effusions actually have transudative pleural effusions. Therefore, if a patient identified by Lights criteria as having an exudative pleural effusion appears clinically to have a condition that usually produces transudative effusions, additional testing is needed. In such cases, albumin levels in blood and pleural fluid are measured. If the difference between the albumin level in the blood and the pleural fluid is greater than 1.2 g/dL (12 g/L), this suggests that the patient has a transudative pleural effusion. However, pleural fluid testing is not perfect, and the final decision about whether a fluid is a transudate or an exudate is based not on chemical analysis of the fluid, but an accurate diagnosis of the disease that produces the fluid. The traditional definitions of transudate as a pleural effusion due to systemic factors and an exudate as a pleural effusion due to local factors have been used since 1940 or earlier (Light et al., 1972). Previous to Lights landmark study, which was based on work by Chandrasekhar, investigators unsuccessfully attempted to use other criteria, such as specific gravity, pH, and protein content of the fluid, to differentiate between transudates and exudates. Lights criteria are highly statistically sensitive for exudates (although not very statistically specific). More recent studies have examined other characteristics of pleural fluid that may help to determine whether the process producing the effusion is local (exudate) or systemic (transudate). The table above illustrates some of the results of these more recent studies. However, it should be borne in mind that Lights criteria are still the most widely used criteria.The Rational Clinical Examination Series review found that bilateral effusions, symmetric and asymmetric, are the most common distribution in heart failure (60% of effusions in heart failure will be bilateral). When there is asymmetry in heart failure-associated pleural effusions (either unilateral or one side larger than the other), the right side is usually more involved than the left. The instruments pictured are accurately shaped, however, most hospitals now use safer disposable trocars. Because these are single use, they are always sharp and have a much smaller risk of cross patient contamination. Treatment Treatment depends on the underlying cause of the pleural effusion. Therapeutic aspiration may be sufficient; larger effusions may require insertion of an intercostal drain (either pigtail or surgical). When managing these chest tubes, it is important to make sure the chest tubes do not become occluded or clogged. A clogged chest tube in the setting of continued production of fluid will result in residual fluid left behind when the chest tube is removed. This fluid can lead to complications such as hypoxia due to lung collapse from the fluid, or fibrothorax if scarring occurs. Repeated effusions may require chemical (talc, bleomycin, tetracycline/doxycycline), or surgical pleurodesis, in which the two pleural surfaces are scarred to each other so that no fluid can accumulate between them. This is a surgical procedure that involves inserting a chest tube, then either mechanically abrading the pleura or inserting the chemicals to induce a scar. This requires the chest tube to stay in until the fluid drainage stops. This can take days to weeks and can require prolonged hospitalizations. If the chest tube becomes clogged, fluid will be left behind and the pleurodesis will fail.Pleurodesis fails in as many as 30% of cases. An alternative is to place a PleurX Pleural Catheter or Aspira Drainage Catheter. This is a 15Fr chest tube with a one-way valve. Each day the patient or caregivers connect it to a simple vacuum tube and remove from 600 to 1000 mL of fluid, and can be repeated daily. When not in use, the tube is capped. This allows patients to be outside the hospital. For patients with malignant pleural effusions, it allows them to continue chemotherapy if indicated. Generally, the tube is in for about 30 days, and then it is removed when space undergoes spontaneous pleurodesis. Tubercular pleural effusion is one of the common extrapulmonary forms of tuberculosis. Treatment consists of antituberculosis treatment (ATT). The currently recommended ATT regime is two months of isoniazid, rifampicin, ethambutol and pyrazinamide followed by four months of isoniazid, rifampicin and ethambutol. See also Pleural disease Empyema Heart failure Pulmonary embolism Subpulmonic effusion Thoracentesis References External links MedlinePlus Encyclopedia: Pleural Effusion Pleural Effusion Images from MedPix
Lennox–Gastaut syndrome	Lennox–Gastaut syndrome (LGS) is a complex, rare, and severe childhood-onset epilepsy. It is characterized by multiple and concurrent seizure types, cognitive dysfunction, and slow spike waves on electroencephalogram (EEG). Typically, it presents in children aged 3–5 years and can persist into adulthood. It has been associated with several gene mutations, perinatal injuries, congenital infections, brain tumors/malformations, and genetic disorders such as tuberous sclerosis and West syndrome. The prognosis for LGS is poor with a 5% mortality in childhood and persistent seizures into adulthood (80%–90%).LGS was named for neurologists William G. Lennox (Boston, USA) and Henri Gastaut (Marseille, France), who independently described the condition. The international LGS Awareness Day is on November 1. Signs and symptoms The symptoms vary and progress with age and are characterized by a triad of seizures, cognitive dysfunction, and EEG findings. The triad may not fully emerge until 1–2 years after first seizure episode. Seizures The peak age of onset of seizures is typically between 3 and 5 years of age. The mainstay symptoms are seizures that are frequent – occurring daily and difficult to treat with antiseizure medications. An estimated 30% of patients with infantile spasms (West syndrome) have been reported to progress with LGS.The seizures are most commonly tonic seizures. They occur most frequently during non-REM sleep (90%). They initially last only a few seconds and are activated by sleep. The presentation can be subtle. They present often as tonic eyelid opening with some changes in breathing coupled with pupillary dilation, urinary incontinence, increased heart rate, and flushing can occur.Nonconvulsive status epilepticus occurs in about 50% of patients. The seizures can cause sudden falling often leading to injury. These "drop attacks" are typically the first manifestation of LGS. The attacks are characterized by a single, generalized monoclonic jerk that precedes tonic contraction of axial muscles. EEG findings Findings that strongly suggest LGS include consistent slow spike-wave (< 3 hertz [Hz]) on awake EEG. The complexes typically consist of a spike (duration < 70 milliseconds) or a sharp wave (70-200 milliseconds), followed first by a positive deep trough, then a negative wave (350-400 milliseconds). Not every wave is preceded by a spike. Bursts increase and decrease without clear onset and offset. Slow spike waves may occur during seizure or between seizures, or may occur in absence of any observable clinical changes which helps distinguish pattern from extended 3-Hz spike-wave discharges. Ocular abnormality Ocular abnormalities affect around 90% of children. They can present as refractive error, strabismus, cortical visual impairment, and premature retinopathy. Causes The disease pathophysiology is mostly unknown, but some evidence implicates cortical hyperexcitability occurring at critical periods of brain development.There are two types of LGS: idiopathic and secondary. The cause of the idiopathic subtype is unknown. Secondary LGS occurs when an identifiable underlying pathology is responsible. The most common type of LGS (70–78%) is secondary. These patients tend to have a worse prognosis than those with idiopathic LGS. In up to one-third of cases no cause can be found. Brain injury Lennox–Gastaut most often occurs secondary to brain damage. The brain damage can occur from perinatal insults, encephalitis, meningitis, tumor, and brain malformation. Genetic mutations Other identified disorders include genetic disorders such as tuberous sclerosis and inherited deficiency of methylene tetrahydrofolate reductase. Some of these cases once thought to be of unknown cause may have definitive etiology by modern genetic testing.Progress in genome and exome sequencing is revealing that some individuals diagnosed with Lennox-Gastaut Syndrome have de novo mutations in a variety of genes, including CHD2, GABRB3, ALG13 and SCN2A. The Epi4K study consortium (2013) observed de novo mutations in at least 15% of a study cohort of 165 patients with LGS and infantile spasms using whole exome sequencing. A 2013 study found a high frequency of rare copy-number variation (CNVs) in adult patients with LGS or LGS-like epilepsy.Mutations in the IQSEC2 gene have been associated with this syndrome. This gene is located on the short arm of the X chromosome (Xp11.22). Diagnosis The diagnosis of LGS should be suspected in children less than 8 years old with seizures of multiple types that cannot be treated with antiseizure medications. Because of high risk of irreversible brain damage in early stages of syndrome (particularly in infants and young children), early diagnosis is essential. It may take 1–2 years after first initial seizure for all criteria for diagnosis to emerge, so LGS should be considered if there are suggestive signs and symptoms without presence of complete triad.To confirm diagnosis, awake and asleep EEG and magnetic resonance imaging (MRI) are performed. MRI is used to detect focal brain lesions. Ruling out other diagnoses Certain diagnoses must be ruled out before diagnosing LGS. These diagnoses are: Doose syndrome Dravet syndrome pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy)LGS is more easily distinguished from Doose syndrome by seizure type after the syndrome has progressed. Doose syndrome has more myoclonic seizures and LGS has more tonic seizures. The Doose syndromes is less likely to have cognitive disabilities.Pseudo-Lennox–Gastaut syndrome can be distinguished from LGS because pseudo-LGS has different spike-and-wave patterns on EEG. Treatment There are several treatment options, including medications, surgery, and diet. Medications In most patients with LGS, the treatment does not end seizure recurrence. The goals of treatment are to lower frequency and severity of seizures to greatest extent possible. There are no studies using only one medication. Lamotrigine and rufinamide used as add-ons are very effective in reducing overall seizures, but do not stop them.The treatments for LGS has evolved over the years. Various treatments have been shown to have some degree of efficacy. In 1997–1999, lamotrigine was found to be effective and approved by the Food and Drug Administration and Health Canada. In 1999, topiramate trials showed that topiramate decreased seizure occurrence by more than 50%.Felbamate is the treatment of last resort in the event that everything else fails, and was found to be superior to placebo in controlling treatment resistant partial seizures and atonic seizures. However, it has been known to cause aplastic anemia and liver toxicity. First-line drugs valproate (valproic acid, sodium valproate and valproate semisodium) Second-line drugs lamotrigineThird-line drugs rufinamide topiramateTreatment of last resort felbamate Adjuvant drugs Are the following: benzodiazepines, specifically clonazepam, nitrazepam, and clobazam zonisamide cannabidiol Surgery In the past, LGS patients were not eligible for surgery, as the medical community thought it to involve the whole brain as a generalized epilepsy in all cases. Since 2010, this assumption has been challenged. Two studies on LGS patients series who underwent curative surgery in Korea and China, showed very good results, up to seizure freedom for 80% of these patients below 5 years old, and 40% above 5 years old. Like all epilepsy curative surgeries, seizures may recur in the years following surgery, but surgery allows the child to have better brain development during the seizure free period.There are several procedures that have shown efficacy: vagus nerve stimulation, which involves implantation of battery-operated generator of intermittent electrical stimuli to an electrode wrapped around left vagus nerve. Some studies have been shown it to have greater than 50% reduction in seizures reported in more than half of patients. corpus callosotomy, which has shown to be effective with atonic seizures. This procedure is considered in cases in which vagus nerve stimulation has failed transcranial direct current stimulation resection Diet A ketogenic diet is a diet that causes ketosis, a state in which there is an increased amount of ketones in the body. Adopting and maintaining rigid diet may be difficult for some families. Short-term ketogenic diet might be associated with nonsignificant decreases in frequency of parent-reported seizures in children with LGS. A case series study showed 50% seizure reduction reported in almost half of children with LGS after 1 year of ketogenic diet. However, the strength of the study is challenged because it represents reports rather than scientific analysis of the clinical outcomes such as in a randomized controlled trial. Prognosis The mortality rate ranges from 3–7% in a mean follow up period of 8.5 to 9.7 years. Death is often related to accidents. Epidemiology LGS is seen in approximately 4% of children with epilepsy, and is more common in males than in females. Usual onset is between the ages of three and five. Children can have no neurological problems prior diagnosis, or have other forms of epilepsy. West syndrome is diagnosed in 20% of patients before it evolves into LGS at about 2 years old. Finland According to a 1997 community-based retrospective study in the Helsinki metropolitan area and the province of Uusimaa, the annual incidence of Lennox–Gastaut was 2 in 100,000 (0.002%) from 1975 to 1985. United States 0.026% of all children in the Atlanta, Georgia metropolitan area were estimated to have LGS in 1997, which was defined as, "onset of multiple seizure types before age 11 years, with at least one seizure type resulting in falls, and an EEG demonstrating slow spike-wave complexes (<2.5 Hz)." The study concluded that LGS accounts for 4% of childhood epilepsies. Research Vigabatrin was found by Feucht et al. to be an effective add-on in patients whose seizures were not satisfactorily controlled by valproate. Out of 20 children, only 1 experienced a serious side effect (dyskinesia).Zonisamide showed promise in an overview of controlled and uncontrolled trials conducted in Japan. However, in a physician survey conducted December 2004, only 28% of Lennox–Gastaut and West syndrome patients improved on zonisamide.One yet to be published study from 2017 supported the use of cannabidiol. A study published in the New England Journal of Medicine has shown a significant reduction of seizures in patients taking 10 and 20 mg/kg a day compared to placebo. References == External links ==
Hyperprolactinaemia	Hyperprolactinaemia is the presence of abnormally high levels of prolactin in the blood. Normal levels average to about 13 ng/mL in women, and 5 ng/mL in men, with an upper normal limit of serum prolactin levels being 15-25 ng/mL for both. When the fasting levels of prolactin in blood exceed this upper limit, hyperprolactinemia is indicated. Prolactin (PRL) is a peptide hormone produced by lactotroph cells in the anterior pituitary gland. PRL is involved in lactation after pregnancy and plays a vital role in breast development. Hyperprolactinemia may cause galactorrhea (production and spontaneous flow of breast milk), infertility, and disruptions in the normal menstrual period in women; as well as hypogonadism, infertility and erectile dysfunction in men. Although hyperprolactinemia can result from normal physiological changes during pregnancy and breastfeeding, it can also be caused by other etiologies. For example, high prolactin levels could result from diseases affecting the hypothalamus and pituitary gland. Other organs, such as the liver and kidneys, could affect prolactin clearance and consequently, prolactin levels in the serum. The disruption of prolactin regulation could also be attributed to external sources such as medications.In the general population, the prevalence of hyperprolactinemia is 0.4%. The prevalence increases to as high as 17% in women with reproductive diseases, such as polycystic ovary syndrome. In cases of tumor-related hyperprolactinemia, prolactinoma is the most common culprit of consistently high levels of prolactin as well as the most common type of pituitary tumor. For non-tumor related hyperprolactinemia, the most common cause is medication-induced prolactin secretion. Particularly, antipsychotics have been linked to a majority of non-tumor related hyperprolactinemia cases due to their prolactin-rising and prolactin-sparing mechanisms. Typical antipsychotics have been shown to induce significant, dose-dependent increases in prolactin levels up to 10-fold the normal limit. Atypical antipsychotics vary in their ability to elevate prolactin levels, however, medications in this class such as risperidone and paliperidone carry the highest potential to induce hyperprolactinemia in a dose-dependent manner similar to typical antipsychotics. Signs and symptoms In women, high blood levels of prolactin are typically associated with hypoestrogenism, anovulatory infertility, and changes in menstruation. Menstruation disturbances experienced in women commonly manifests as amenorrhea or oligomenorrhea. In the latter case, irregular menstrual flow may result in abnormally heavy and prolonged bleeding (menorrhagia). Women who are not pregnant or nursing may also unexpectedly begin producing breast milk (galactorrhea), a condition that is not always associated with high prolactin levels. For instance, many premenopausal women experiencing hyperprolactinemia do not experience galactorrhea and only some women who experience galactorrhea will be diagnosed with hyperprolactinemia. Thus, galactorrhea may be observed in individuals with normal prolactin levels and does not necessarily indicate hyperprolactinemia. This phenomenon is likely due to galactorrhea requiring adequate levels of progesterone or estrogen to prepare the breast tissue. Additionally, some women may also experience loss of libido and breast pain, particularly when prolactin levels rise initially, as the hormone promotes tissue changes in the breast.In men, the most common symptoms of hyperprolactinemia are decreased libido, sexual dysfunction, erectile dysfunction/impotence, infertility, and gynecomastia. Unlike women, men do not experience reliable indicators of elevated prolactin such as menstruation to prompt immediate medical consultation. As a result, the early signs of hyperprolactinemia are generally more difficult to detect and may go unnoticed until more severe symptoms are present. For instance, symptoms such as loss of libido and sexual dysfunction are subtle, arise gradually, and may falsely indicate a differential cause. Many men with pituitary tumor-associated hyperprolactinemia may forego clinical help until they begin to experience serious endocrine and vision complications, such as major headaches or eye problems.Long-term hyperprolactinaemia can lead to detrimental changes in bone metabolism as a result of hypoestrogenism and hypoandrogenism. Studies have shown that chronically elevated prolactin levels lead to increased bone resorption and suppression of bone formation, leading to reduced bone density, increased risk of fractures, and increased risk of osteoporosis. The chronic presence of hyperprolactinemia can lead to hypogonadism and osteolysis in men. Causes Prolactin secretion is regulated by both stimulatory and inhibitory mechanisms. Dopamine acts on pituitary lactotroph D2 receptors to inhibit prolactin secretion while other peptides and hormones, such as thyrotropin releasing hormone (TRH), stimulate prolactin secretion. As a result, hyperprolactinemia may be caused by disinhibition (e.g., compression of the pituitary stalk or reduced dopamine levels) or excess production. The most common cause of hyperprolactinemia is prolactinoma (a type of pituitary adenoma). A blood serum prolactin level of 1000–5000 mIU/L (47-235 ng/mL) may arise from either mechanism, however levels >5000 mIU/L (>235 ng/mL) is likely due to the activity of an adenoma. Prolactin blood levels are typically correlated to the size the tumors. Pituitary tumors smaller than 10 mm in diameter, or microadenomas, tend to have prolactin levels <200 ng/mL. Macroadenomas larger than 10 mm in diameter possess prolactin >1000 ng/mL.Hyperprolactinemia inhibits the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn inhibits the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland and results in diminished gonadal sex hormone production (termed hypogonadism). This is the cause of many of the symptoms described below. In many people, elevated prolactin levels remain unexplained and may represent a form of hypothalamic–pituitary–adrenal axis dysregulation. Physiological causes Physiological (i.e., non-pathological) causes include: ovulation, pregnancy, breastfeeding, chest wall injury, stress, stress-associated REM sleep, and exercise. During pregnancy, prolactin levels can range up to 600 ng/mL, depending on estrogen concentration. At 6 weeks post-birth (postpartum), estradiol concentrations decrease, and prolactin concentrations return to normal even during breastfeeding. Stress-related factors include physical, exercise, hypoglycemia, myocardial infarction, and surgery. Coitus and sleep can also contribute to an increased prolactin release. Medications Prolactin secretion in the pituitary is normally suppressed by the brain chemical dopamine, which binds to dopamine receptors. Drugs that block the effects of dopamine at the pituitary or deplete dopamine stores in the brain may cause the pituitary to secrete prolactin without an inhibitory effect. These drugs include the typical antipsychotics: phenothiazines such as chlorpromazine (Thorazine), and butyrophenones such as haloperidol (Haldol); atypical antipsychotics such as risperidone (Risperdal) and paliperidone (Invega); gastroprokinetic drugs used to treat gastro-esophageal reflux and medication-induced nausea (such as that from chemotherapy): metoclopramide (Reglan) and domperidone; less often, alpha-methyldopa and reserpine, used to control hypertension; and TRH. The use of estrogen-containing oral contraceptives are also known to increase prolactin levels when taken in high doses >35 μg. The sleep drug ramelteon (Rozerem) also increases the risk of hyperprolactinaemia. Particularly, the dopamine antagonists metoclopramide and domperidone are both powerful prolactin stimulators and have been used to stimulate breast milk secretion for decades. However, since prolactin is antagonized by dopamine and the body depends on the two being in balance, the risk of prolactin stimulation is generally present with all drugs that deplete dopamine, either directly or as a rebound effect. Specific diseases Prolactinoma or other tumors arising in or near the pituitary — such as those that cause acromegaly may block the flow of dopamine from the brain to the prolactin-secreting cells, likewise, division of the pituitary stalk or hypothalamic disease. Other causes include chronic kidney failure, hypothyroidism, bronchogenic carcinoma and sarcoidosis. Some women with polycystic ovary syndrome may have mildly-elevated prolactin levels. Nonpuerperal mastitis may induce transient hyperprolactinemia (neurogenic hyperprolactinemia) of about three weeks duration; conversely, hyperprolactinemia may contribute to nonpuerperal mastitis.Apart from diagnosing hyperprolactinemia and hypopituitarism, prolactin levels are often checked by physicians in those who have had a seizure, when there is need to differentiate between epileptic seizure or a non-epileptic seizure. Shortly after epileptic seizures, prolactin levels often rise, whereas they are normal in non-epileptic seizures. Diagnosis An appropriate diagnosis of hyperprolactinemia starts with conducting a complete clinical history before performing any treatment. Physiological causes, systemic disorders, and the use of certain drugs must be ruled out before the condition is diagnosed. Screening is indicated for those who are asymptomatic and those with elevated prolactin without an associated cause. The most common causes of hyperprolactinemia are prolactinomas, drug-induced hyperprolactinemia, and macroprolactinemia. Individuals with hyperprolactinemia may present with symptoms including galactorrhea, hypogonadism effects, and/or infertility. The magnitude that prolactin is elevated can be used as an indicator of the etiology of the hyperprolactinemia diagnosis. Prolactin levels over 250 ng/mL may suggest prolactinoma. Prolactin levels less than 100 ng/mL may suggest drug-induced hyperprolactinemia, macroprolactinemia, nonfunctioning pituitary adenomas, or systemic disorders.Elevated prolactin blood levels are typically assessed in women with unexplained breast milk secretion (galactorrhea) or irregular menses or infertility, and in men with impaired sexual function and milk secretion. If high prolactin levels are present, all known conditions and medications which raises prolactin secretion must be assessed and excluded for diagnosis. After ruling out other causes and prolactin levels remain high, TSH levels are assessed. If TSH levels are elevated, hyperprolactinemia is secondary to hypothyroidism and treated accordingly. If TSH levels are normal, an MRI or CT scan is conducted to assess for any pituitary adenomas. Although hyperprolactinemia is often uncommon in postmenopausal women, prolactinomas detected after menopause are typically macroadenomas. While a plain X-ray of the bones surrounding the pituitary may reveal the presence of a large macroadenoma, small microadenomas will not be apparent. Magnetic resonance imaging (MRI) is the most sensitive test for detecting pituitary tumors and determining their size. MRI scans may be repeated periodically to assess tumor progression and the effects of therapy. Computed Tomography (CT scan) is another indicator of abnormalities in pituitary gland size; it also gives an image of the pituitary, but is less sensitive than the MRI. In addition to assessing the size of the pituitary tumor, physicians also look for damage to surrounding tissues, and perform tests to assess whether production of other pituitary hormones are normal. Depending on the size of the tumor, physicians may request an eye exam that includes the measurement of visual fields.However, a high measurement of prolactin may also result from the presence of macroprolactin, otherwise known as big prolactin or big-big prolactin, in the serum. Macroprolactin occurs when prolactin polymerizes together and can bind with IgG to form complexes. Although this can result in high prolactin levels in some assay tests, macroprolactin is biologically inactive and will not cause symptoms typical of hyperprolactinemia. In those who are asymptomatic or without obvious causes of hyperprolactinemia, macroprolactin should be assessed and ruled out. Treatment Treatment for hyperprolactinemia is usually dependent upon its cause, ranging from hypothyroidism, drug-induced hyperprolactinemia, hypothalamic disease, idiopathic hyperprolactinemia, macroprolactin, or prolactinoma. Therefore, in order to provide the proper management of hyperprolactinemia, the pathological form and physiological increase in prolactin levels are differentiated, and the correct cause of hyperprolactinemia must be identified before treatment. For functional asymptomatic hyperprolactinemia, the treatment of choice is removing the associated cause, including antipsychotic therapy. However, prolactin levels should be drawn and monitored both prior to any discontinuation or changes to therapy, and afterwards. With symptomatic hyperprolactinemia, stopping antipsychotic drugs for a short trial period are not recommended due to the risk of exacerbation or relapse of symptoms. Options for treatment include decreasing the dose of antipsychotics, adding aripiprazole as an adjunctive therapy, and switching antipsychotics as a last resort. In pharmacologic hyperprolactinemia, the concerning drug can be switched to another treatment or discontinued entirely. Vitex agnus-castus extract may be tried in cases of mild hyperprolactinemia. No treatment is required in asymptomatic macroprolactin and instead, serial prolactin measurements and pituitary imaging is monitored in a regular follow-up appointments.Medical therapy is the preferred treatment in prolactinomas. In most cases, medications that are dopamine agonists, such as cabergoline and bromocriptine (often preferred when pregnancy is possible), are the treatment of choice used to decrease prolactin levels and tumor size upon the presence of microadenomas or macroadenomas. A systematic review and meta-analyses has shown that cabergoline is more effective in treatment of hyperprolactinemia than bromocriptine. Other dopamine agonists that have been used less commonly to suppress prolactin include dihydroergocryptine, ergoloid, lisuride, metergoline, pergolide, quinagolide, and terguride. If the prolactinoma does not initially respond to dopamine agonist therapy, such that prolactin levels are still high or the tumor is not shrinking as expected, the dose of the dopamine agonist can be increased in a stepwise fashion to the maximum tolerated dose. Another option is to consider switching between dopamine agonists. It is possible for the prolactinoma to be resistant to bromocriptine but respond well to cabergoline and vice versa. Surgical therapy can be considered if pharmacologic options have been exhausted.There is evidence to support improvement in outcomes of hyperprolactinemic individuals who have shown to be resistant to or intolerant of the treatment of choice, dopamine agonists, through radiotherapy and surgery. See also Hypothalamic–pituitary–prolactin axis Hypopituitarism References == External links ==
Orf (disease)	Orf is a farmyard pox, a type of zoonosis. It causes small pustules in the skin of primarily sheep and goats, but can also occur on the hands of humans. A pale halo forms around a red centre. It may persist for several weeks before crusting and then either resolves or leaves a hard lump. There is usually only one lesion, but there may be many, and they are not painful. Sometimes there are swollen lymph glands.It is caused by a Parapoxvirus. It can occur in humans who handle infected animals or contaminated objects. One third of cases may develop erythema multiforme. Once resolved, a person can still be infected again.Generally, treatment options are limited. Injecting the lesion with cidofovir or applying imiquimod has been tried. It is sometimes necessary to cut them out. The vaccine used in sheep to prevent orf is live and has been known to cause disease in humans.The disease is endemic in livestock herds worldwide. A recent outbreak emerged in southwest Ethiopia between October 2019 and May 2020. Humans Orf is a zoonotic disease, meaning humans can contract this disorder through direct contact with infected sheep and goats or with fomites carrying the orf virus. It causes a purulent-appearing papule locally and generally no systemic symptoms. Infected locations can include the finger, hand, arm, face and even the penis (caused by infection either from contact with the hand during urination or from bestiality). Consequently, it is important to observe good personal hygiene and to wear gloves when treating infected animals. It may appear similar to cowpox and pseudocowpox. While orf is usually a benign self-limiting illness which resolves in 3-6 weeks, in the immunocompromised it can be very progressive and even life-threatening. One percent topical cidofovir has been successfully used in a few patients with progressive disease. Serious damage may be inflicted on the eye if it is infected by orf, even among healthy individuals. The virus can survive in the soil for at least six months. Other animals Orf is primarily a disease of sheep and goats although it has been reported as a natural disease in humans, steenbok and alpacas, chamois and tahrs, reindeer, musk oxen, dogs, cats, mountain goats, bighorn sheep, dall sheep, and red squirrels. Sheep and goats It has been recorded since the late 19th century and has been reported from most sheep-or goat-raising areas, including those in Europe, the Middle East, the United States, Africa, Asia, South America, Canada, New Zealand and Australia. Orf is spread by fomites and direct contact. In some environments, infection is injected by scratches from thistles of both growing and felled plants. Symptoms include papules and pustules on the lips and muzzle, and less commonly in the mouth of young lambs and on the eyelids, feet, and teats of ewes. The lesions progress to thick crusts which may bleed. Orf in the mouths of lambs may prevent suckling and cause weight loss, and can infect the udder of the mother ewe, thus potentially leading to mastitis. Sheep are prone to reinfection. Occasionally the infection can be extensive and persistent if the animal does not produce an immune response. A live virus vaccine (ATCvet code: QI04AD01 (WHO)) is made from scab material and usually given to ewes at the age of two months, but only to lambs when there is an outbreak. The vaccine can cause disease in humans. In sheep and goats, the lesions mostly appear on or near the hairline and elsewhere on the lips and muzzle. In some cases the lesions appear on and in the nostrils, around the eyes, on the thigh, coronet, vulva, udder, and axilla. In rare cases, mostly involving young lambs, lesions are found on the tongue, gums, roof of the mouth and the oesophagus. It has also been reported a number of times to cause lesions in the rumen. In one case it was shown that a severe form of orf virus caused an outbreak involving the gastrointestinal tract, lungs, heart, as well as the buccal cavity, cheeks, tongue and lips. Another severe case was reported pharyngitis, genital lesions and infection of the hooves which led to lameness and, in some cases, sloughing of the hoof.More typically, sheep will become free of orf within a week or so as the disease runs its course. Sheep custodians can assist by ensuring infected lambs receive sufficient milk and separating out the infected stock to slow down cross-transmission to healthy animals. It is advisable for those handling infected animals to wear disposable gloves to prevent cross infection and self-infection. A veterinarian must be contacted if there is a risk of misdiagnosis with other, more serious conditions. See also Ecthyma List of cutaneous conditions List of immunofluorescence findings for autoimmune bullous conditions Imiquimod Cidofovir References External links Farm Health Online: Disease Management of Orf Virus in Sheep
Niemann–Pick disease, type C	Niemann–Pick type C (NPC) (colloquially, "Childhood Alzheimers") is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people. Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade. Signs and symptoms Niemann–Pick type C has a wide clinical spectrum. Affected individuals may have enlargement of the spleen (splenomegaly) and liver (hepatomegaly), or enlarged spleen or liver combined (hepatosplenomegaly), but this finding may be absent in later onset cases. Prolonged jaundice or elevated bilirubin can present at birth. In some cases, however, enlargement of the spleen or liver does not occur for months or years – or not at all. Enlargement of the spleen or liver frequently becomes less apparent with time, in contrast to the progression of other lysosomal storage diseases such as Niemann–Pick disease, Types A and B or Gaucher disease. Organ enlargement does not usually cause major complications.Progressive neurological disease is the hallmark of Niemann–Pick type C disease, and is responsible for disability and premature death in all cases beyond early childhood. Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia).Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with inturning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, progressive dementia, progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor.In the terminal stages of Niemann–Pick type C disease, the patient is bedridden, with complete ophthalmoplegia, loss of volitional movement and severe dementia. Genetics Approximately 95% of Niemann–Pick type C cases are caused by genetic mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene, referred to as type C2. The clinical manifestations of types Niemann–Pick types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. The NPC1 gene is located on chromosome 18 (18q11-q12) and was described by researchers at the National Institutes of Health in July 1997. The NPC1 gene encodes a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells. A deficiency of this protein leads to the abnormal buildup of lipids and cholesterol within cell membranes. The NPC2 gene encodes a protein that binds and transports cholesterol. It has been shown to closely interact with NPC1. "Type D" variant Type D Niemann–Pick has only been found in the French Canadian population of Yarmouth County, Nova Scotia, and is now known to be allelic with Niemann–Pick type C. Genealogical research indicates that Joseph Muise (c. 1679–1729) and Marie Amirault (1684 – c. 1735) are common ancestors to all people with Type D. This couple is the most likely origin for the type D variant. Pathophysiology Niemann–Pick type C is biochemically, genetically and clinically distinct from Niemann–Pick Types A or and B. In Types A and B, there is complete or partial deficiency of the lysosomal enzyme called acid sphingomyelinase. In Niemann–Pick type C, the protein product of the major mutated gene NPC1 is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes.Cholesterol and glycolipids have varied roles in the cell. Cholesterol is a major component of cell plasma membranes, which define the cell as a whole and its organelles. It is also the basic building block of steroid hormones, including neurosteroids. In Niemann–Pick type C, large amounts of free or unesterified cholesterol accumulate in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis. The accumulation of glycosphingolipids in the nervous system has been linked to structural changes, namely ectopic dendritogenesis and meganeurite formation, and has been targeted therapeutically.Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein. Neufeld et al. hypothesized that the accumulation of mannose 6-phosphate receptors (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans Golgi network. Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the trans Golgi Network cannot bud and form. Iouannou, et al. have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1. Recent 2008 evidence indicates that NPC-1 may play an important role in calcium regulation. Diagnosis Niemann–Pick type C is diagnosed by assaying cultured fibroblasts for cholesterol esterification and staining for unesterified cholesterol with filipin. The fibroblasts are grown from a small skin biopsy taken from a patient with suspected NPC. The diagnosis can be confirmed by identifying mutations in the NPC1 or NPC2 genes in 80–90% of cases. This specialized testing is available at Thomas Jefferson University Lysosomal Disease Testing Lab and the Mayo Clinic. Treatment There is no known cure for Niemann–Pick type C, nor is there any FDA-standard approved disease modifying treatment. Supportive care is essential and substantially improves the quality of life of people affected by NPC. The therapeutic team may include specialists in neurology, pulmonology, gastroenterology, psychiatrist, orthopedics, nutrition, physical therapy and occupational therapy. Standard medications used to treat symptoms can be used in NPC patients. As patients develop difficulty with swallowing, food may need to be softened or thickened, and eventually, parents will need to consider placement of a gastrostomy tube (g-tube, feeding tube). Arimoclomol In 2014, the European Medicines Agency (EMA) granted orphan drug designation to arimoclomol for the treatment of Niemann–Pick type C. This was followed in 2015 by the U.S. Food and Drug Administration (FDA). Dosing in a placebo-controlled phase II/III clinical trial to investigate treatment for Niemann–Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016. Arimoclomol, which is orally administered, induces the heat shock response in cells and is well tolerated in humans. In 2018, the Sponsor announced the trial did not meet either its primary or secondary endpoints. On July 17, 2021, the US Food and Drug Administration rejected the New Drug Application for Arimoclomol, and issued a complete response letter to the company Sponsor. Hydroxypropyl-beta-cyclodextrin (HPbCD) In April 2009, hydroxypropyl-beta-cyclodextrin (HPbCD) was approved under compassionate use by the U.S. Food and Drug Administration (FDA) to treat Addison and Cassidy Hempel, identical twin girls who had Niemann–Pick type C disease. Medi-ports, similar to ports used to administer chemotherapy drugs, were surgically placed into the twins chest walls and allow doctors to directly infuse HPbCD into their bloodstreams. Treatment with cyclodextrin has been shown to delay clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan in both the Niemann–Pick type C mice and feline models. This is the second time in the United States that cyclodextrin alone has been administered in an attempt treat a fatal pediatric disease. In 1987, HPbCD was used in a medical case involving a boy with severe hypervitaminosis A.On May 17, 2010, the FDA granted Hydroxypropyl-beta-cyclodextrin orphan drug status and designated HPbCD cyclodextrin as a potential treatment for Niemann–Pick type C disease. On July 14, 2010, Dr. Caroline Hastings of UCSF Benioff Childrens Hospital Oakland filed additional applications with the FDA requesting approval to deliver HPbCD directly into the central nervous systems of the twins in an attempt to help HPbCD cross the blood–brain barrier. The request was approved by the FDA on September 23, 2010, and bi-monthly intrathecal injections of HPbCD into the spine were administered starting in October 2010.On December 25, 2010, the FDA granted approval for HPbCD to be delivered via IV to an additional patient, Peyton Hadley, aged 13, under an IND through Rogue Regional Medical Center in Medford, Oregon. Soon after in March 2011, approval was sought for similar treatment of his sibling, Kayla, age 11, and infusions of HPbCD began shortly after. Both have since begun intrathecal treatments beginning in January 2012.In April 2011, the National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), announced they were developing a clinical trial utilizing cyclodextrin for Niemann–Pick type C patients.On September 20, 2011, the European Medicines Agency (EMA) granted HPbCD orphan drug status and designated the compound as a potential treatment for Niemann–Pick type C disease.On December 31, 2011, the FDA granted approval for IV HPbCD infusions for a fifth child in the United States, Chase DiGiovanni, under a compassionate use protocol. The child was 29 months old at the time of his first intravenous infusion, which was started in January 2012.Due to unprecedented collaboration between individual physicians and parents of children affected by NPC, approximately 15 patients worldwide have received HPbCD cyclodextrin therapy under compassionate use treatment protocols. Treatment involves a combination of intravenous therapy (IV), intrathecal therapy (IT) and intracerebroventricular (ICV) cyclodextrin therapy. On January 23, 2013, a formal clinical trial to evaluate HPβCD cyclodextrin therapy as a treatment for Niemann–Pick disease, type C was announced by scientists from the NIHs National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). In January 2021, the Sponsor (Mallinckrodt Pharmaceuticals) concluded that the benefit / risk balance for HPβCD cyclodextrin (adrabetadex) for the treatment of neurologic symptoms of NPC was negative, and that the risks associated with the treatment outweigh the potential benefit. Effective immediately, Mallinckrodt recommended that treatment with adrabetadex be discontinued as soon as possible, with the appropriate physician oversight. N-Acetyl-Leucine N-Acetyl-Leucine is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc (Oxford, United Kingdom).N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of various genetic diseases, including Niemann-Pick Disease Type C. The US FDA has granted IntraBio a Rare Pediatric Disease Designation for N-Acetyl-Leucine for the treatment of NPC.Observational studies in NPC patients have demonstrated the symptomatic, as well as disease-modifying, neuroprotective effect of treatment. These studies further demonstrated that the treatment is well tolerated, with a good safety profile.In September 2020, IntraBio announced the successful results of a multinational clinical trial with N-acetyl-L-leucine (IB1001) for NPC, which demonstrated IB1001 demonstrated a statistically significant change in both primary and secondary endpoints, and clinically meaningful improvement in symptoms, functioning, and quality of life. IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff) and Ataxia-Telangiectasia. Future opportunities to develop N-Acetyl-Leucine include Lewy body dementia, amyotrophic lateral sclerosis, restless leg syndrome, multiple sclerosis, and migraine. Other treatments under investigation One drug that has been tried is Miglustat. Miglustat is a glucosylceramide synthase inhibitor, which inhibits the synthesis of glycosphingolipids in cells. It has been shown to delay the onset of disease in the NPC mouse, and published data from a multi-center clinical trial of Miglustat in the United States and England and from case reports suggests that it may ameliorate the course of human NPC.Several other treatment strategies are under investigation in cell culture and animal models of NPC. These include, cholesterol mobilization, neurosteroid (a special type of hormone that affects brain and other nerve cells) replacement using allopregnanolone, rab overexpression to bypass the trafficking block (Pagano lab) and Curcumin as an anti-inflammatory and calcium modulatory agent. The pregnane X receptor has been identified as a potential target.Neural stem cells have also been investigated in an animal model, and clear evidence of life extension in the mouse model has been shown.Low cholesterol diets are often used, but there is no evidence of efficacy.Gene therapy is being used clinically to treat genetic diseases including haemophilia and spinal muscular atrophy. It has been used preclinically, in a mouse model of Niemann-Pick type C, using an adeno-associated virus derived viral vector has been shown to extend lifespan following injection into the lateral ventricles of the neonatal brain. In a separate proof-of-concept study a similar vector, but with a modified capsid capable of delivering genes to the central nervous system following intravenous injection, was given to Niemann-Pick type C mice at around four weeks of age; this resulted in extended lifespan and improved weight gain. Prognosis The lifespan of patients with NPC is usually related to the age of onset. Children with antenatal or infantile onset usually succumb in the first few months or years of life, whereas adolescent and adult onset forms of Niemann–Pick type C have a more insidious onset and slower progression, and affected individuals may survive to the seventh decade. Adult cases of NPC are being recognized with increasing frequency. It is suspected that many patients affected by NPC are undiagnosed, owing to lack of awareness of the disease and the absence of readily available screening or diagnostic tests. For the same reasons the diagnosis is often delayed by many years. Research directions Loss of myelin in the central nervous system is considered to be a main pathogenic factor. Research uses animal models carrying the underlying mutation for Niemann–Pick disease, e.g. a mutation in the NPC1 gene Niemann–Pick type C disease. In this model the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased. MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths. A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.Recent neuroimaging studies have shown patients with Niemann–Pick, type C to have a corpus callosum with microstructural abnormalities. Clear reductions in corpus callosum mean thickness and surface area have been shown when compared to age-matched controls. Also, studies using diffusion tensor imaging have shown marked reductions in callosal fractional anisotropy, which suggests architectural abnormalities based on the directional flow of water. These conclusions suggest that the corpus callosum plays an important role in the disease and should be explored for use as a biomarker of disease progression.Parents of children with NPC are being studied in an attempt to gain insight into the Ebola virus, which uses the protein encoded by NPC1 to enter cells. Researchers have found that mice with one normal copy of the NPC1 gene are more likely to survive Ebola infection than mice with normal two copies of the gene. Mice lacking any normal copy of NPC1 all survived. Studying cells from parents who are NPC disease carriers may allow for better understanding of how changes to the NPC1 gene affect Ebola risk.Findings from Zhang et al. suggest that NPC is a late endocytic trafficking disease resulted, at least in part, from disruption of communication within late endocytic (LE) compartments and possibly between LE and other subcellular organelles. Crosstalk between the late endocytic compartment and other organelles such as mitochondria, endoplasmic reticulum, plasma membrane, as well as early endocytic compartments has become one of the most interesting frontiers in neurondegenerative disease research including Alzheimers disease, Parkinsons disease, as well as lysosomal storage disorders. References External links PubMed
Hepatomegaly	Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass. Depending on the cause, it may sometimes present along with jaundice. Signs and symptoms The individual may experience many symptoms, including weight loss, poor appetite and lethargy (jaundice and bruising may also be present). Causes Among the causes of hepatomegaly are the following: Infective Mechanism The mechanism of hepatomegaly consists of vascular swelling, inflammation (due to the various causes that are infectious in origin) and deposition of (1) non-hepatic cells or (2) increased cell contents (such due to iron in hemochromatosis or hemosiderosis and fat in fatty liver disease). Diagnosis Suspicion of hepatomegaly indicates a thorough medical history and physical examination, wherein the latter typically includes an increased liver span.On abdominal ultrasonography, the liver can be measured by the maximum dimension on a sagittal plane view through the midclavicular line, which is normally up to 18 cm in adults. It is also possible to measure the cranio-caudal dimension, which is normally up to 15 cm in adults. This can be measured together with the ventro-dorsal dimension (or depth), which is normally up to 13 cm. Also, the caudate lobe is enlarged in many diseases. In the axial plane, the caudate lobe should normally have a cross-section of less than 0.55 of the rest of the liver.Other ultrasound studies have suggested hepatomegaly as being defined as a longitudinal axis > 15.5 cm at the hepatic midline, or > 16.0 cm at the midclavicular line. Workup Blood tests should be done, importantly liver-function series, which will give a good impression of the patients broad metabolic picture.A complete blood test can help distinguish intrinsic liver disease from extrahepatic bile-duct obstruction. An ultrasound of the liver can reliably detect a dilated biliary-duct system, it can also detect the characteristics of a cirrhotic liver.Computerized tomography (CT) can help to obtain accurate anatomical information, in individuals with hepatomegaly for the purpose of a complete diagnosis. Treatment Treatment of hepatomegaly will vary depending on the cause of the liver enlargement and hence accurate diagnosis is the primary concern. In the case of auto-immune liver disease, prednisone and azathioprine may be used for treatment.In the case of lymphoma the treatment options include single-agent (or multi-agent) chemotherapy and regional radiotherapy, also surgery may be an option in specific situations. Meningococcal group C conjugate vaccine are also used in some cases.In primary biliary cirrhosis ursodeoxycholic acid helps the bloodstream remove bile which may increase survival in some affected individuals. See also Hepatosplenomegaly Liver function tests References Further reading Hoffmann, Georg F.; Zschocke, Johannes; Nyhan, William L. (2009-11-21). Inherited Metabolic Diseases: A Clinical Approach. Springer Science & Business Media. ISBN 9783540747239. Kim, Sun Bean; Kim, Do Kyung; Byun, Sun Jeong; Park, Ji Hye; Choi, Jin Young; Park, Young Nyun; Kim, Do Young (2015-12-01). "Peliosis hepatis presenting with massive hepatomegaly in a patient with idiopathic thrombocytopenic purpura". Clinical and Molecular Hepatology. 21 (4): 387–392. doi:10.3350/cmh.2015.21.4.387. ISSN 2287-2728. PMC 4712167. PMID 26770928. External links Merck Manual: Hepatomegaly
Military operation	A military operation is the coordinated military actions of a state, or a non-state actor, in response to a developing situation. These actions are designed as a military plan to resolve the situation in the state or actors favor. Operations may be of a combat or non-combat nature and may be referred to by a code name for the purpose of national security. Military operations are often known for their more generally accepted common usage names than their actual operational objectives. Types of military operations Military operations can be classified by the scale and scope of force employment, and their impact on the wider conflict. The scope of military operations can be: Theater: this describes an operation over a large, often continental, area of operation and represents a strategic national commitment to the conflict, such as Operation Barbarossa, with general goals that encompass areas of consideration outside the military, such as the economic and political impact of military goals on areas concerned. Campaign: this describes either a subset of the theatre of operation, or a more limited geographic and operational strategic commitment, such as the Battle of Britain, and need not represent total national commitment to a conflict, or have broader goals outside the military impact.The United States just recently got out of some of the longest conflicts in the Military history. Operations Enduring Freedom and Operation Iraqi Freedom are some of the most recognizable campaigns as they have to do with the Iraq and a Afghanistan conflicts.<Owens, John, Charles, 2008)> Battle: this describes a subset of a campaign that will have specific military goals and geographic objectives, as well as clearly defined use of forces, such as the Battle of Gallipoli, which operationally was a combined arms operation originally known as the "Dardanelles landings" as part of the Dardanelles Campaign, where about 480,000 Allied troops took part. Engagement: this describes a tactical combat event or contest for a specific area or objective by actions of distinct units. For example, the Battle of Kursk, also known from its German designation as Operation Citadel, included many separate engagements, several of which were combined into the Battle of Prokhorovka. The Battle of Kursk, in addition to describing the initial German offensive operation, also included two Soviet counter-offensive operations: Operation Kutuzov and Operation Polkovodets Rumyantsev. Strike: this describes a single attack, upon a specified target. This often forms part of a broader engagement. Strikes have an explicit goal, such as rendering facilities such as airports inoperable, assassinating enemy leaders, or limiting the delivery of supplies to enemy troops. Definition Parallel to and reflecting this framework for operations are organized elements within the armed forces which prepare for and conduct operations at various levels of war. While there is a general correlation between the size of units, the area within which they operate, and the scope of mission they perform, the correlation is not absolute. In fact, it is ultimately the mission that a unit performs that determines the level of war within which it operates. Operational level of war The operational level of war occupies roughly the middle ground between the campaigns strategic focus and the tactics of an engagement. It describes "a distinct intermediate level of war between military strategy, governing war in general, and tactics, involving individual battles". For example, during World War II, the concept applied to use of Soviet Tank Armies. See also Civil-military operations Effects-Based Operations (EBO) List of military operations List of coalition military operations of the Iraq War List of World War II military operations Military operation plan Military operations other than war (MOOTW) Offensive (military) Operational View (OV) Notes References Armstrong, Richard N. Red Army Tank Commanders: The Armored Guards. Atglen, Penn.: Schiffer Military History, 1994. ISBN 0-88740-581-9. Glantz, David M. Soviet Military Operational Art: In Pursuit of Deep Battle. London: Frank Cass, 1991. ISBN 0-7146-3362-3, ISBN 0-7146-4077-8.
Glycogen storage disease type II	Glycogen storage disease type II, also called Pompe disease, is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. It is the only glycogen storage disease with a defect in lysosomal metabolism, and the first glycogen storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe. The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and the nervous system. Signs and symptoms Newborn The infantile form usually comes to medical attention within the first few months of life. The usual presenting features are cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%), respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%) and failure to thrive (50%).The main clinical findings include floppy baby appearance, delayed motor milestones, and feeding difficulties. Moderate hepatomegaly may or may not be present. Facial features include macroglossia, wide open mouth, wide open eyes, nasal flaring (due to respiratory distress), and poor facial muscle tone. Cardiopulmonary involvement is manifested by increased respiratory rate, use of accessory muscles for respiration, recurrent chest infections, decreased air entry in the left lower zone (due to cardiomegaly), arrhythmias, and evidence of heart failure.Before developing a treatment, median age at death in untreated cases was 8.7 months, usually due to cardiorespiratory failure; However, this outcome is drastically changed since treatment has been available, improving with early access to treatment. Late onset form This form differs from the infantile principally in the relative lack of cardiac involvement. The onset is more insidious and has a slower progression. Cardiac involvement may occur but is milder than in the infantile form. Skeletal involvement is more prominent with a predilection for the lower limbs.Late onset features include impaired cough, recurrent chest infections, hypotonia, progressive muscle weakness, delayed motor milestones, difficulty swallowing or chewing and reduced vital capacity. Prognosis depends on the age of onset of symptoms with a better prognosis being associated with later onset disease. Cause It has an autosomal recessive inheritance pattern. This means the defective gene is located on an autosome, and two faulty copies of the gene — one from each parent — are required to be born with the disorder. As with all cases of autosomal recessive inheritance, children have a 1 in 4 chance of inheriting the disorder when both parents carry the defective gene, and although both parents carry one copy of the defective gene, they are usually not affected by the disorder.The disease is caused by a mutation in a gene (acid alpha-glucosidase: also known as acid maltase) on long arm of chromosome 17 at 17q25.2-q25.3 (base pair 75,689,876 to 75,708,272). The number of mutations described is currently (in 2010) 289 with 67 being non-pathogenic mutations and 197 pathogenic mutations. The remainder are still being evaluated for their association with disease.The gene spans approximately 20 kb and contains 20 exons with the first exon being noncoding. The coding sequence of the putative catalytic site domain is interrupted in the middle by an intron of 101 bp. The promoter has features characteristic of a housekeeping gene. The GC content is high (80%) and distinct TATA and CCAAT motifs are lacking. Most cases appear to be due to three mutations. A transversion (T → G) mutation is the most common among adults with this disorder. This mutation interrupts a site of RNA splicing. The gene encodes a protein—acid alpha-glucosidase (EC 3.2.1.20)—which is a lysosomal hydrolase. The protein is an enzyme that normally degrades the alpha -1,4 and alpha -1,6 linkages in glycogen, maltose and isomaltose and is required for the degradation of 1–3% of cellular glycogen. The deficiency of this enzyme results in the accumulation of structurally normal glycogen in lysosomes and cytoplasm in affected individuals. Excessive glycogen storage within lysosomes may interrupt normal functioning of other organelles and lead to cellular injury. A putative homologue—acid alpha-glucosidase-related gene 1—has been identified in the nematode Caenorhabditis elegans. Diagnosis In the early-onset form, an infant will present with poor feeding causing failure to thrive, or with difficulty breathing. The usual initial investigations include chest X ray, electrocardiogram and echocardiography. Typical findings are those of an enlarged heart with non specific conduction defects. Biochemical investigations include serum creatine kinase (typically increased 10 fold) with lesser elevations of the serum aldolase, aspartate transaminase, alanine transaminase and lactic dehydrogenase. Diagnosis is made by estimating the acid alpha glucosidase activity in either skin biopsy (fibroblasts), muscle biopsy (muscle cells) or in white blood cells. The choice of sample depends on the facilities available at the diagnostic laboratory.In the late-onset form, an adult will present with gradually progressive arm and leg weakness, with worsening respiratory function. Electromyography may be used initially to distinguish Pompe from other causes of limb weakness. The findings on biochemical tests are similar to those of the infantile form, with the caveat that the creatine kinase may be normal in some cases. The diagnosis is by estimation of the enzyme activity in a suitable sample.On May 17, 2013, the Secretarys Discretionary Advisory Committee on Heritable Diseases in Newborns and Children (DACHDNC) approved a recommendation to the Secretary of Health and Human Services to add Pompe to the Recommended Uniform Screening Panel (RUSP). The HHS secretary must first approve the recommendation before the disease is formally added to the panel. Classification There are exceptions, but levels of alpha-glucosidase determines the type of GSD II an individual may have. More alpha glucosidase present in the individuals muscles means symptoms occur later in life and progress more slowly. GSD II is broadly divided into two onset forms based on the age symptoms occur.Infantile-onset form is usually diagnosed at 4–8 months; muscles appear normal but are limp and weak preventing the child from lifting their head or rolling over. As the disease progresses, heart muscles thicken and progressively fail. Without treatment, death usually occurs due to heart failure and respiratory weakness.Late or later onset form occurs later than one to two years and progresses more slowly than Infantile-onset form. One of the first symptoms is a progressive decrease in muscle strength starting with the legs and moving to smaller muscles in the trunk and arms, such as the diaphragm and other muscles required for breathing. Respiratory failure is the most common cause of death. Enlargement of the heart muscles and rhythm disturbances are not significant features but do occur in some cases. Treatment Cardiac and respiratory complications are treated symptomatically. Physical and occupational therapy may be beneficial for some patients. Alterations in diet may provide temporary improvement but will not alter the course of the disease. Genetic counseling can provide families with information regarding risk in future pregnancies.On April 28, 2006, the US Food and Drug Administration approved a Biologic License Application (BLA) for alglucosidase alfa, rhGAA (Myozyme), the first treatment for patients with Pompe disease, developed by a team of Duke University researchers. This was based on enzyme replacement therapy using biologically active recombinant human alglucosidase alfa produced in Chinese Hamster Ovary cells. Myozyme falls under the FDA Orphan Drug designation and was approved under a priority review.The FDA has approved Myozyme for administration by intravenous infusion of the solution. The safety and efficacy of Myozyme were assessed in two separate clinical trials in 39 infantile-onset patients with Pompe disease ranging in age from 1 month to 3.5 years at the time of the first infusion. Myozyme treatment clearly prolongs ventilator-free survival and overall survival. Early diagnosis and early treatment leads to much better outcomes. The treatment is not without side effects which include fever, flushing, skin rash, increased heart rate and even shock; these conditions, however, are usually manageable.Myozyme costs an average of US$300,000 a year and must be taken for the patients entire life, so some American insurers have refused to pay for it. On August 14, 2006, Health Canada approved Myozyme for the treatment of Pompe disease. On June 14, 2007, the Canadian Common Drug Review issued their recommendations regarding public funding for Myozyme therapy. Their recommendation was to provide funding to treat a tiny subset of Pompe patients (Infants less one year of age with cardiomyopathy).On May 26, 2010, FDA approved Lumizyme, a similar version of Myozyme, for the treatment of late-onset Pompe disease. Lumizyme and Myozyme have the same generic ingredient (alglucosidase alfa) and manufacturer (Genzyme Corporation). The difference between these two products is in the manufacturing process. Myozyme is made using a 160-L bioreactor, while Lumizyme uses a 4000-L bioreactor. Because of the difference in the manufacturing process, the FDA claims that the two products are biologically different. Moreover, Lumizyme is FDA approved as replacement therapy for late-onset (noninfantile) Pompe disease without evidence of cardiac hypertrophy in people 8 years and older. Myozyme is FDA approved for replacement therapy for infantile-onset Pompe disease.In July 2021, the European Medicines Agency (EMA) recommended the authorization of avalglucosidase alfa. Avalglucosidase alfa (Nexviazyme) was approved for medical use in the United States in August 2021. Prognosis The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms, along with lifestyle factors. Without treatment the infantile form (which can typically be predicted by mutation analysis) of the disease is particularly lethal - in these cases time to get on treatment is critical, with evidence that days (not weeks or months) matter.Myozyme (alglucosidase alfa) is a recombinant form of the human enzyme acid alpha-glucosidase, and is also currently being used to replace the missing enzyme. In a study which included the largest cohort of patients with Pompe disease treated with enzyme replacement therapy (ERT) to date findings showed that Myozyme treatment clearly prolongs ventilator-free survival and overall survival in patients with infantile-onset Pompe disease as compared to an untreated historical control population. Furthermore, the study demonstrated that initiation of ERT prior to 6 months of age, which could be facilitated by newborn screening, shows great promise to reduce the mortality and disability associated with this devastating disorder. Taiwan and several states in the United States have started the newborn screening and results of such regimen in early diagnosis and early initiation of the therapy have dramatically improved the outcome of the disease; many of these babies have reached the normal motor developmental milestones.Another factor affecting the treatment response is generation of antibodies against the infused enzyme, which is particularly severe in Pompe infants who have complete deficiency of the acid alpha-glucosidase. Immune tolerance therapy to eliminate these antibodies has improved the treatment outcome.A Late Onset Treatment Study (LOTS) was published in 2010. The study was undertaken to evaluate the safety and efficacy of aglucosidase alfa in juvenile and adult patients with Pompe disease. LOTS was a randomized, double-blind, placebo-controlled study that enrolled 90 patients at eight primary sites in the United States and Europe. Participants received either aglucosidase alfa or a placebo every other week for 18 months. The average age of study participants was 44 years. The primary efficacy endpoints of the study sought to determine the effect of Myozyme on functional endurance as measured by the six-minute walk test and to determine the effect of aglucosidase alfa on pulmonary function as measured by percent predicted forced vital capacity. The results showed that, at 78 weeks, patients treated with aglucosidase alfa increased their distance walked in six minutes by an average of approximately 25 meters as compared with the placebo group which declined by 3 meters (P=0.03). The placebo group did not show any improvement from baseline. The average baseline distance walked in six minutes in both groups was approximately 325 meters. Percent predicted forced vital capacity in the group of patients treated with aglucosidase alfa increased by 1.2 percent at 78 weeks. In contrast, it declined by approximately 2.2 percent in the placebo group (P=0.006). There is an emerging recognition of the role that diet and exercise can play in functionally limiting symptom progression. This is an area for further study, as there is not a clear consensus guideline, but rather a body of case study work that suggests that appropriate physical activity can be an effective tool in managing disease progression. In one such study, side-alternating vibration training was used 3 times per week for 15 weeks. The results showed that, at 15 weeks, the patient had a 116-meter (70%) improvement to their 6MWT, which is significant compared with the results from the aforementioned LOTS study. Epidemiology The disease affects approximately 1 in 13,000. History The disease is named after Joannes Cassianus Pompe, who characterized it in 1932. Pompe described accumulation of glycogen in muscle tissue in some cases of a previously unknown disorder. This accumulation was difficult to explain as the enzymes involved in the usual metabolism of glucose and glycogen were all present and functioning. The basis for the disease remained a puzzle until Christian de Duves discovery of lysosomes in 1955 for which he won the Nobel Prize in 1974. His co-worker Henri G. Hers realised in 1965 that the deficiency of a lysosomal enzyme (alpha glucosidase) for the breakdown of glycogen could explain the symptoms of Pompe disease. This discovery led to establishing the concept of lysosomal storage diseases, of which 49 have been described (to date). Despite recognizing the basis for the disease, treatment proved difficult. Administration of the enzyme lead to its uptake by the liver and not the muscle cells where it is needed. In the early 1990s Dutch scientists Arnold Reuser and Ans van der Ploeg were able to show that using alpha-glucosidase containing phosphorylated mannose residues purified from bovine testes increased the enzymes activity in normal mouse muscles.Later in 1998, Dr. Yuan-Tsong Chen and colleagues at Duke University, using the enzyme produced in Chinese Hamster Ovary cells demonstrated for the first time that the enzyme can clear the glycogen and improved the muscle function in Pompe disease quail. The results of the work at Duke were impressive with one treated bird recovering to the point of being able to fly again.This was followed by production of clinical grade alpha-glucosidase in Chinese hamster ovary (CHO) cells and in the milk of transgenic rabbits. This work eventually culminated in the start of clinical trials with the first clinical trial including 4 babies receiving enzyme from rabbit milk at Erasmus MC Sophia Childrens Hospital and 3 babies receiving enzyme grown in CHO cells at Duke University in 1999. The currently approved Myozyme is manufactured by Genzyme Corp. in Cambridge, Massachusetts. Its development was a complex process. Genzyme first partnered with Pharming Group NV who had managed to produce acid alpha-glucosidase from the milk of transgenic rabbits. They also partnered with a second group based at Duke University using Chinese hamster ovary cells. In 2001, Genzyme acquired Novazyme which was also working on this enzyme. Genzyme also had its own product (Myozyme) grown in CHO cells under development. In November 2001, Genzyme chief executive Henri Termeer organised a systematic comparison of the various potential drugs in a mouse model of Pompe disease. It was found that the Duke enzyme was the most efficacious, followed by Myozyme. However, due to easier manufacture of Myozyme, work on the other products was discontinued. Funding for research in this field was in part provided by the Muscular Dystrophy Association and the Acid Maltase Deficiency Association in the US, and by the Association of Glycogen Storage Disorders in the UK, as well as the International Pompe Association. John Crowley became involved in the fund-raising efforts in 1998 after two of his children were diagnosed with Pompe. He joined the company Novazyme in 1999, which was working on enzyme replacement treatment for Pompe. Novazyme was sold to Genzyme in 2001 for over US$100 million. The 2010 film Extraordinary Measures is based on Crowleys search for a cure. As of 2019, many biomedical companies are developing Gene therapy in hopes of helping the body create alpha-glucosidase on its own. In 2021, in utero infusions were provided to the fetus of an Ottawa, Ontario, mother who had had two previous children with Pompe disease. The medical team was a collaboration between an Ottawa group and a group at the University of California, San Francisco. The child, born in June 2021, is thriving as of November 2022. References External links GeneReview/NIH/UW entry on Glycogen Storage Disease Type II (Pompe Disease) Understanding Pompe Disease - US National Institute of Arthritis and Musculoskeletal and Skin Diseases
Husband	A husband is a male in a marital relationship, who may also be referred to as a spouse. The rights and obligations of a husband regarding his spouse and others, and his status in the community and in law, vary between societies and cultures, and have varied over time. In monogamous cultures, there are only two parties to a marriage, which is enforced by laws against bigamy and polygamy. Traditionally, the husband was regarded as the head of the household and was expected to be the sole provider or breadwinner, a role that continues in some cultures (sometimes described as paternalistic). Today, a husband is not necessarily considered the breadwinner of the family, especially if his spouse has a more financially rewarding occupation or career. In such cases, it is not uncommon for a husband to be considered a stay-at-home father if the married couple have children. The term continues to be applied to such a man who has separated from his spouse and ceases to be applied to him only when his marriage has come to an end following a legally recognized divorce or the death of his spouse. On the death of his spouse, a husband is referred to as a widower; after a divorce a man may be referred to as the "ex-husband" of his former spouse. Origin and etymology The term husband refers to Middle English huseband, from Old English hūsbōnda, from Old Norse hūsbōndi (hūs, house + bōndi, būandi, present participle of būa, to dwell, so, etymologically, a householder). See also torp. Related terms At the conclusion of a valid wedding, the marrying parties acquire the status of married persons and, while the marriage persists, a man is called a husband. In heterosexual marriages the woman is called a wife; in same-sex marriages between males, each male is called a husband. Although husband is a close term to groom, the latter is a male participant in a wedding ceremony, while a husband is a married man after the wedding and for the duration of the marriage. The term husband refers to the institutionalized role of the married male, while the term father refers to the male in context of his offspring, a state which may or may not indicate that a marriage ceremony has taken place. In some cases of heterosexual marriage, before the marriage, the forthcoming husband or his family may have received a dowry, or have had to pay a bride price, or both were exchanged. The dowry not only supported the establishment of a household, but also served as a condition that if the husband committed grave offenses upon his wife, he had to return the dowry to the wife or her family. For the time of the marriage, they were made inalienable by the husband. He might leave his wife (or wives), then widow (or widows), a dower (often a third or a half of his estate) to support her as dowager.As an external symbol of the fact that they are married, each spouse commonly wears a wedding ring on the ring finger; whether this is on the left or right hand depends on the countrys tradition. Husband further refers to the institutionalized form in relation to the spouse and offspring, unlike father, a term that puts a man into the context of his children. Also compare the similar husbandry, which in the 14th century referred to the care of the household, but today means the "control or judicious use of resources", conservation, and in agriculture, the cultivation of plants and animals, and the science about its profession. Western culture Historical status In premodern heterosexual unions (ancient Roman, medieval, and early modern history), a husband was obliged to protect and support not only his wife and children, but servants and animals of his domain. The father (as the "patron") was awarded with much authority, differing from that of his wife (in these cultures, no polygamy existed).In the Middle Ages and Early Modern European history, it was unusual to marry out of love, but then doing so became an influential ideal. During this period, a husband in a heterosexual marriage had more opportunities in society than his wife, who was not recognized as legally independent. Contemporary status In contemporary secularized Western culture, the rights of the spouses have been made equal. The civil marriage generally forces the wealthier spouse, "breadwinner", to provide alimony to the former spouse, even after separation and also after a divorce (see also Law and divorce around the world). The legal status of marriage allows each spouse to speak on the others behalf when one is incapacitated (e.g., in a coma); a husband is also responsible for his spouses child(ren) in states where he is automatically assumed to be the biological father. Religion Christianity In Christianity, according to the Bible, a husband in a heterosexual marriage has a number of duties: To present his bride to God throughout their lives as perfectly holy and virtuous as can be. To protect his wife with his own life, physically, emotionally and "spiritually". To "lay down" his life, counting her more important than himself. To lead his wife and his family into the best things for them. To be the best that he can be in Gods power. To not withhold his body from her. Islam In Islamic marital jurisprudence, husbands are considered protectors of the household and their wives. As protector, the husband has various rights and obligations that he is expected to fulfill and thus is offered opportunities different from that of his wife or wives, not only in legal and economical affairs of the family but within the family as well. As in most cases in Islam law and culture, everything is being related to the Quran. Many Muslims may agree on a perfectly equal relationship. Islam is the only major religion that puts a cap on polygamy, limiting the number of a mans wives to four—provided the husband can do justice to all of them. Although some religions, such as Catholicism for instance, puts a cap on polygamy all together, or even serial monogamy, allowing one spouse until death does them apart, not even accepting divorce. According to the teachings of Islam a Muslim man should have a valid reason and have to get permission from his existing wife (without any force) if he requires to marry again. Islam vehemently abhors any intimate relationship outside the bond of marriage. There is no external sign to show his status as a husband, unless he adopted the tradition of wearing a wedding ring. Hinduism A Hindu husband traditionally takes his wife to his home. He is expected to provide for her and to prove his abilities to do so. The marriage in Hinduism is a relationship for Seven births (सात जन्मों का सम्बन्ध). Before 1951 there was no divorce allowed in Hindu marriage. In modern times once again after 1951, equal rights for women through society and law jurisdiction is given. In Hinduism, based on the different regions, marriage process is observed differently with the same Saat Pheras around agni kund (light pyre) to be taken to become a husband and wife. The Encyclopædia Britannica mentions that "In Hindu law, the male members of a joint family, together with their wives, widows, and children, are entitled to support out of the joint property." Buddhism and Chinese folk religions Chinas family laws were changed by the Communist revolution; and in 1950, the Peoples Republic of China enacted a comprehensive marriage law including provisions giving the spouses equal rights with regard to ownership and management of marital property. Other cultures In Japan, before enactment of the Meiji Civil Code of 1898, all of the womans property such as land or money passed to her husband except for personal clothing and a mirror stand. Expectation of fidelity Although there is generally an expectation for a spouse not to have sexual relations with anyone other than his spouse(s), historically, in most cultures, this expectation was not as strong as in the case of wives, a situation which was evident in legal codes which prohibited adultery, with male adultery often being criminalized only if "aggravating" circumstances existed, such as if he brought his mistress into the conjugal home, or if there was public scandal. The double standard was also evident in divorce laws of many countries, such as the UK or Australia, which differentiated between female adultery, which was a ground of adultery by itself, and male adultery, which was a ground only under certain circumstances. This double standard continues to be seen today in many parts of the world. For instance, in the Philippines, a wife can be charged with the crime of adultery (for merely having one act of sexual intercourse with a man other than her husband), while a husband can only be charged with the related crime of concubinage, which is more loosely defined (it requires either keeping the mistress in the family home, or cohabiting with her, or having sexual relations under scandalous circumstances).A breach of this expectation of fidelity is commonly referred to as adultery or extramarital sex. Historically, adultery has been considered a serious offense, sometimes a crime. Even if that is not so, it may still have legal consequences, particularly a divorce. Adultery may be a factor to consider in a property settlement, it may affect the status of children, the custody of children, etc. See also Cuckold Female husband Husband-selling Hypergamy Polyandry Polygamy in Christianity Wife References Further reading Wedgwood, Hensleigh (1855). "On False Etymologies". Transactions of the Philological Society (6).
Abrasion	Abrasion may refer to: Abrasion (dental), the loss of tooth structure by mechanical forces from a foreign element Abrasion (medical), a wound consisting of superficial damage to the skin Abrasion (mechanical), the process of scuffing, scratching, wearing down, marring, or rubbing away Abrasion (geology), mechanical scraping of a surface by friction between moving particles See also Abrasion coast, a coastline that is characterised by the removal (abrasion) of material Abrasives
Schwannomatosis	Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF). Originally described in Japanese patients, it consists of multiple cutaneous schwannomas, central nervous system tumors, and other neurological complications, excluding hallmark signs of NF. The exact frequency of schwannomatosis cases is unknown, although some populations have noted frequencies as few as 1 case per 1.7 million people.Schwannomas are mostly benign tumors that commonly occur in individuals with NF2 and schwannomatosis (sometimes called neurofibromatosis type III). Schwann cells are glial cells that myelinate the axons of nerve cells. Myelin is a lipid covering that speeds the conduction of action potentials. When Schwann cells proliferate out of control in an encapsulation it is called a schwannoma. Although schwannomas are benign they become detrimental when the growing tumor compresses the nerve. Schwannomas on sensory nerve axons cause chronic severe pain. Treatment options for schwannomas are to surgically remove them, have radiation, cyberknife or Intracapsular Enucleation. Previous designations for schwannomas include neurinoma and neurilemmoma. Cause The candidate schwannomatosis gene, named SMARCB1, is a tumor suppressor gene that regulates cell cycle, growth and differentiation. An inactivating germline mutation in exon 1 of the tumor suppressor gene SMARCB1 has been reported in patients with schwannomatosis. It is located on chromosome 22 a short distance from the NF2 gene. However, molecular analysis of the NF2 gene in schwannomatosis patients has shown the presence of inactivating mutations in the tumor cells, but no evidence of the germline mutations that are found in NF2 patients.A mechanism involving both the SMARCB1 and NF2 genes may be responsible for the development of the disease because tumor analysis of schwannomas indicates the presence of inactivating mutations in both the SMARCB1 and NF2 genes. However, there is speculation about the involvement of an unidentified schwannomatosis gene(s) in most cases. This is because one study found no SMARCB1 germinal mutations in patients with familial schwannomatosis. Some schwannomatosis patients do not have SMARCB1 or NF2 mutations. Furthermore, many patients exhibit somatic mosaicism for mutations in the NF2 or SMARCB1 gene, which means that some somatic cells have the mutation and some do not in the same patient. Ultimately, the tumorigenesis of schwannomas is not solely dependent on one gene locus alone. In regards to the SMARCB1 and NF2 genes, it is important to understand constitutional mutations and somatic mutations. Constitutional mutations are the first inactivation events that are often small mutations, such as point mutations and deletion/insertion of single base pairs. Somatic mutations are the second mutations that occur and may also be another small mutation or the loss of the remaining allele of the gene. Schwannomas from one patient share the same constitutional mutations but have distinct somatic mutations. In addition, the constitutional mutation may be present in non-tumor.SMARCB1 is also known as INI1, hSNF5, or BAF47. SMARCB1 is mutated in additional tumors including malignant brain & kidney tumors in children. It seems that heterozygotes for mutations in the SMARCB1 gene have an increased risk to develop a malignant kidney tumor in early childhood but if they survive to adulthood, they may be predisposed to the development of schwannomas. One schwannomatosis patient had a mutation in exon 2 of the SMARCB1 gene. Another patient exhibited a novel germline deletion of the SMARCB1, because most SMARCB1 mutations are point or frameshift. In this patient genetic analysis from different schwannomas indicated inactivation of both the SMARCB1 and NF2 genes. Schwannomatosis is known to be a genetic disorder. However, familial occurrence is inexplicably rare. Diagnosis Prenatal Schwannomatosis can be tested prenatally on the NHS. Postnatal Ferner et al. give the following diagnostic criteria for Schwannomatosis: Definite Age >30 years and ≥2 nonintradermal schwannomas, at least one with histologic confirmation and no evidence of vestibular tumor on MRI scan and no known NF mutation, or One nonvestibular schwannoma plus a first-degree relative with schwannomatosis Possible Age <30 and ≥2 nonintradermal schwannomas, at least one with histologic confirmation and no evidence of vestibular tumor on MRI scan and no known NF mutation, or Age >45 and ≥2 nonintradermal schwannomas, at least one with histologic confirmation and no symptoms of 8th nerve dysfunction and no NF2, or Nonvestibular schwannoma and first-degree relative with schwannomatosis Segmental. Diagnosed as definite or possible but limited to one limb or ≤5 contiguous segments of spine.Another set of criteria are: Two or more nonintradermal (cutaneous) schwannomas No evidence of vestibular tumor No known NF-2 mutationor One pathologically confirmed nonvestibular schwannoma plus a first degree relative who meets the above criteria. Treatment Schwannomatosis patients represent 2.4% to 5% of patients undergoing surgical resection of their schwannomas. In isolated regions of the body schwannomas are small and difficult to locate. Intraoperative sonography offers invaluable assistance in such cases by localizing small schwannomas and decreasing operative time and extent of the surgical incision. If feasible, the schwannomas can be surgically removed. Any tumor-associated pain usually subsides after tumor removal. Damaged nerves and scar tissue can be a result of surgery and pain can be an ongoing problem. Sometimes, a tumor will reappear at the same site after surgery. If surgery is unfeasible, then pain management will have to be used. Schwannomatosis can sometimes cause severe, untreatable pain over time. Other than surgery and/or pain management, there are no other medical treatments available. There are no drugs available to treat Schwannomatosis. Gamma knife radiosurgery can be performed on head tumors to help stop growth of a tumor, although there is no guarantee that it will work. The University of Pittsburgh published their experience with over 829 cases and reported 97% of patients had long term tumor control (defined as requiring no further treatment) with Gamma knife radiosurgery. Recently, many advances are being made in the treatment of schwannomas. Of interest is CyberKnife, manufactured by Accuray. Success rates, although limited in data, appear to be in the low to mid ninety percent range. As most schwannomas are benign, many doctors will take the “watch and wait” approach and leave the tumors alone until they start causing harmful side effects. Schwannomatosis patients have multiple tumors and the risks of having so many surgeries outweigh the benefits. Prognosis Many of the symptoms of schwannomatosis overlap with NF2. Schwannomas occur instead of the neurofibromas that are hallmarks of neurofibromatosis Type 1 (NF1). Multiple schwannomas manifest throughout the body or in isolated regions. The schwannomas develop on cranial, spinal and peripheral nerves. Chronic pain, and sometimes numbness, tingling and weakness. About 1/3 of patients have segmental schwannomatosis, which means that the schwannomas are limited to a single part of the body, such as an arm, a leg or the spine. There are several cases where people with schwannomatosis have developed a vestibular schwannoma (acoustic neuroma). An acoustic neuroma is a schwannoma on the vestibular nerve in the brain. This nerve is involved in hearing and patients with vestibular schwannomas experience hearing loss. However, bilateral vestibular schwannomas (vestibular schwannomas on both sides of the brain) do not occur in schwannomatosis. Juvenile vestibular tumors do not occur either. Patients with schwannomatosis do not have learning disabilities related to the disease. Symptoms are sometimes brought on by hormonal changes such as puberty and pregnancy. == References ==
Hemoptysis	Hemoptysis is the coughing up of blood or blood-stained mucus from the bronchi, larynx, trachea, or lungs. In other words, it is the airway bleeding. This can occur with lung cancer, infections such as tuberculosis, bronchitis, or pneumonia, and certain cardiovascular conditions. Hemoptysis is considered massive at 300 mL (11 imp fl oz; 10 US fl oz). In such cases, there are always severe injuries. The primary danger comes from choking, rather than blood loss. Diagnosis Past history, history of present illness, family historyhistory of tuberculosis, bronchiectasis, chronic bronchitis, mitral stenosis, etc. history of cigarette smoking, occupational diseases by exposure to silica dust, etc. Blood duration, frequency, amount Amounts of blood: large amounts of blood, or is there blood-streaked sputum Probable source of bleeding: Is the blood coughed up, or vomited? Bloody sputum color, characters: blood-streaked, fresh blood, frothy pink, bloody gelatinous. Accompanying symptoms fever, chest pain, coughing, purulent sputum, mucocutaneous bleeding, jaundice. Imaging examination chest X-ray, CT scan and 3D reconstruction images or CT virtual bronchoscopy, bronchial angiography. Laboratory tests blood test: WBC Sputum: cells and bacterial examinations, sputum culture Bronchial fiber endoscopy Differential diagnosis The most common causes for hemoptysis in adults are chest infections such as bronchitis or pneumonia. In children, hemoptysis is commonly caused by the presence of a foreign body in the airway. Other common causes include lung cancers and tuberculosis. Less common causes include aspergilloma, bronchiectasis, coccidioidomycosis, pulmonary embolism, pneumonic plague, and cystic fibrosis. Rarer causes include hereditary hemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome), Goodpastures syndrome, and granulomatosis with polyangiitis. A rare cause of hemoptysis in women is endometriosis, which leads to intermittent hemoptysis coinciding with menstrual periods in 7% of women with thoracic endometriosis syndrome. Hemoptysis may be exacerbated or even caused by overtreatment with anticoagulant drugs such as warfarin.Blood-laced mucus from the sinus or nose area can sometimes be misidentified as symptomatic of hemoptysis (such secretions can be a sign of nasal or sinus cancer, but also a sinus infection). Extensive non-respiratory injury can also cause one to cough up blood. Cardiac causes like congestive heart failure and mitral stenosis should be ruled out.The origin of blood can be identified by observing its color. Bright-red, foamy blood comes from the respiratory tract, whereas dark-red, coffee-colored blood comes from the gastrointestinal tract. Sometimes hemoptysis may be rust-colored. Lung cancer, including both non-small cell lung carcinoma and small cell lung carcinoma. Sarcoidosis Aspergilloma Tuberculosis Histoplasmosis Pneumonia Pulmonary edema Endometriosis and thoracic endometriosis syndrome Foreign body aspiration and aspiration pneumonia Goodpastures syndrome Microscopic polyangiitis Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis Bronchitis Bronchiectasis Pulmonary embolism Anticoagulant use Trauma Lung abscess Mitral stenosis Tropical pulmonary eosinophilia Bleeding disorders Hughes-Stovin syndrome and other variants of Behçets disease Pulmonary arteriovenous malformations Massive hemoptysis and mortality Although there are reports that the fatality rate is as high as 80%, the in-hospital mortality rate for hospitalized hemoptysis patients is 2669/28539=9.4%, calculated from the data in the article by Kinoshita et al. This is probably the most reasonable figure considering the overwhelming number of cases.The general definition of massive hemoptysis is more than 200 ml within 24 hours, but there is a wide range in the literature (100-600 ml). Considering that the total volume of the tracheal and bronchial lumen is about 150 cc, it may be reasonable to define massive hemoptysis as 200 ml, which is a little more than 150 ml, in terms of setting the threshold for fatal hemoptysis. More than 400ml/day is not adequate for screening purposes. Treatment Treatment depends on the underlying cause. Treatments include iced saline, and topical vasoconstrictors such as adrenalin or vasopressin. Tranexamic acid was proved to improve in-hospital mortality. Selective bronchial intubation can be used to collapse the lung that is bleeding. Also, endobronchial tamponade can be used. Laser photocoagulation can be used to stop bleeding during bronchoscopy. Angiography of bronchial arteries can be performed to locate the bleeding, and it can often be embolized. Bronchial artery embolization (BAE) is the first line treatment nowadays. Surgical option is usually the last resort and can involve removal of a lung lobe or removal of the entire lung. Cough suppressants can increase the risk of choking. References Further reading == External links ==
Todds paresis	Todds paresis (or postictal paresis/paralysis, "after seizure") is focal weakness in a part or all of the body after a seizure. This weakness typically affects appendages and is localized to either the left or right side of the body. It usually subsides completely within 48 hours. Todds paresis may also affect speech, eye position (gaze), or vision. The condition is named after Robert Bentley Todd (1809–1860), an Irish-born London physiologist who first described the phenomenon in 1849. It may occur in up to 13% of seizure cases. It is most common after a focal motor seizure affecting one limb or one side of the body. The generally postulated cause is the exhaustion of the primary motor cortex, although no conclusive evidence is available to support this. Presentation The classic presentation of Todds paresis is a transient weakness of a hand, arm, or leg after focal seizure activity within that limb. The weakness may range in severity from mild to complete paralysis.When seizures affect areas other than the motor cortex, other transient neurological deficits can take place. These include sensory changes if the sensory cortex is involved by the seizure, visual field defects if the occipital lobe is involved, and aphasia if speech, comprehension or conducting fibers are involved.Postictal paresis (PP), although familiar to neurologists, has not been well-studied. One retrospective observational study evaluated 328 selected patients from ages 16 to 57 years who had prolonged video-electroencephalogram (EEG) monitoring for medically intractable epilepsy and focal seizure onset; those with nonepileptic seizures, status epilepticus, and Lennox-Gastaut syndrome were excluded. The following observations were made: PP occurred in 44 patients (13.4 percent) PP was always unilateral and always contralateral to the seizure focus The mean duration of PP was 174 seconds (range 11 seconds to 22 minutes)Of all seizures followed by PP, the following features were noted: Obvious ictal motor activity was seen in 78 percent (Todds paresis is more common after any clonic seizure activity) Very slight ictal motor activity was seen in 10 percent No ictal motor activity was seen in nearly 10 percent The most common ictal lateralizing sign was unilateral clonic activity in 56 percent Ictal dystonic posturing occurred in 48 percent Ictal limb immobility occurred in 25 percentThe results of this study are valuable because few other data exist on the frequency, duration, and seizure characteristics associated with PP. However, the study is likely biased by the inclusion only of patients with medically intractable seizures who had undergone video-EEG monitoring, and the results may not extrapolate to a general epilepsy population.Other post-ictal neurological findings that do not involve activity of the area affected by the seizure have been described. They are thought to be caused by a different mechanism than Todds paresis, and including paralysis of the contralateral limb, and rare genetic causes of hemiplegia and seizures. Causes The cause of Todds paresis has been attributed to the affected cortex being ‘exhausted’ or silenced due to increased inhibition, but these conjectures are not supported. It has been observed that the impairments that follow seizures are similar to those that follow strokes, where for a period of time blood flow to certain areas of the brain is restricted and these areas are starved of oxygen. Diagnosis The most significant issue regarding the Todds paresis is its differentiation from a stroke. The issue is further complicated by the fact that some strokes trigger a focal seizure during the acute phase. A Todds paresis in this context may overestimate the extent of neurological deficit due to the vascular process itself resulting in erroneous decisions with regards to acute stroke therapy such as thrombolysis. For this reason a seizure during an acute stroke is generally accepted to be a relative contraindication to thrombolytic therapy, especially in the absence of documented cerebrovascular occlusion using vascular imaging techniques.An infant with Todds paresis does not necessarily preclude the diagnosis of a febrile convulsion. This view is as a result of a recent study that showed the incidence of Todds paresis to be in 0.4% of infants that have been diagnosed with a febrile convulsion. Treatment There is no treatment for Todds paralysis. Individuals must rest as comfortably as possible until the paralysis disappears. Prognosis An occurrence of Todds paralysis indicates that a seizure has occurred. The prognosis for the patient depends upon the effects of the seizure, not the occurrence of the paralysis. References == External links ==
Pemphigoid	Pemphigoid is a group of rare autoimmune blistering diseases of the skin, and mucous membranes. As its name indicates, pemphigoid is similar in general appearance to pemphigus, but, unlike pemphigus, pemphigoid does not feature acantholysis, a loss of connections between skin cells.Pemphigoid is more common than pemphigus, and is slightly more common in women than in men. It is also more common in people aged over 70 years than it is in younger people. Classification IgG The forms of pemphigoid are considered to be connective tissue autoimmune skin diseases. There are several types: Gestational pemphigoid (PG) (formerly called Herpes gestationis) Bullous pemphigoid (BP) Rarely affects the mouth Mucous membrane pemphigoid (MMP) or (cicatricial pemphigoid), (No skin involvement)Bullous and mucous membrane pemphigoid usually affect persons who are over age 60. Gestational pemphigoid occurs during pregnancy, typically in the second or third trimester, or immediately following pregnancy. IgA Pemphigoid is usually considered to be mediated by IgG, but IgA-mediated forms have also been described.IgA-mediated immunobullous diseases can often be difficult to treat even with usually effective medications such as rituximab. Bullous pemphigoid Bullous pemphigoid is a rare and chronic autoimmune disorder characterised by large sub-epidermal blisters called bullae, that predominantly involves the skin and less commonly the mucous membranes. It is the most common type of the pemphigoid group, representing 80% of sub-epidermal immunobullous cases. It is more commonly known as cutaneous pemphigoid. Presentation Primary lesions of small and large blisters, known as vesicles and bullae, are found on the skin and sometimes on the mucous membranes. Non-bullous pemphigoid In some patients, pemphigoid starts off with cutaneous manifestations of BP without bullae, as the only sign of the disease. Pruritic eczematous, papular, or urticaria-like skin lesions may also persist for weeks to months. Bullous phase The bullous stage of BP shows vesicles and bulla, appearing on apparently normal or erythematous skin, predominantly at the flexural aspects of the extremities and the lower trunk. Mucosal lesions, which typically are erosions of the oral mucosa, are present in 10 to 30 percent of patients. Occasionally, the blister fluid becomes blood-tinged. The blisters are tense, about 1–4 cm in diameter, leaving eroded and crusted areas, together with urticarial and infiltrated papules and plaques in an annular or figurate pattern.Homology between bullous pemphigoid antigens in the skin and neuronal antigens in the central nervous system has been proposed as a cause for the observed link between bullous pemphigoid and neurologic disease, along with a genetic predisposition. Patients with bullous pemphigoid usually present with two or more other chronic diseases such as neurological disorders(dementia, Parkinsons disease, or stroke). However, further studies are necessary to explore the relationship between these disorders. Cause The pathogenetic mechanism of blister formation is known, the trigger to the formation of the antibodies to the hemidesmosome antigens is still unknown. Most of the bullous pemphigoid cases are due to autoantibodies (mostly IgG) directed at antigens (BP180 and BP230) arranged at the dermal-epidermal junction. However, most commonly, drug can be one of the cause of bullous pemphigoid, such as thiazide diuretics, antibiotics (e.g., penicillins, vancomycin), nonsteroidal anti-inflammatory drugs (NSAIDs) and angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril) and possibly angiotensin receptor blockers (ARBs, e.g., valsartan).The implicated drugs include penicillin derivatives, sulfasalazine, ibuprofen, phenacetin, enalapril, captopril, lisinopril, gabapentin, novoscabin, levobunolol ophthalmic solution, tetracoq, influenza, tetanus, and other vaccinations, a homeopathy regimen, nifedipine, 5-aminosalicylic acid, doxazosin, serratiopeptidase, losartan, cephalexin, bumetanide, fluoxetine, chloroquine, antipsychotic drugs, enoxaparin, ciprofloxacin, furosemide (frusemide), neuroleptics, penicillamine, gliptin plus metformin, intravenous iodine, etanercept, levofloxacin, and topical fluorouracil. Influenza vaccination does not appear to be an important trigger for bullous pemphigoid. Trauma, burns, lymphedema, phototherapy, and radiation have been implicated in a very small number of cases. Pathophysiology The pathophysiology of bullous pemphigoid consists of two major components, which are immunologic and inflammatory. In the immunologic component, autoantibodies act against the hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP 180(BPAg2 or type XVII collagen) which are located at the lamina lucida of the basement membrane zone. These antigens play an important role in the adhesion complexes that promote epithelial-stromal adhesion. The predominant subclass of antibodies that acts against the antigens is IgG4. IgG1 and IgG2 antibodies are less frequently detected compared to IgG4 antibodies, while IgG3 antibodies are usually absent. When the autoantibodies bind specifically to the target antigens, the complement system and mast cells are activated, thereby representing the inflammatory component. Inflammatory cells such as neutrophils and eosinophils are then attracted to the affected area. They are postulated to release proteolytic enzymes which degrade the hemidesmosomal proteins, resulting in blister formation.Other potential contributory factors including genetic factors, environmental exposures to infections and drugs as well as the phenomenon of epitope spreading are also known to cause bullous pemphigoid. Diagnosis Diagnosis of bullous pemphigoid includes clinical assessment, skin biopsy for histopathology and direct immunofluorescence, indirect immunofluorescence and ELISA test. Among all, direct immunofluorescence is the gold standard for diagnosis of bullous pemphigoid. Clinical assessment For patients greater than 70 years old Blistering skin disease characterized by the presence of tense blisters and erosions that occur without another identifiable cause and rarely on mucosa. Unexplained pruritus, pruritic eczematous eruptions, or urticarial plaques Histopathology Lesional tissue, preferably of an intact vesicle or the edge of an intact bulla is obtained using punch biopsy for Haemotoxylin and Eosin (H&E)staining. Typical histopathologic findings include: Sub-epidermal split with numerous eosinophils within the cleft. A superficial dermal inflammatory cell infiltrate of variable intensity with lymphocytes, eosinophils, and neutrophils. Eosinophlic spongiosis (Specifically in early lesion or may be seen in clinically erythematous skin surrounding the blister) Direct immunofluorescence Direct immunofluorescence (DIF) studies involves directly detecting tissue bound antibodies. Biopsy specimens for DIF should be taken from perilesional skin instead of lesional skin for H&E histopathologic evaluation. DIF specimens should be placed in Michels solution or Zeuss transport media instead of formalin. DIF of bullous pemphigoid will show the presence of fine, continuous and linear deposits of IgG and/or C3 along the epidermal basement membrane. Other classes of immunoglobulins such as IgM and IgA are present in approximately 20% of cases and usually are less intense. In some cases with the deposits of IgA, patient may have oral lesion. At early stages of the disease, only C3 may be present. Indirect immunofluorescence Indirect immunofluorescence is used to detect circulating antibodies targeting the antigens at the basement membrane zone in patients with pemphigoid. In this procedure, patients serum is collected and overlaid on salt-split normal human skin and incubated. Following this, the specimen will be stained for fluorescent detection of antibodies. In bullous pemphigoid, circulating IgG targeting the basement membrane, mainly BP180 and BP230 hemidesmosomal proteins are detectable in 60-80% of patients. IgA and IgE classes can also be detected, but less frequently. Enzyme-linked immunosorbent assay (ELISA) ELISA for bullous pemphigoid are commercially available to test for circulating Ig against NC16A domain of BP180 and BP230, known as bullous pemphigoid antigen 2 [BPAg2] and bullous pemphigoid antigen 1 [BPAg1] respectively. Antibodies to BP180NC16A domain is useful for the diagnosis of bullous pemphigoid as it has a sensitivity of 89% and specificity of 98%.Detection of BP180 and/or BP230 antibodies in serum does not give a confirmative diagnosis of bullous pemphigoid. A study has reported that 7% were tested positive for one or both autoantibodies in one series of 337 people without bullous pemphigoid. ELISA findings should be correlated with DIF to reduce the risk of misdiagnosis. Treatment The treatment for bullous pemphigoid include: 1. Corticosteroids i. Topical Corticosteroids ii. Systemic corticosteroids 2. Glucocorticoid-sparing drugs i. Immunosuppressive drugs ii. Anti-inflammatory drugs 3. Biologic therapy i. Intravenous immunoglobulin ii. Rituximab Among all, topical or systemic corticosteroids are considered as the first line therapy in controlling bullous pemphigoid. Other drugs and immunomodulatory therapies are often used as adjunct to minimize the adverse effect of long term use of corticosteroids and improve the healing of the disease. There are several factors that have to be taken into account when choosing the therapies given to the patient: (a) patients age (b) underlying disease such as hypertension, diabetes mellitus and other cardiovascular disease (c) side effect with the use of drugs (d) patients ability to compliant to the therapy (d) severity and extent of disease (e) cost of drugs. Corticosteroids High potency topical corticosteroid is preferred as the first line treatment due to its efficacy and fewer systemic adverse effects when compared to systemic corticosteroids. Studies have shown that patients with extensive bullous pemphigoid (defined as >10 new bullae per day) treated with topical corticosteroids (Topical Clobetasol Propionate 0.05% cream) had better clinical outcomes than patients with extensive bullae pemphigoid who were treated with systemic glucocorticoid therapy (Prednisone).Systemic glucocorticoids can be used for patients when there are factors that make the use of topical corticosteroids not feasible, such as elderly patient inability to apply the cream on their own, cost or patients own preference. Topical Corticosteroids Topical Clobetasol Propionate 0.05% cream is usually used and applied twice daily. A study by Joly et al. demonstrated that the use of 10 to 20g of Clobetasol Propionate per day for moderate disease and 20 to 30g per day for extensive disease until 15 days after disease control, then tapered to discontinuation over four months was as effective as the standard regime (40g per day tapered slowly over 12 months). Systemic corticosteroids Prednisone is usually used to treat bullous pemphigoid. The dose varies between 0.2 and 0.5 mg/kg/day and will continue until active inflammation, new blister formation, pruritus has stopped for at least 2 weeks. The dose is then slowly tapered over the months. Initially, prednisolone can be reduced by relative large amounts (approximately 10 mg) and smaller amount (2.5–5 mg) subsequently. Should the patient develop flare up of the lesion, the dose should be increased to the previous level or higher and maintained longer before further, slower tapering. Glucocorticoid sparing drugs For patients who require high dose of corticosteroids for clearing or maintenance, glucocorticoid sparing agents such as immunosuppressive drugs and anti-inflammatory drugs can be used as an adjunct therapy to reduce the systemic side effects of corticosteroids. Patients who have comorbidities and contraindications for corticosteroids may also consider these glucocorticoid sparing agents. Immunosuppressant drug Immunosuppressant drugs include azathioprine (1–3 mg/kg/day in two equally divided doses), mycophenolate mofetil (1000–3000 mg/day or 40 mg/kg/day in two divided doses), and methotrexate (10–15 mg/week). Anti-inflammatory drugs Tetracycline antibiotics are often used in combination of nicotinamide to treat bullous pemphigoid. For the administration of drugs, tetracycline is prescribed as 500 mg four times daily, doxycycline and minocycline as 100 mg twice daily and nicotinamide, 500 mg 4 times daily. Dapsone is also shown to be effective in treating bullous pemphigoid. However, the efficacy of dapsone is limited. Dapsone is usually commenced at a low dose of 25 to 50 mg/day and increase by 25 mg every week until the condition improves. Maximum dose that can be prescribed is 250 mg/day. Biologic therapy For refractory disease, biologic therapies such as intravenous immunoglobulin and Rituximab should be considered. [1,19,20] Epidemiology Bullous pemphigoid is primarily a disease of older adults and it rarely occurs in children. The vast majority of cases involved individuals between the ages of 60 and 80 years. Two European studies have also suggested the increased risk of bullous pemphigoid with advancing age.According to the results of several retrospective studies, there is an increasing incidence of bullous pemphigoid. Bullous pemphigoid can be considered as the most common autoimmune blistering disease in Europe, while pemphigus may be more common in locations such as Thailand and Malaysia. It is reported that bullous pemphigoid has a slight female preponderance. However, the reasons for this are unknown. Mucous membrane pemphigoid Mucous membrane pemphigoid (MMP), or cicatricial pemphigoid, is a rare, chronic, autoimmune sub-epidermal blistering disorder which predominantly involves the mucosae and has a tendency towards scarring of the affected areas. Any mucous membrane can be involved, but the most commonly involved site is the oral mucosa, followed by conjunctiva, skin, pharynx, external genitalia, nasal mucosa, larynx, anus, and esophagus. As MMP may lead to serious complications such as blindness and airway compression, early and aggressive treatment initiation may be needed. Presentation Scarring is a common consequence of MMP that distinguishes this variant from mucosal involvement in bullous pemphigoid, which typically does not scar. Reticulated, white striations representing mucosal fibrosis often are present at sites of healed lesions, and functional limitations secondary to scarring may occur. As examples, MMP involving the ocular mucosa can lead to symblepharon, ankyloblepharon, and eventual blindness, and progressive laryngeal and tracheal involvement can result in asphyxiation. Oral disease Most commonly affecting the mouth, including the buccal mucosa, gingiva, tongue, vermillion lips, and palate. Desquamative gingivitis is the most frequent manifestation. The gingiva is erythematous, in which patients usually complaint of bleeding upon brushing. Rupturing of oral vesiculobullous lesions leave clean, noninflamed, painless erosions. The vermilion border of the lips is spared, which is typical in pemphigus. Hoarseness due to laryngeal involvement can be seen in 8% of cases. A subset of patients have only oral disease, which has a relatively benign course compared with patients with oral cavity and other mucosae and skin involvement. Ocular disease The eye is involved in 65% of cases. Initially presented with unilateral conjunctivitis (such as burning or excessive tearing), then fibrosis beneath the conjunctival epithelium. Shrinkage of the conjunctiva leads to obliteration of the conjunctival sac. Symblepharons are fibrous strands connecting the conjunctiva of the lid to the globe. Besides, reduced tearing with erosion and neovascularization of the cornea leads to corneal opacification and perforation. Scarring of the lid results in entropion (inward turning of the lid) and trichiasis (in-turning of the eyelashes). These conditions ultimately lead to blindness in approximately 20% of cases. It is crucial to go for follow-up because relapse occurs in 22% of those who were in remission and not undergoing therapy. Other mucous membranes Less common sites that might get involved are nasopharynx, esophagus, and urethra. Nasopharyngeal involvement can lead to ulcerations of the septum and airway obstruction which might require tracheostomy. Esophageal disease may present with ulcerations, dysphagia, odynophagia, and stenosis. Stenosis at urethra, vaginal orifice and rectal have also resulted from chronic inflammation and scarring. Skin disease About 25% of patients have cutaneous lesions, with tense vesicles or bullae, mainly on the face, neck, and scalp. Healing of erosion is either with or without atrophic scars. Cutaneous lesions of mucous membrane pemphigoid presents in 2 subtypes: (1)presents as generalized eruption of tense bullae without scarring (2) presents as localised blisters on an erythematous base, resulting in atrophic scarring. Mucous membrane pemphigoid is also associated with malignancy Malignancy — MMP with antibodies directed against laminin 332 (previously known as laminin 5 and epiligrin) has been associated with an increased risk for internal malignancy. In a cohort of 35 patients with this type of pemphigoid (diagnosed with immunoprecipitation), 10 (29 percent) developed solid organ malignancies, 7 of which were diagnosed within 14 months after a diagnosis of MMP. Occurrences of non-Hodgkin lymphoma and cutaneous T cell lymphoma have also been reported in individual patients with anti-laminin 332 MMP. The pathophysiologic relationship of this subtype of MMP to cancer is unknown. However, expression of laminin 332 has been detected in malignant cells, and laminin 332 appears to be capable of promoting tumor cell growth, invasion, and metastasis.The clinical manifestations of MMP in patients with laminin 332 antibodies are similar to the features of MMP with other antibody profiles. Therefore, clinical examination cannot reliably distinguish anti-laminin 332 MMP from other forms of MMP. Additional studies are necessary to confirm the findings of a retrospective study of 154 patients with MPP that associated the detection of laminin 332 antibodies via a novel enzyme-linked immunosorbent assay (ELISA) with a greater likelihood for severe disease. Since diagnostic laboratory testing for laminin 332 antibodies is not commercially available, suspicion for laminin 332 primarily is based upon immunofluorescence microscopy findings. Although not exclusive to laminin 332 MPP, the detection of antibodies bound to the dermal side of basement membrane zone-split (salt-split) skin suggests the possibility of this diagnosis. Until definitive testing for laminin 332 antibodies becomes available, we recommend that patients with MMP in whom serum indirect immunofluorescence (IIF) studies reveal antibodies bound to the dermal side of basement membrane zone-split skin undergo age and gender appropriate cancer screening. Additional evaluation for malignancy should be performed as indicated based upon a review of symptoms, physical examination, and the results of age-appropriate screening. Cause Autoantibodies targeted to components of the basement membrane zone have been identified as pathogenic in mucous membrane pemphigoid. Antigens include 180-kD bullous pemphigoid antigen (BP180), laminin 332, beta-4-integrin, and other antigens that are not fully discovered are identified against the basement membrane. Complication of D- penicillamine therapy may trigger and causes mucous membrane pemphigoid. It also occurs after acute severe ocular inflammation in patients with Stevens-Johnson syndrome. Pathophysiology Autoantibodies target the basement membrane zone proteins which are responsible to promote adhesion within the basement membrane zone of the mucosa and the skin. The major basement membrane zone proteins identified include : C-terminus of BP180 BP230 Laminin 332(also known as laminin 5 or epiligrin) Alpha-6-beta-4 integrin Type VII collagen.In contrast to the target of the N-terminus of BP180 that is located in the hemidesmosomes and upper lamina lucida in bullous pemphigoid, the target antigen in MMP is the C-terminus of BP180 which is located in the lower lamina lucida and lamina densa. This results in a deeper separation that is more likely to scar as compared to a more superficial blister that is unlikely to scar in bullous pemphigoid. Antibodies to the beta-4 integrin subunit of alpha-6-beta-4 integrin is shown to be associated with ocular disease while oral involvement is suggested to be linked with antibody reaction towards the alpha-6 subunit. Besides, MMP with antibody reaction against laminin 332 has an association with an increased risk for internal malignancy. Similar to bullous pemphigoid, other factors such as genetic factors, environmental exposures and the phenomenon of epitope spreading potentially result in MMP. Multiple studies have also reported an association of HLA-DQB1*0301 with MPP. Diagnosis Diagnosis of bullous pemphigoid includes clinical assessment, skin biopsy for histopathology and direct immunofluorescence, indirect immunofluorescence and ELISA test. Among all, direct immunofluorescence is the gold standard for diagnosis of mucous membrane pemphigoid. Clinical assessment Presence of tense blisters and erosions that occur on skin without another identifiable cause. Desquamative gingivitis or mucositis involving oral, ocular, nasal, genital, anal, pharyngeal, laryngeal, and/or esophageal mucosae Presence of pruritic eczematous eruptions, or urticarial plaques without identifiable cause. Patients age over 60 years old. Histopathology Lesional tissue, preferably of an intact vesicle or the edge of an intact bulla is obtained using punch biopsy for Haemotoxylin and Eosin (H&E) staining. The findings are sub-epidermal blister with dermal infiltrated with lymphocytes, neutrophils and eosinophils. Additional findings include sub-epidermal fibrosis which is consistent with the scarring nature of mucous membrane pemphigoid in older lesions and plasma cell infiltration. Direct immunofluorescence studies Direct immunofluorescence (DIF) studies involves directly detecting tissue bound antibodies. Biopsy specimens for DIF should be taken from perilesional skin instead of lesional skin for H&E histopathologic evaluation. Linear band of IgG and C3 deposits are found along the basement membrane. Occasionally, linear deposition of IgA at the basement membrane zone can also be seen. Multiple and repeated biopsies increase the sensitivity of DIF studies to diagnose MMP. Indirect immunofluorescence Indirect immunofluorescence is used to detect circulating antibodies targeting the antigens at the basement membrane zone in patients with pemphigoid. In early studies using routine techniques, only one third of patient with MPP were being tested positive. Circulating IgG and IgA antibodies are found in patients serum. To increase the likelihood of detecting circulating antibodies, human basement membrane zone-split skin and/or concentrated serum should be used. Antigen-specific serologic testing Autoantibodies directed against a variety of antigens, including BP180, BP230, laminin 332, and type VII collagen may be detected. However, this test could not be used as the only diagnostic tool for testing as ELISA testing has limited sensitivity. Treatment The factors that determine the type of therapy used for mucous membrane pemphigoid are: [1] site(s) of involvement, [2] severity of disease, [3] rate of progression. Oral mucosa is the most common site being affected in mucous membrane pemphigoid. For the mild oral mucosa lesion, high potency topical steroids such as 0.05% Clobetasol propionate is used. Patients are instructed to apply the ointment or gel 2-3 times a day after drying the oral mucosa to enhance the adherence of mediation to oral mucosa. Patients are instructed to avoid drinking or eating for at least 30 minutes after application. Dental tray can also be fabricated to help in the application of topical steroids to lesional sites under occlusion for patients with gingival involvement. Furthermore, topical tacrolimus, a calcineurin inhibitor, has also shown to be effective to control the disease, including some patients who failed to respond well to topical corticosteroids. Topical tacrolimus 0.1% ointment is applied two to three times a day and tapered after improvement in healing of pemphigoid. Another method is to use intralesional corticosteroids (Triamcinolone acetonide, dilution of 5 to 10 mg/ml; repeated every 2–4 weeks). Intralesional therapy is used when the patient does not respond to local therapies. For moderate to severe disease (including the ones involving ocular, nasopharyngeal, or anogenital mucosa) and patient who did not respond to local therapy adequately, systemic agents should be used. Systemic corticosteroids and dapsone are used in such cases. The dose of dapsone ranges from 50 to 200 mg daily. Dapsone is shown to be effective in treating mucous membrane pemphigoid that does not respond to systemic corticosteroids. Whereas for systemic corticosteroids, 0.25 to 0.5 mg/kg of prednisolone is prescribed per day (twice-daily dosage is used during the acute stage and change to a single daily morning dose after new blister formation stops). Thereafter, the dosage of prednisolone is slowly tapered over the months in combination with topical therapy or glucocorticoid-sparing agent (e.g., dapsone, azathioprine). Patients with severe mucous membrane pemphigoid that cannot be controlled by the intervention above and would need aggressive immunosuppressive regimens and biologic therapies to control the lesions. Azathioprine or Cyclosphosphamide are the choices of immunosuppressive drugs that can be used. Sometimes, immunosuppressive agents and pred
Pemphigoid	nisolone can be combined if dapsone fails to improve the condition. Lastly, in patients who do not respond to the conventional therapy, rituximab may be an option.There is insufficient evidence that cyclophosphamide combined with corticosteriods are effective in treating mucous membrane pemphigoid.Other than that, oral hygiene instructions should be given to patients as oral care is a critical part in treating mucous membrane pemphigoid. Before meals, patients are advised to rinse with hydrogen peroxide (diluted with water to a concentration of 1:4 or 1:6) and diphenhydramine to reduce the pain. Patient would then rinse with hydrogen peroxide to remove food particles and debris and later rinse with dexamethasone for anti-inflammatory effect. Hydrogen peroxide, elixir of dexamethasone and elixir of diphenhydramine are each diluted with water to a concentration of 1:4 or 1:6 and are instructed not to swallow in the end. Epidemiology MMP mainly affect the elderly population of ages between 60 and 80 years and rarely children. Women are affected twice as frequently than in men. There is no known racial or geographic predilection, but several studies have suggested that there is an association of specific immunogenetic haplotype HLA-DQB1*0301 with MMP. See also List of cutaneous conditions List of target antigens in pemphigoid References Further reading == External links ==
Spinal disease	Spinal disease refers to a condition impairing the backbone. These include various diseases of the back or spine ("dorso-"), such as kyphosis. Dorsalgia refers to back pain. Some other spinal diseases include spinal muscular atrophy, ankylosing spondylitis, lumbar spinal stenosis, spina bifida, spinal tumors, osteoporosis and cauda equina syndrome. Types There are many recognized spinal diseases, some more common than others. Spinal disease also includes cervical spine diseases, which are diseases in the vertebrae of the neck. A lot of flexibility exists within the cervical spine and because of that, it is common for an individual to damage that area, especially over a long period of time. Some of the common cervical spine diseases include degenerative disc disease, cervical stenosis, and cervical disc herniation. Degenerative disc disease occurs over time when the discs within each vertebra in the neck begin to fall apart and begin to disintegrate. Because each vertebra can cause pain in different areas of the body, the pain from the disease can be sensed in the back, leg, neck area, or even the arms. When the spinal canal begins to lose its gap and gets thinner, it can cause pain in the neck, which can also cause a numb feeling in the arms and hands. Those are symptoms of cervical stenosis disease. The discs between each vertebra have fibers that can begin to deteriorate, and this can occur in cervical disc herniation. This disease is less common in younger people as it is usually a function of aging. Scoliosis Scoliosis is a common spinal disease in which the spine has a curvature usually in the shape of the letter "C" or "S". This is most common in girls, but there is no specific cause for scoliosis. Only a few symptoms occur for one with this disease, which include feeling tired in the spinal region or backaches. Generally, if the hips or shoulders are uneven, or if the spine curves, it is due to scoliosis and should be seen by a doctor. Lumbar spinal stenosis Lumbar spinal stenosis is classified as a narrowing of the spinal canal in the lumbar region of the vertebrae. This may lead to compression of the nerve root of the spinal cord and result in pain of the lower back and lower extremities. Other symptoms include impaired walking and a slightly stooped posture due to loss of disc height and bulging of the disc. Lumbar spinal stenosis is very prevalent with 9.3% of the general population producing symptoms and the number is continuing to rise in patients older than 60. Its generally an indication for spinal surgery in patients older than 65 years of age. However, there is a myth and fear among most patients that only surgery is the cure for such conditions and spine surgery is very risky. There are many non-surgical treatments available to prevent, halt and even reverse many spine diseases. Also, some surgery patients can be operated on in a daycare procedure or with minimum length of stay in hospital, with statistically good outcomes. Spina bifida Spina bifida is the most common defect impacting the Central Nervous System (CNS). The most common and most severe form of Spina Bifida is Myelomeningocele. Individuals with Myelomeningocele are born with an incompletely fused spine, and therefore exposing the spinal cord through an opening in the back. In general, the higher the spinal lesion, the greater the functional impairment to the individual. Symptoms may include bowel and bladder problems, weakness and/or loss of sensation below the level of the lesion, paralysis, or orthopedic issues. Severity of symptoms can vary per situation. Cauda equina syndrome Cauda equina syndrome is a rare syndrome that effects the spinal nerves in the region of the lower back called the cauda equine (Latin for "horses tail"). Injury to the cauda equine can have long lasting ramifications for the individual. Symptoms include lower back pain, bladder disturbances, bowel dysfunction, and anesthesia or paresthesia between the thighs. In order to prevent progressive neurological changes surgery can be a viable option. Tumors A spinal tumor is when unusual tissue begins growing and spreading in the spinal columns or spinal cords. The unusual tissue builds up from abnormal cells that multiply quickly in a specific region. Tumors generally are broken down into categories known as benign, meaning non-cancerous, or malignant, meaning cancerous, and also primary or secondary. Primary spinal tumors begin in either the spinal cord or spinal column, whereas secondary spinal tumors begin elsewhere and spread to the spinal region. Symptoms for spinal tumors may vary due to factors such as the type of tumor, the region of the spine, and the health of the patient. Back pain is the most common symptom and it can be a problem if the pain is severe, has a time frame that lasts longer than it would for a normal injury, and becomes worse while laying down or at rest. Other symptoms, excluding back pains, are loss of muscle function, loss of bowel or bladder function, pain in the legs, scoliosis, or even unusual sensations in the legs. The primary tumor has no known cause, although there are possible answers that scientists have researched. Cancer may be linked to genes because research shows that in certain families, the incidents of spinal tumors are higher. Two of the genetic disorders that may affect spinal tumors, include Von Hippel-Lindau disease and Neurofibromatosis 2. Von Hippel-Lindau disease is a non-cancerous tumor of blood vessels that occur in the brain, spinal cord, or even tumors in the kidneys. The Neuroflibromatosis 2 is a non-cancerous tumor that usually affects the nerves for hearing. Loss of hearing in one or both ears, is a common effect of this genetic disorder. References == External links ==
Pregnancy	Pregnancy is the time during which one or more offspring develops (gestates) inside a womans uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but can also occur through assisted reproductive technology procedures. A pregnancy may end in a live birth, a miscarriage, an induced abortion, or a stillbirth. Childbirth typically occurs around 40 weeks from the start of the last menstrual period (LMP), a span known as the gestational age. This is just over nine months. Counting by fertilization age, the length is about 38 weeks. Pregnancy is "the presence of an implanted human embryo or fetus in the uterus"; implantation occurs on average 8–9 days after fertilization. An embryo is the term for the developing offspring during the first seven weeks following implantation (i.e. ten weeks gestational age), after which the term fetus is used until birth.Signs and symptoms of early pregnancy may include missed periods, tender breasts, morning sickness (nausea and vomiting), hunger, implantation bleeding, and frequent urination. Pregnancy may be confirmed with a pregnancy test. Methods of birth control—or, more accurately, contraception—are used to avoid pregnancy. Pregnancy is divided into three trimesters of approximately three months each. The first trimester includes conception, which is when the sperm fertilizes the egg. The fertilized egg then travels down the Fallopian tube and attaches to the inside of the uterus, where it begins to form the embryo and placenta. During the first trimester, the possibility of miscarriage (natural death of embryo or fetus) is at its highest. Around the middle of the second trimester, movement of the fetus may be felt. At 28 weeks, more than 90% of babies can survive outside of the uterus if provided with high-quality medical care, though babies born at this time will likely experience serious health complications such as heart and respiratory problems and long-term intellectual and developmental disabilities. Prenatal care improves pregnancy outcomes. Nutrition during pregnancy is important to ensure healthy growth of the fetus. Prenatal care may also include avoiding drugs, tobacco smoking, and alcohol, taking regular exercise, having blood tests, and regular physical examinations. Complications of pregnancy may include disorders of high blood pressure, gestational diabetes, iron-deficiency anemia, and severe nausea and vomiting. In the ideal childbirth labor begins on its own when a woman is "at term". Babies born before 37 weeks are "preterm" and at higher risk of health problems such as cerebral palsy. Babies born between weeks 37 and 39 are considered "early term" while those born between weeks 39 and 41 are considered "full term". Babies born between weeks 41 and 42 weeks are considered "late term" while after 42 weeks they are considered "post term". Delivery before 39 weeks by labor induction or caesarean section is not recommended unless required for other medical reasons.About 213 million pregnancies occurred in 2012, of which, 190 million (89%) were in the developing world and 23 million (11%) were in the developed world. The number of pregnancies in women aged between 15 and 44 is 133 per 1,000 women. About 10% to 15% of recognized pregnancies end in miscarriage. In 2016, complications of pregnancy resulted in 230,600 maternal deaths, down from 377,000 deaths in 1990. Common causes include bleeding, infections, hypertensive diseases of pregnancy, obstructed labor, miscarriage, abortion, or ectopic pregnancy. Globally, 44% of pregnancies are unplanned. Over half (56%) of unplanned pregnancies are aborted. Among unintended pregnancies in the United States, 60% of the women used birth control to some extent during the month pregnancy began. Terminology Associated terms for pregnancy are gravid and parous. Gravidus and gravid come from the Latin word meaning "heavy" and a pregnant female is sometimes referred to as a gravida. Gravidity refers to the number of times that a female has been pregnant. Similarly, the term parity is used for the number of times that a female carries a pregnancy to a viable stage. Twins and other multiple births are counted as one pregnancy and birth. A woman who has never been pregnant is referred to as a nulligravida. A woman who is (or has been only) pregnant for the first time is referred to as a primigravida, and a woman in subsequent pregnancies as a multigravida or as multiparous. Therefore, during a second pregnancy a woman would be described as gravida 2, para 1 and upon live delivery as gravida 2, para 2. In-progress pregnancies, abortions, miscarriages and/or stillbirths account for parity values being less than the gravida number. Women who have never carried a pregnancy more than 20 weeks are referred to as nulliparous.A pregnancy is considered term at 37 weeks of gestation. It is preterm if less than 37 weeks and postterm at or beyond 42 weeks of gestation. American College of Obstetricians and Gynecologists have recommended further division with early term 37 weeks up to 39 weeks, full term 39 weeks up to 41 weeks, and late term 41 weeks up to 42 weeks. The terms preterm and postterm have largely replaced earlier terms of premature and postmature. Preterm and postterm are defined above, whereas premature and postmature have historical meaning and relate more to the infants size and state of development rather than to the stage of pregnancy. Signs and symptoms The usual signs and symptoms of pregnancy do not significantly interfere with activities of daily living or pose a health-threat to the mother or baby. However, pregnancy complications can cause other more severe symptoms, such as those associated with anemia. Common signs and symptoms of pregnancy include: Tiredness Morning sickness Constipation Pelvic girdle pain Back pain Braxton Hicks contractions. Occasional, irregular, and often painless contractions that occur several times per day. Peripheral edema swelling of the lower limbs. Common complaint in advancing pregnancy. Can be caused by inferior vena cava syndrome resulting from compression of the inferior vena cava and pelvic veins by the uterus leading to increased hydrostatic pressure in lower extremities. Low blood pressure often caused by compression of both the inferior vena cava and the abdominal aorta (aortocaval compression syndrome). Increased urinary frequency. A common complaint, caused by increased intravascular volume, elevated glomerular filtration rate, and compression of the bladder by the expanding uterus. Urinary tract infection Varicose veins. Common complaint caused by relaxation of the venous smooth muscle and increased intravascular pressure. Hemorrhoids (piles). Swollen veins at or inside the anal area. Caused by impaired venous return, straining associated with constipation, or increased intra-abdominal pressure in later pregnancy. Regurgitation, heartburn, and nausea. Stretch marks Breast tenderness is common during the first trimester, and is more common in women who are pregnant at a young age. Melasma, also known as the mask of pregnancy, is a discoloration, most often of the face. It usually begins to fade several months after giving birth. Timeline The chronology of pregnancy is, unless otherwise specified, generally given as gestational age, where the starting point is the beginning of the womans last menstrual period (LMP), or the corresponding age of the gestation as estimated by a more accurate method if available. This model means that the woman is counted as being "pregnant" two weeks before conception and three weeks before implantation. Sometimes, timing may also use the fertilization age, which is the age of the embryo since conception. Start of gestational age The American Congress of Obstetricians and Gynecologists recommend the following methods to calculate gestational age: Directly calculating the days since the beginning of the last menstrual period. Early obstetric ultrasound, comparing the size of an embryo or fetus to that of a reference group of pregnancies of known gestational age (such as calculated from last menstrual periods), and using the mean gestational age of other embryos or fetuses of the same size. If the gestational age as calculated from an early ultrasound is contradictory to the one calculated directly from the last menstrual period, it is still the one from the early ultrasound that is used for the rest of the pregnancy. In case of in vitro fertilization, calculating days since oocyte retrieval or co-incubation and adding 14 days. Trimesters Pregnancy is divided into three trimesters, each lasting for approximately three months. The exact length of each trimester can vary between sources. The first trimester begins with the start of gestational age as described above, that is, the beginning of week 1, or 0 weeks + 0 days of gestational age (GA). It ends at week 12 (11 weeks + 6 days of GA) or end of week 14 (13 weeks + 6 days of GA). The second trimester is defined as starting, between the beginning of week 13 (12 weeks +0 days of GA) and beginning of week 15 (14 weeks + 0 days of GA). It ends at the end of week 27 (26 weeks + 6 days of GA) or end of week 28 (27 weeks + 6 days of GA). The third trimester is defined as starting, between the beginning of week 28 (27 weeks + 0 days of GA) or beginning of week 29 (28 weeks + 0 days of GA). It lasts until childbirth. Estimation of due date Due date estimation basically follows two steps: Determination of which time point is to be used as origin for gestational age, as described in the section above. Adding the estimated gestational age at childbirth to the above time point. Childbirth on average occurs at a gestational age of 280 days (40 weeks), which is therefore often used as a standard estimation for individual pregnancies. However, alternative durations as well as more individualized methods have also been suggested.The American College of Obstetricians and Gynecologists divides full term into three devisions: Early-term: 37 weeks and 0 days through 38 weeks and 6 days Full-term: 39 weeks and 0 days through 40 weeks and 6 days Late-term: 41 weeks and 0 days through 41 weeks and 6 days Post-term: greater than or equal to 42 weeks and 0 daysNaegeles rule is a standard way of calculating the due date for a pregnancy when assuming a gestational age of 280 days at childbirth. The rule estimates the expected date of delivery (EDD) by adding a year, subtracting three months, and adding seven days to the origin of gestational age. Alternatively there are mobile apps, which essentially always give consistent estimations compared to each other and correct for leap year, while pregnancy wheels made of paper can differ from each other by 7 days and generally do not correct for leap year.Furthermore, actual childbirth has only a certain probability of occurring within the limits of the estimated due date. A study of singleton live births came to the result that childbirth has a standard deviation of 14 days when gestational age is estimated by first trimester ultrasound, and 16 days when estimated directly by last menstrual period. Physiology Capacity Fertility and fecundity are the respective capacities to fertilize and establish a clinical pregnancy and have a live birth. Infertility is an impaired ability to establish a clinical pregnancy and sterility is the permanent inability to establish a clinical pregnancy.The capacity for pregnancy depends on the reproductive system, its development and its variation, as well as on the condition of a person. Women as well as intersex and transgender people who have a functioning female reproductive system are capable of pregnancy. In some cases, someone might be able to produce fertilizable eggs, but might not have a womb or none that can sufficiently gestate, in which case they might find surrogacy. Initiation Through an interplay of hormones that includes follicle stimulating hormone that stimulates folliculogenesis and oogenesis creates a mature egg cell, the female gamete. Fertilization is the event where the egg cell fuses with the male gamete, spermatozoon. After the point of fertilization, the fused product of the female and male gamete is referred to as a zygote or fertilized egg. The fusion of female and male gametes usually occurs following the act of sexual intercourse. Pregnancy rates for sexual intercourse are highest during the menstrual cycle time from some 5 days before until 1 to 2 days after ovulation. Fertilization can also occur by assisted reproductive technology such as artificial insemination and in vitro fertilisation. Fertilization (conception) is sometimes used as the initiation of pregnancy, with the derived age being termed fertilization age. Fertilization usually occurs about two weeks before the next expected menstrual period. A third point in time is also considered by some people to be the true beginning of a pregnancy: This is time of implantation, when the future fetus attaches to the lining of the uterus. This is about a week to ten days after fertilization. Development of embryo and fetus The sperm and the egg cell, which has been released from one of the females two ovaries, unite in one of the two Fallopian tubes. The fertilized egg, known as a zygote, then moves toward the uterus, a journey that can take up to a week to complete. Cell division begins approximately 24 to 36 hours after the female and male cells unite. Cell division continues at a rapid rate and the cells then develop into what is known as a blastocyst. The blastocyst arrives at the uterus and attaches to the uterine wall, a process known as implantation. The development of the mass of cells that will become the infant is called embryogenesis during the first approximately ten weeks of gestation. During this time, cells begin to differentiate into the various body systems. The basic outlines of the organ, body, and nervous systems are established. By the end of the embryonic stage, the beginnings of features such as fingers, eyes, mouth, and ears become visible. Also during this time, there is development of structures important to the support of the embryo, including the placenta and umbilical cord. The placenta connects the developing embryo to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mothers blood supply. The umbilical cord is the connecting cord from the embryo or fetus to the placenta. After about ten weeks of gestational age—which is the same as eight weeks after conception—the embryo becomes known as a fetus. At the beginning of the fetal stage, the risk of miscarriage decreases sharply. At this stage, a fetus is about 30 mm (1.2 inches) in length, the heartbeat is seen via ultrasound, and the fetus makes involuntary motions. During continued fetal development, the early body systems, and structures that were established in the embryonic stage continue to develop. Sex organs begin to appear during the third month of gestation. The fetus continues to grow in both weight and length, although the majority of the physical growth occurs in the last weeks of pregnancy. Electrical brain activity is first detected at the end of week 5 of gestation, but as in brain-dead patients, it is primitive neural activity rather than the beginning of conscious brain activity. Synapses do not begin to form until week 17. Neural connections between the sensory cortex and thalamus develop as early as 24 weeks gestational age, but the first evidence of their function does not occur until around 30 weeks, when minimal consciousness, dreaming, and the ability to feel pain emerges.Although the fetus begins to move during the first trimester, it is not until the second trimester that movement, known as quickening, can be felt. This typically happens in the fourth month, more specifically in the 20th to 21st week, or by the 19th week if the woman has been pregnant before. It is common for some women not to feel the fetus move until much later. During the second trimester, when the body size changes, maternity clothes may be worn. Maternal changes During pregnancy, a woman undergoes many physiological changes, which are entirely normal, including behavioral, cardiovascular, hematologic, metabolic, renal, and respiratory changes. Increases in blood sugar, breathing, and cardiac output are all required. Levels of progesterone and estrogens rise continually throughout pregnancy, suppressing the hypothalamic axis and therefore also the menstrual cycle. A full-term pregnancy at an early age (< 25) reduces the risk of breast, ovarian and endometrial cancer and the risk declines further with each additional full-term pregnancy. The fetus is genetically different from its mother, and can be viewed as an unusually successful allograft. The main reason for this success is increased immune tolerance during pregnancy. Immune tolerance is the concept that the body is able to not mount an immune system response against certain triggers.During the first trimester, minute ventilation increases by 40%. The womb will grow to the size of a lemon by eight weeks. Many symptoms and discomforts of pregnancy like nausea and tender breasts appear in the first trimester.During the second trimester, most women feel more energized, and begin to put on weight as the symptoms of morning sickness subside and eventually fade away. The uterus, the muscular organ that holds the developing fetus, can expand up to 20 times its normal size during pregnancy. Braxton Hicks contractions are sporadic uterine contractions that may start around six weeks into a pregnancy; however, they are usually not felt until the second or third trimester.Final weight gain takes place during the third trimester, which is the most weight gain throughout the pregnancy. The womans abdomen will transform in shape as it drops due to the fetus turning in a downward position ready for birth. During the second trimester, the womans abdomen would have been upright, whereas in the third trimester it will drop down low. The fetus moves regularly, and is felt by the woman. Fetal movement can become strong and be disruptive to the woman. The womans navel will sometimes become convex, "popping" out, due to the expanding abdomen. Head engagement, also called "lightening" or "dropping", occurs as the fetal head descends into a cephalic presentation. While it relieves pressure on the upper abdomen and gives a renewed ease in breathing, it also severely reduces bladder capacity resulting in a need to void more frequently, and increases pressure on the pelvic floor and the rectum. It is not possible to predict when lightening occurs. In a first pregnancy it may happen a few weeks before the due date, though it may happen later or even not until labor begins, as is typical with subsequent pregnancies.It is also during the third trimester that maternal activity and sleep positions may affect fetal development due to restricted blood flow. For instance, the enlarged uterus may impede blood flow by compressing the vena cava when lying flat, which is relieved by lying on the left side. Childbirth Childbirth, referred to as labor and delivery in the medical field, is the process whereby an infant is born.A woman is considered to be in labour when she begins experiencing regular uterine contractions, accompanied by changes of her cervix—primarily effacement and dilation. While childbirth is widely experienced as painful, some women do report painless labours, while others find that concentrating on the birth helps to quicken labour and lessen the sensations. Most births are successful vaginal births, but sometimes complications arise and a woman may undergo a cesarean section. During the time immediately after birth, both the mother and the baby are hormonally cued to bond, the mother through the release of oxytocin, a hormone also released during breastfeeding. Studies show that skin-to-skin contact between a mother and her newborn immediately after birth is beneficial for both the mother and baby. A review done by the World Health Organization found that skin-to-skin contact between mothers and babies after birth reduces crying, improves mother–infant interaction, and helps mothers to breastfeed successfully. They recommend that neonates be allowed to bond with the mother during their first two hours after birth, the period that they tend to be more alert than in the following hours of early life. Childbirth maturity stages In the ideal childbirth labor begins on its own when a woman is "at term". Events before completion of 37 weeks are considered preterm. Preterm birth is associated with a range of complications and should be avoided if possible.Sometimes if a womans water breaks or she has contractions before 39 weeks, birth is unavoidable. However, spontaneous birth after 37 weeks is considered term and is not associated with the same risks of a preterm birth. Planned birth before 39 weeks by caesarean section or labor induction, although "at term", results in an increased risk of complications. This is from factors including underdeveloped lungs of newborns, infection due to underdeveloped immune system, feeding problems due to underdeveloped brain, and jaundice from underdeveloped liver.Babies born between 39 and 41 weeks gestation have better outcomes than babies born either before or after this range. This special time period is called "full term". Whenever possible, waiting for labor to begin on its own in this time period is best for the health of the mother and baby. The decision to perform an induction must be made after weighing the risks and benefits, but is safer after 39 weeks.Events after 42 weeks are considered postterm. When a pregnancy exceeds 42 weeks, the risk of complications for both the woman and the fetus increases significantly. Therefore, in an otherwise uncomplicated pregnancy, obstetricians usually prefer to induce labour at some stage between 41 and 42 weeks. Postnatal period The postpartum period also referred to as the puerperium, is the postnatal period that begins immediately after delivery and extends for about six weeks. During this period, the mothers body begins the return to pre-pregnancy conditions that includes changes in hormone levels and uterus size. Diagnosis The beginning of pregnancy may be detected either based on symptoms by the woman herself, or by using pregnancy tests. However, an important condition with serious health implications that is quite common is the denial of pregnancy by the pregnant woman. About 1 in 475 denials will last until around the 20th week of pregnancy. The proportion of cases of denial, persisting until delivery is about 1 in 2500. Conversely, some non-pregnant women have a very strong belief that they are pregnant along with some of the physical changes. This condition is known as a false pregnancy. Physical signs Most pregnant women experience a number of symptoms, which can signify pregnancy. A number of early medical signs are associated with pregnancy. These signs include: the presence of human chorionic gonadotropin (hCG) in the blood and urine missed menstrual period implantation bleeding that occurs at implantation of the embryo in the uterus during the third or fourth week after last menstrual period increased basal body temperature sustained for over two weeks after ovulation Chadwicks sign (darkening of the cervix, vagina, and vulva) Goodells sign (softening of the vaginal portion of the cervix) Hegars sign (softening of the uterine isthmus) Pigmentation of the linea alba – linea nigra, (darkening of the skin in a midline of the abdomen, resulting from hormonal changes, usually appearing around the middle of pregnancy). Darkening of the nipples and areolas due to an increase in hormones. Biomarkers Pregnancy detection can be accomplished using one or more various pregnancy tests, which detect hormones generated by the newly formed placenta, serving as biomarkers of pregnancy. Blood and urine tests can detect pregnancy 12 days after implantation. Blood pregnancy tests are more sensitive than urine tests (giving fewer false negatives). Home pregnancy tests are urine tests, and normally detect a pregnancy 12 to 15 days after fertilization. A quantitative blood test can determine approximately the date the embryo was conceived because hCG doubles every 36 to 48 hours. A single test of progesterone levels can also help determine how likely a fetus will survive in those with a threatened miscarriage (bleeding in early pregnancy). Ultrasound Obstetric ultrasonography can detect fetal abnormalities, detect multiple pregnancies, and improve gestational dating at 24 weeks. The resultant estimated gestational age and due date of the fetus are slightly more accurate than methods based on last menstrual period. Ultrasound is used to measure the nuchal fold in order to screen for Down syndrome. Management Prenatal care Pre-conception counseling is care that is provided to a woman or couple to discuss conception, pregnancy, current health issues and recommendations for the period before pregnancy.Prenatal medical care is the medical and nursing care recommended for women during pregnancy, time intervals and exact goals of each visit differ by country. Women who are high risk have better outcomes if they are seen regularly and frequently by a medical professional than women who are low risk. A woman can be labeled as high risk for different reasons including previous complications in pregnancy, complications in the current pregnancy, current medical diseases, or social issues.The aim of good prenatal care is prevention, early identification, and treatment of any medical complications. A basic prenatal visit consists of measurement of blood pressure, fundal height, weight and fetal heart rate, checking for symptoms of labor, and guidance for what to expect next. Nutrition Nutrition during pregnancy is important to ensure healthy growth of the fetus. Nutrition during pregnancy is different from the non-pregnant state. There are increased energy requirements and specific micronutrient requirements. Women benefit from education to encourage a balanced energy and protein intake during pregnancy. Some women may need professional medical advice if their diet is affected by medical conditions, food allergies, or specific religious/ ethical beliefs. Further studies are needed to access the effect of dietary advice to prevent gestational diabetes, although low quality evidence suggests some benefit.Adequate periconceptional (time before and right after conception) folic acid (also called folate or Vitamin B9) intake has been shown to decrease the risk of fetal neural tube defects, such as spina bifida. The neural tube develops during the first 28 days of pregnancy, a urine pregnancy test is not usually positive until 14 days post-conception, explaining the necessity to guarantee adequate folate intake before conception. Folate is abundant in green leafy vegetables, legumes, and citrus. In the United States and Canada, most wheat products (flour, noodles) are fortified with folic acid. Weight gain The amount of healthy weight gain during a pregnancy varies. Weight gain is related to the weight of the baby, the placenta, extra circulatory fluid, larger tissues, and fat and protein stores. Most needed weight gain occurs later in pregnancy.The Institute of Medicine recommends an overall pregnancy weight gain for those of normal weight (body mass index of 18.5–24.9), of 11.3–15.9 kg (25–35 pounds) having a singleton pregnancy. Women who are underweight (BMI of less than 18.5), should gain between 12.7 and 18 kg (28–40 lb), while those who are overweight (BMI of 25–29.9) are advised to gain between 6.8 and 11.3 kg (15–25 lb) and those who are obese (BMI ≥ 30) should gain between 5–9 kg (11–20 lb). These values reference the expectations for a term pregnancy. During pregnancy, insufficient or excessive weight gain can compromise the health of the mother and fetus. The most effective intervention for weight gain in underweight women is not clear. Being or becoming overweight in pregnancy increases the risk of complications for mother and fetus, including cesarean section, gestational hypertension, pre-eclampsia, macrosomia and shoulder dystocia. Excessive weight gain can make losing weight after the pregnancy difficult. Some of these complications are risk factors for stroke.Around 50% of women of childbearing age in developed countries like the United Kingdom are overweight or obese before pregnancy. Diet modification is the most effective way to reduce weight gain and associated risks in pregnancy. Medication Drugs used during pregnancy can have temporary or permanent effects on the fetus. Anything (including drugs) that can cause permanent deformities in the fetus are labeled as teratogens. In the U.S., drugs were classified into categories A, B, C, D and
Pregnancy	X based on the Food and Drug Administration (FDA) rating system to provide therapeutic guidance based on potential benefits and fetal risks. Drugs, including some multivitamins, that have demonstrated no fetal risks after controlled studies in humans are classified as Category A. On the other hand, drugs like thalidomide with proven fetal risks that outweigh all benefits are classified as Category X. Recreational drugs The use of recreational drugs in pregnancy can cause various pregnancy complications. Alcoholic drinks consumed during pregnancy can cause one or more fetal alcohol spectrum disorders. According to the CDC, there is no known safe amount of alcohol during pregnancy and no safe time to drink during pregnancy, including before a woman knows that she is pregnant. Tobacco smoking during pregnancy can cause a wide range of behavioral, neurological, and physical difficulties. Smoking during pregnancy causes twice the risk of premature rupture of membranes, placental abruption and placenta previa. Smoking is associated with 30% higher odds of preterm birth. Prenatal cocaine exposure is associated with premature birth, birth defects and attention deficit disorder. Prenatal methamphetamine exposure can cause premature birth and congenital abnormalities. Short-term neonatal outcomes in methamphetamine babies show small deficits in infant neurobehavioral function and growth restriction. Long-term effects in terms of impaired brain development may also be caused by methamphetamine use. Cannabis in pregnancy has been shown to be teratogenic in large doses in animals, but has not shown any teratogenic effects in humans. Exposure to toxins Intrauterine exposure to environmental toxins in pregnancy has the potential to cause adverse effects on prenatal development, and to cause pregnancy complications. Air pollution has been associated with low birth weight infants. Conditions of particular severity in pregnancy include mercury poisoning and lead poisoning. To minimize exposure to environmental toxins, the American College of Nurse-Midwives recommends: checking whether the home has lead paint, washing all fresh fruits and vegetables thoroughly and buying organic produce, and avoiding cleaning products labeled "toxic" or any product with a warning on the label.Pregnant women can also be exposed to toxins in the workplace, including airborne particles. The effects of wearing an N95 filtering facepiece respirator are similar for pregnant women as for non-pregnant women, and wearing a respirator for one hour does not affect the fetal heart rate. Death by violence Pregnant women or those who have recently given birth in the U.S. are more likely to be murdered than to die from obstetric causes. These homicides are a combination of intimate partner violence and firearms. Health authorities have called the violence "a health emergency for pregnant women," but say that pregnancy-related homicides are preventable if healthcare providers identify those women at risk and offer assistance to them. Sexual activity Most women can continue to engage in sexual activity, including sexual intercourse, throughout pregnancy. Research suggests that during pregnancy both sexual desire and frequency of sexual relations decrease during the first and third trimester, with a rise during the second trimester. I Sex during pregnancy is a low-risk behavior except when the healthcare provider advises that sexual intercourse be avoided for particular medical reasons. For a healthy pregnant woman, there is no single safe or right way to have sex during pregnancy. Exercise Regular aerobic exercise during pregnancy appears to improve (or maintain) physical fitness. Physical exercise during pregnancy appears to decrease the need for C-section, and even vigorous exercise carries no significant risks to babies and provides significant health benefits to the mother. Bed rest, outside of research studies, is not recommended as there is no evidence of benefit and potential harm.The Clinical Practice Obstetrics Committee of Canada recommends that "All women without contraindications should be encouraged to participate in aerobic and strength-conditioning exercises as part of a healthy lifestyle during their pregnancy". Although an upper level of safe exercise intensity has not been established, women who were regular exercisers before pregnancy and who have uncomplicated pregnancies should be able to engage in high intensity exercise programs, without a higher risk of prematurity, lower birth weight, or gestational weight gain. In general, participation in a wide range of recreational activities appears to be safe, with the avoidance of those with a high risk of falling such as horseback riding or skiing or those that carry a risk of abdominal trauma, such as soccer or hockey.The American College of Obstetricians and Gynecologists reports that in the past, the main concerns of exercise in pregnancy were focused on the fetus and any potential maternal benefit was thought to be offset by potential risks to the fetus. However, they write that more recent information suggests that in the uncomplicated pregnancy, fetal injuries are highly unlikely. They do, however, list several circumstances when a woman should contact her healthcare provider before continuing with an exercise program: vaginal bleeding, dyspnea before exertion, dizziness, headache, chest pain, muscle weakness, preterm labor, decreased fetal movement, amniotic fluid leakage, and calf pain or swelling (to rule out thrombophlebitis). Sleep It has been suggested that shift work and exposure to bright light at night should be avoided at least during the last trimester of pregnancy to decrease the risk of psychological and behavioral problems in the newborn. Dental care The increased levels of progesterone and estrogen during pregnancy make gingivitis more likely; the gums become edematous, red in colour, and tend to bleed. Also a pyogenic granuloma or "pregnancy tumor", is commonly seen on the labial surface of the papilla. Lesions can be treated by local debridement or deep incision depending on their size, and by following adequate oral hygiene measures. There have been suggestions that severe periodontitis may increase the risk of having preterm birth and low birth weight; however, a Cochrane review found insufficient evidence to determine if periodontitis can develop adverse birth outcomes. Flying In low risk pregnancies, most health care providers approve flying until about 36 weeks of gestational age. Most airlines allow pregnant women to fly short distances at less than 36 weeks, and long distances at less than 32 weeks. Many airlines require a doctors note that approves flying, especially at over 28 weeks. During flights, the risk of deep vein thrombosis is decreased by getting up and walking occasionally, as well as by avoiding dehydration.Full body scanners do not use ionizing radiation, and are safe in pregnancy. Pregnancy classes and birth plan To prepare for the birth of the baby, health care providers recommend that parents attend antenatal classes during the third trimester of pregnancy. Classes include information about the process of labor and birth and the various kinds of births, including both vaginal and caesarean delivery, the use of forceps, and other interventions that may be needed to safely deliver the infant. Types of pain relief, including relaxation techniques, are discussed. Partners or others who may plan to support a woman during her labor and delivery learn how to assist in the birth. It is also suggested that a birth plan be written at this time. A birth plan is a written statement that outlines the desires of the mother during labor and delivery of the baby. Discussing the birth plan with the midwife or other care provider gives parents a chance to ask questions and learn more about the process of labour.In 1991 the WHO launched the Baby-Friendly Hospital Initiative, a global program that recognizes birthing centers and hospitals that offer optimal levels of care for giving birth. Facilities that have been certified as "Baby Friendly" accept visits from expecting parents to familiarize them with the facility and the staff. Complications Each year, ill health as a result of pregnancy is experienced (sometimes permanently) by more than 20 million women around the world. In 2016, complications of pregnancy resulted in 230,600 deaths down from 377,000 deaths in 1990. Common causes include bleeding (72,000), infections (20,000), hypertensive diseases of pregnancy (32,000), obstructed labor (10,000), and pregnancy with abortive outcome (20,000), which includes miscarriage, abortion, and ectopic pregnancy.The following are some examples of pregnancy complications: Pregnancy induced hypertension Anemia Postpartum depression, a common but solvable complication following childbirth that may result from decreased hormonal levels. Postpartum psychosis Thromboembolic disorders, with an increased risk due to hypercoagulability in pregnancy. These are the leading cause of death in pregnant women in the US. Pruritic urticarial papules and plaques of pregnancy (PUPPP), a skin disease that develops around the 32nd week. Signs are red plaques, papules, and itchiness around the belly button that then spreads all over the body except for the inside of hands and face. Ectopic pregnancy, including abdominal pregnancy, implantation of the embryo outside the uterus Hyperemesis gravidarum, excessive nausea and vomiting that is more severe than normal morning sickness. Pulmonary embolism, a blood clot that forms in the legs and migrates to the lungs. Acute fatty liver of pregnancy is a rare complication thought to be brought about by a disruption in the metabolism of fatty acids by mitochondria.There is also an increased susceptibility and severity of certain infections in pregnancy. Miscarriage and stillbirth Miscarriage is the most common complication of early pregnancy. It is defined as the loss of an embryo or fetus before it is able to survive independently. The most common symptom of miscarriage is vaginal bleeding with or without pain. The miscarriage may be evidenced by a clot-like material passing through and out of the vagina. About 80% of miscarriages occur in the first 12 weeks of pregnancy. The underlying cause in about half of cases involves chromosomal abnormalities.Stillbirth is defined as fetal death after 20 or 28 weeks of pregnancy, depending on the source. It results in a baby born without signs of life. Each year about 21,000 babies are stillborn in the U.S. Sadness, anxiety, and guilt may occur after a miscarriage or a stillbirth. Emotional support may help with processing the loss.Fathers may experience grief over the loss as well. A large study found that there is a need to increase the accessibility of support services available for fathers. Diseases in pregnancy A pregnant woman may have a pre-existing disease, which is not directly caused by the pregnancy, but may cause complications to develop that include a potential risk to the pregnancy; or a disease may develop during pregnancy. Diabetes mellitus and pregnancy deals with the interactions of diabetes mellitus (not restricted to gestational diabetes) and pregnancy. Risks for the child include miscarriage, growth restriction, growth acceleration, large for gestational age (macrosomia), polyhydramnios (too much amniotic fluid), and birth defects. Thyroid disease in pregnancy can, if uncorrected, cause adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Demand for thyroid hormones is increased during pregnancy, which may cause a previously unnoticed thyroid disorder to worsen. Untreated celiac disease can cause a miscarriage, intrauterine growth restriction, small for gestational age, low birthweight and preterm birth. Often reproductive disorders are the only manifestation of undiagnosed celiac disease and most cases are not recognized. Complications or failures of pregnancy cannot be explained simply by malabsorption, but by the autoimmune response elicited by the exposure to gluten, which causes damage to the placenta. The gluten-free diet avoids or reduces the risk of developing reproductive disorders in pregnant women with celiac disease. Also, pregnancy can be a trigger for the development of celiac disease in genetically susceptible women who are consuming gluten. Lupus in pregnancy confers an increased rate of fetal death in utero, miscarriage, and of neonatal lupus. Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis (blood clots). Pregnancy itself is a factor of hypercoagulability (pregnancy-induced hypercoagulability), as a physiologically adaptive mechanism to prevent postpartum bleeding. However, in combination with an underlying hypercoagulable state, the risk of thrombosis or embolism may become substantial. Abortion An abortion is the termination of an embryo or fetus via medical method. It is usually done within the first trimester, sometimes in the second, and rarely in the third. Reasons for pregnancies being undesired are broad, rape being the most legally accepted. Birth control and education Family planning, as well as the availability and use of contraception, along with increased comprehensive sex education, has enabled many to prevent pregnancies when they are not desired. Schemes and funding to support education and the means to prevent pregnancies when they are not intended have been instrumental and are part of the third of the Sustainable Development Goals (SDGs) advanced by the United Nations. Technologies and science Assisted reproductive technology Modern reproductive medicine offers many forms of assisted reproductive technology for couples who stay childless against their will, such as fertility medication, artificial insemination, in vitro fertilization and surrogacy. Medical imaging Medical imaging may be indicated in pregnancy because of pregnancy complications, disease, or routine prenatal care. Medical ultrasonography including obstetric ultrasonography, and magnetic resonance imaging (MRI) without contrast agents are not associated with any risk for the mother or the fetus, and are the imaging techniques of choice for pregnant women. Projectional radiography, CT scan and nuclear medicine imaging result in some degree of ionizing radiation exposure, but in most cases the absorbed doses are not associated with harm to the baby. At higher dosages, effects can include miscarriage, birth defects and intellectual disability. Epidemiology About 213 million pregnancies occurred in 2012 of which 190 million were in the developing world and 23 million were in the developed world. This is about 133 pregnancies per 1,000 women aged 15 to 44. About 10% to 15% of recognized pregnancies end in miscarriage. Globally, 44% of pregnancies are unplanned. Over half (56%) of unplanned pregnancies are aborted. In countries where abortion is prohibited, or only carried out in circumstances where the mothers life is at risk, 48% of unplanned pregnancies are aborted illegally. Compared to the rate in countries where abortion is legal, at 69%.Of pregnancies in 2012, 120 million occurred in Asia, 54 million in Africa, 19 million in Europe, 18 million in Latin America and the Caribbean, 7 million in North America, and 1 million in Oceania. Pregnancy rates are 140 per 1000 women of childbearing age in the developing world and 94 per 1000 in the developed world.The rate of pregnancy, as well as the ages at which it occurs, differ by country and region. It is influenced by a number of factors, such as cultural, social and religious norms; access to contraception; and rates of education. The total fertility rate (TFR) in 2013 was estimated to be highest in Niger (7.03 children/woman) and lowest in Singapore (0.79 children/woman).In Europe, the average childbearing age has been rising continuously for some time. In Western, Northern, and Southern Europe, first-time mothers are on average 26 to 29 years old, up from 23 to 25 years at the start of the 1970s. In a number of European countries (Spain), the mean age of women at first childbirth has crossed the 30-year threshold. This process is not restricted to Europe. Asia, Japan and the United States are all seeing average age at first birth on the rise, and increasingly the process is spreading to countries in the developing world like China, Turkey and Iran. In the US, the average age of first childbirth was 25.4 in 2010.In the United States and United Kingdom, 40% of pregnancies are unplanned, and between a quarter and half of those unplanned pregnancies were unwanted pregnancies.In the US, a womans educational attainment and her marital status are correlated with childbearing: the percentage of women unmarried at the time of first birth drops with increasing educational level. In other words: among uneducated women, a large fraction (~80%) have their first child while they are unmarried. By contrast, few women with a bachelors degree or higher (~25%) have their first child while unmarried. However, this phenomenon also has a strong generational component: in 1996, about 50% of women without a university degree had their first child being unmarried while that number increased to ~85% in 2018. Similarly, in 1996, only 4% of women with a BA degree or similar had their first child being unmarried. In 2018, that fraction increased to ~25%. Legal and social aspects Legal protection Many countries have various legal regulations in place to protect pregnant women and their children. Many countries have laws against pregnancy discrimination.Maternity Protection Convention ensures that pregnant women are exempt from activities such as night shifts or carrying heavy stocks. Maternity leave typically provides paid leave from work during roughly the last trimester of pregnancy and for some time after birth. Notable extreme cases include Norway (8 months with full pay) and the United States (no paid leave at all except in some states). In the United States, some actions that result in miscarriage or stillbirth, such as beating a pregnant woman, are considered crimes. One law that does so is the federal Unborn Victims of Violence Act. In 2014, the American state of Tennessee passed a law which allows prosecutors to charge a woman with criminal assault if she uses illegal drugs during her pregnancy and her fetus or newborn is harmed as a result.However, protections are not universal. In Singapore, the Employment of Foreign Manpower Act forbids current and former work permit holders from becoming pregnant or giving birth in Singapore without prior permission. Violation of the Act is punishable by a fine of up to S$10,000 (US$7300) and deportation, and until 2010, their employers would lose their $5,000 security bond. Teenage pregnancy Teenage pregnancy is also known as adolescent pregnancy. The WHO defines adolescence as the period between the ages of 10 and 19 years. Adolescents face higher health risks than women who give birth at age 20 to 24 and their infants are at a higher risk for preterm birth, low birth weight, and other severe neonatal conditions. Their children continue to face greater challenges, both behavioral and physical, throughout their lives. Teenage pregnancies are also related to social issues, including social stigma, lower educational levels, and poverty. Studies show that female adolescents are often in abusive relationships at the time of their conceiving.Nurse-Family Partnership (NFP) is a non-profit organization operating in the United States and the UK designed to serve the needs of low income young mothers who may have special needs in their first pregnancy. Each mother served is partnered with a registered nurse early in her pregnancy and receives ongoing nurse home visits that continue through her childs second birthday. NFP intervention has been associated with improvements in maternal health, child health, and economic security. Racial disparities There are significant racial imbalances in pregnancy and neonatal care systems. Midwifery guidance, treatment, and care have been related to better birth outcomes. Diminishing racial inequities in health is an increasingly large public health challenge in the United States. Despite the fact that average rates have decreased, data on neonatal mortality demonstrates that racial disparities have persisted and grown. The death rate for African American babies is nearly double that of white neonates. According to studies, congenital defects, SIDS, preterm birth, and low birth weight are all more common among African American babies.Midwifery care has been linked to better birth and postpartum outcomes for both mother and child. It caters to the needs of the woman and provides competent, sympathetic care, and is essential for maternal health improvement. The presence of a doula, or birth assistant, during labor and delivery, has also been associated with improved levels of satisfaction with medical birth care. Providers recognized their profession from a historical standpoint, a link to African origins, the diaspora, and prevailing African American struggles. Providers participated in both direct clinical experience and activist involvement. Advocacy efforts aimed to enhance the number of minority birth attendants and to promote the benefits of woman-centered birth care to neglected areas. Transgender people Transgender people have experienced significant advances in societal acceptance in recent years leaving many health professionals unprepared to provide quality care. A 2015 report suggests that "numbers of transgender individuals who are seeking family planning, fertility, and pregnancy services could certainly be quite large". Regardless of prior hormone replacement therapy treatments, the progression of pregnancy and birthing procedures for transgender people who carry pregnancies are typically the same as those of cisgender women however, they may be subjected to discrimination, which can include a variety of negative social, emotional, and medical experiences, as pregnancy is regarded as an exclusively female activity. According to a study by the American College of Obstetricians and Gynecologists, there is a lack of awareness, services, and medical assistance available to pregnant trans men. Culture In most cultures, pregnant women have a special status in society and receive particularly gentle care. At the same time, they are subject to expectations that may exert great psychological pressure, such as having to produce a son and heir. In many traditional societies, pregnancy must be preceded by marriage, on pain of ostracism of mother and (illegitimate) child. Overall, pregnancy is accompanied by numerous customs that are often subject to ethnological research, often rooted in traditional medicine or religion. The baby shower is an example of a modern custom. Pregnancy is an important topic in sociology of the family. The prospective child may preliminarily be placed into numerous social roles. The parents relationship and the relation between parents and their surroundings are also affected. A belly cast may be made during pregnancy as a keepsake. Arts Images of pregnant women, especially small figurines, were made in traditional cultures in many places and periods, though it is rarely one of the most common types of image. These include ceramic figures from some Pre-Columbian cultures, and a few figures from most of the ancient Mediterranean cultures. Many of these seem to be connected with fertility. Identifying whether such figures are actually meant to show pregnancy is often a problem, as well as understanding their role in the culture concerned. Among the oldest surviving examples of the depiction of pregnancy are prehistoric figurines found across much of Eurasia and collectively known as Venus figurines. Some of these appear to be pregnant. Due to the important role of the Mother of God in Christianity, the Western visual arts have a long tradition of depictions of pregnancy, especially in the biblical scene of the Visitation, and devotional images called a Madonna del Parto.The unhappy scene usually called Diana and Callisto, showing the moment of discovery of Callistos forbidden pregnancy, is sometimes painted from the Renaissance onwards. Gradually, portraits of pregnant women began to appear, with a particular fashion for "pregnancy portraits" in elite portraiture of the years around 1600. Pregnancy, and especially pregnancy of unmarried women, is also an important motif in literature. Notable examples include Thomas Hardys 1891 novel Tess of the dUrbervilles and Goethes 1808 play Faust. See also Couvade syndrome Cryptic pregnancy False pregnancy Simulated pregnancy References Further reading External links Pregnancy at Curlie Merck Manual Home Health Handbook – further details on the diseases, disorders, etc., which may complicate pregnancy. Pregnancy care – NHS guide to having a baby including preconception, pregnancy, labor, and birth.
Blood-injection-injury type phobia	Blood-injection-injury (BII) type phobia is a type of specific phobia characterized by the display of excessive, irrational fear in response to the sight of blood, injury, or injection, or in anticipation of an injection, injury, or exposure to blood. Blood-like stimuli (paint, ketchup) may also cause a reaction. This is a common phobia with an estimated 3-4% prevalence in the general population, though it has been found to occur more often in younger and less educated groups. Prevalence of fear of needles which does not meet the BII phobia criteria is higher. A proper name for BII has yet to be created. When exposed to phobic triggers, those with the phobia often experience a two-phase response: an initial increase in heart rate and blood pressure, followed quickly by bradycardia (decreased heart rate) and hypotension (decreased blood pressure). This diminishes cerebral blood supply, and will often result in a fainting response. In an individual with BII phobia, expression of these or similar phobic symptoms in response to blood, injection, or injury typically begins before the age of ten. Many who have the phobia will take steps to actively avoid exposure to triggers. This can lead to health issues in phobic individuals as a result of avoidance of hospitals, doctors’ appointments, blood tests, and vaccinations, or of necessary self-injections in those with diabetes and multiple sclerosis (MS). Due to frequent avoidance of phobic triggers, BII phobics personal and professional lives may be limited. Some may feel that their phobia precludes them from joining a healthcare profession, or from getting pregnant. The phobia is also able to affect the health of those who dont have it; a BII-phobic, for instance, may have difficulty providing aid to someone else in an emergency situation in which blood is present.Causes of BII phobia have yet to be fully understood. There is a body of evidence which suggests the phobia has genetic underpinnings, though many phobics also cite a traumatic life event as a cause of their fear. The fainting response accompanying the phobia may have originated as an adaptive evolutionary mechanism.Applied tension (AT), a method in which individuals alternately tense and relax their muscles while being exposed to a phobic trigger, is widely recognized as an effective form of treatment for BII phobia. While AT is generally the default treatment suggestion, methods of applied relaxation (AR) and exposure-only cognitive-behavioral therapy (CBT) have been found to be effective in diminishing phobic response in some instances. Certain other strategies can be employed to temporarily alleviate symptoms associated with phobic response, such as coughing to increase cranial blood flow. The acute symptoms associated with an episode of triggering are often fully resolved within a few minutes of stimuli removal.BII phobia does bear some similarity to other phobic disorders: specifically, dental phobia (commonly considered a sub-type of BII phobia) and hemophobia. In each of these phobias, a biphasic fainting response is a common reaction to a trigger. Signs and symptoms In a majority of specific phobias, affected individuals experience heightened anxiety when exposed to a phobic trigger. While BII-phobics experience a similar reaction initially upon exposure, most ultimately respond to a trigger with a biphasic, or two-phase, fainting response. In the first phase, phobics often experience an anxiety reaction characterized by elevated heart rate and heightened blood pressure, as occurs in most other phobias. This is the result of increased activation of the sympathetic nervous system. However, with BII phobia, a second phase usually follows closely, in which the phobic individual experiences a massive dip in heart rate and blood pressure known as vasovagal response. Stimulation of the vagus nerve, a part of the parasympathetic nervous system, is responsible for promoting the lowered heart rate and decreased blood pressure. These physiological changes limit blood flow to the brain and can promote pre-syncope (lightheadedness, feelings of faintness) and syncope (fainting): categorized in this instance as vasovagal fainting. This second, fainting phase is not common to other phobias.A fainting response pattern is not seen in all individuals with BII phobia, but is found in a majority. Up to 80% of those with BII phobia report either syncope or pre-syncope as a symptom when exposed to a trigger.Other symptoms that may evolve when exposed to phobic triggers include extreme chest discomfort, tunnel vision, becoming pale, shock, vertigo, diaphoresis (profuse sweating), nausea, and in very rare cases asystole (cardiac arrest) and death. Increase in stress hormone release (particularly of cortisol and corticotrophin) is typical.Neurological responses to phobic triggers include activation of the bilateral occipito-parietal cortex and the thalamus. It has also been suggested that exposing a BII-phobic individual to a trigger will lead to decreased activity in the brains medial prefrontal cortex (MPFC). Diminished MPFC activity has been linked with impaired ability to control emotional responses. This lessened emotional control could contribute to a general lack of control over symptoms of anxiety arising when exposed to a phobic trigger. Complications On the health of those with the phobia The health of individuals with BII phobia can be jeopardized by the condition as a result of avoidance of phobic triggers. As modern healthcare relies increasingly on injections, it can be difficult for phobics to receive the care they need, since situations involving injections, vaccinations, drawing of blood, etc. are usually avoided. Avoidant behaviors can be especially detrimental to an individuals well-being if they are diabetic and require insulin injections, or experience another pathology or disease which requires treatment via self-injection, such as MS. There may be inappropriate cessation of injection treatment by individuals with the phobia, potentially causing adverse events or reducing treatment efficacy.Bodily injuries may also be sustained in the course of a fainting response to a phobic trigger. Comorbidity with other health conditions Substantial rates of comorbidity with BII phobia have been demonstrated for the following: other life-long phobias marijuana abuse clinical depression panic disorder obsessive-compulsive disorder (OCD) agoraphobia (AG) social anxiety disorder (SAD)In individuals with diabetes: peripheral vascular disease cardiovascular disease On the health of the broader population BII phobia is able to affect the health of a broader population than just the community of individuals with the phobia. Someone with the phobia may, for instance, be unable to respond appropriately and/or offer assistance in an emergency event in which another person was injured or cut.Avoidance of vaccinations due to BII phobia may also prove detrimental to public health at large, as lowered rates of vaccination in a population tend to increase risk of infectious disease outbreak.Given BII phobics will very often avoid situations involving exposure to blood or needles, these individuals are likely to avoid donating blood. Public health benefit could result from helping them overcome their phobia, such that donation becomes a viable option. Limitations on personal and professional life BII phobia may influence the personal and professional decisions of those with the condition. BII-phobic females may, for instance, choose not to get pregnant, as they fear the injections, vaccinations, and labor-induced pain associated with maternity.Those with the phobia may also be unable to pursue a profession in a health-related field, such as nursing, which would require repeated exposure to feared stimuli. Phobic individuals may find their ability to complete medical school severely impaired. Related disorders Dental phobia Dental phobia is often considered a sub-type of BII phobia, as dental phobics generally fear the aspects of dentistry that are invasive (those commonly involving blood and injections). Some individuals with dental phobia do, however, have fears which center mainly around choking or gagging during a dental procedure.As with many individuals with BII phobia, many dental phobics will attempt to avoid their triggers. This can lead to refusal to seek dental care, potentially contributing to tooth decay and overall poor oral health. Individuals with dental phobia exhibit symptoms similar to those with BII phobia when exposed to a phobic trigger, including syncope and pre-syncope. Hemophobia BII phobia is closely related to hemophobia (fear of blood), though the two are not the same condition. While the anxieties of BII-phobics tend to extend beyond the fear of blood to ideas of pain, needle breakage inside the body, or needle contact with bones, hemophobics tend to be specifically concerned with exposure to blood. However, in both phobias, individuals experience similar symptoms when exposed to phobic triggers. Causes The cause of BII phobia is not yet well understood. Various studies indicate an underlying genetic cause, wherein certain genes make an individual more vulnerable to developing specific phobias. The contributing genes have not yet been identified.BII phobia has markedly strong familial aggregation — if present in a family, multiple members are likely to have the phobia. This aggregation is stronger in BII phobia than in any other known phobic disorder: upwards of 60% of those with the phobia have first-degree relatives who are also BII-phobics. It is believed that this evidences the phobias genetic underpinnings. One study estimated actual heritability of the phobia at 59%.Additionally, a majority of phobics attribute their fear to environmental factors. For instance, some sort of traumatic event involving blood, injury, or injection that conditioned them to fear those particular stimuli. Others self-report being conditioned by seeing another person react to the stimuli with a consistent pattern of fear.It has been theorized that exhibiting vasovagal response when exposed to blood was evolutionarily advantageous, and that this phobia is a vestige of an ancestral evolutionary mechanism. Fainting may have acted as a form of tonic immobility, allowing primitive humans to play dead in a situation where blood was being spilled, perhaps helping them to avoid the attention of enemies. It has also been suggested that the drop in blood pressure associated with seeing blood — as with an individual seeing blood from their own wound — occurs in order to minimize blood loss. Treatments Individuals typically seek therapeutic treatment for BII phobia in a bid to alleviate symptoms that arise when exposed to a phobic trigger. Therapists may use a combination of physical and psychological measures, such as cognitive-behavioral-therapy and applied tension (AT), in order to aid in extinguishing the individuals fear response.Early studies of methods to combat vasovagal fainting found that certain leg exercises and that individuals making themselves angry over imagined scenarios could increase blood pressure, thus elevating cerebral blood flow and preventing fainting upon exposure to a phobic trigger. A later study tested applied muscle tension as a way of preventing fainting when an individual with a fear of injuries was exposed to triggering visual stimuli. Lars-Göran Öst expanded upon this research, having BII-phobic individuals engage in applied muscle tension while shown blood stimuli. Those who were trained in the technique showed notable symptom improvement over the course of five one-hour treatment sessions.An AT treatment program most often involves an individual being instructed to clench their arm, leg, and chest muscles in 10 to 15 second intervals as they are systematically exposed to triggers of increasing likeness to real blood or needles. This program is designed to increase heart rate and blood pressure, counteracting vasovagal response.The method of applied tension remains popular — it is the most common BII phobia treatment suggestion, and has been found to be highly effective in a majority of BII-phobics. However, exposure-only cognitive-behavioral therapy (CBT) can also be effective, as can the method of applied relaxation (AR).CBT is a technique which promotes fear extinguishment by way of gradual, repeated exposure to feared stimuli. BII-phobics may be given pictures of needles or blood, asked to illustrate needles or scenes with blood, or to speak about their phobic triggers. This systematically progresses to the point of the individual directly confronting a phobic stimulus: being given a needle, witnessing blood being drawn, etc. As exposure continues, it is expected that the phobic response will become less pronounced, and symptoms less debilitating.While AT targets the phobia’s physiological response, aiming to raise blood pressure and directly prevent fainting, AR focuses mainly on helping an individual avoid the phobia’s associated anxiety. A phobic will learn progressive relaxation techniques to help to calm themselves upon exposure to a trigger. Temporary alleviation of symptoms Drinking water before a triggering experience such as blood donation has been indicated to aid in prevention of a fainting response. Water will increase sympathetic nervous system activation, raising blood pressure and combating vasovagal response.Certain physical maneuvers also have the capacity to temporarily boost blood pressure, alleviating symptoms of pre-syncope like lightheadedness by boosting blood flow to the brain. These include the phobic individual crossing their legs, making tight fists with both hands, or engaging muscles of the trunk or arms. Coughing, which can similarly increase cranial blood flow, can also be useful as a coping mechanism to avoid pre-syncope and syncope.Symptoms of a phobic response are generally able to be fully alleviated within a few minutes simply by removing the phobic trigger. Epidemiology BII phobia is one of the more common types of phobia — it is estimated to affect about 3-4% of the general population.Onset of the phobia generally occurs in middle childhood, before the age of ten. There are more reports of incidence of the phobia in younger individuals and those with low education levels. Some studies suggest that women also experience the phobia more frequently, however results are mixed concerning relative prevalences of the phobia between the sexes. == References ==
Osteophyte	Osteophytes are exostoses (bony projections) that form along joint margins. They should not be confused with enthesophytes, which are bony projections that form at the attachment of a tendon or ligament. Osteophytes are not always distinguished from exostoses in any definite way, although in many cases there are a number of differences. Osteophytes are typically intra-articular (within the joint capsule). Cause A range of bone-formation processes are associated with aging, degeneration, mechanical instability, and disease (such as diffuse idiopathic skeletal hyperostosis). Osteophyte formation has classically been related to sequential and consequential changes in such processes. Often osteophytes form in osteoarthritic joints as a result of damage and wear from inflammation. Calcification and new bone formation can also occur in response to mechanical damage in joints. Pathophysiology Osteophytes form because of the increase in a damaged joints surface area. This is most common from the onset of arthritis. Osteophytes usually limit joint movement and typically cause pain.Osteophytes form naturally on the back of the spine as a person ages and are a clinical sign of degeneration in the spine. In this case, the osteophytes are commonly not the source of back pains, but instead are a sign of an underlying problem. However, osteophytes on the spine can impinge on nerves that leave the spine for other parts of the body. This impingement can cause pain in both upper and lower limbs and a numbness or tingling sensations in the hands and feet because the nerves are supplying sensation to their dermatomes.Osteophytes on the fingers or toes are known as Heberdens nodes (if on the distal interphalangeal joint) or Bouchards nodes (if on the proximal interphalangeal joints). Treatments Normally, asymptomatic cases are not treated. Non-steroidal anti inflammatory drugs and surgery are two typical options for cases requiring treatment. References External links Mayo Clinic website concise information on bone spurs
Prediabetes	Prediabetes is a component of the metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms but people with prediabetes often have obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension. It is also associated with increased risk for cardiovascular disease (CVD). Prediabetes is more accurately considered an early stage of diabetes as health complications associated with type 2 diabetes often occur before the diagnosis of diabetes. Prediabetes can be diagnosed by measuring hemoglobin A1c, fasting glucose, or glucose tolerance test. Many people may be diagnosed through routine screening tests. The primary treatment approach includes lifestyle changes such as exercise and dietary adjustments. Some medications can be used to reduce the risks associated with prediabetes. There is a high rate of progression to type 2 diabetes but not everyone with prediabetes develops type 2 diabetes. Prediabetes can be a reversible condition with lifestyle changes. For many people, prediabetes and diabetes are diagnosed through a routine screening at a check-up. However, an additional routine screening done by dentists, a new and promising concept, and not only medical doctors, can be very effective in early detection and treatment. The earlier prediabetes is diagnosed, the more likely an intervention will be successful. Signs and symptoms Prediabetes typically has no distinct signs or symptoms except the sole sign of high blood sugar. Patients should monitor for signs and symptoms of type 2 diabetes mellitus such as increased thirst, increased urination, and feeling tired. Causes The cause of prediabetes is multifactorial and is known to have contributions from lifestyle and genetic factors. Ultimately prediabetes occurs when control of insulin and blood glucose in the body becomes abnormal, also known as insulin resistance. Risk factors for prediabetes include family history of diabetes, older age, women who have a history of gestational diabetes or high birth weight babies (greater than 9 lbs.).The increasing rates of prediabetes and diabetes suggest lifestyle and/or environmental factors that contribute to prediabetes. It remains unclear which dietary components are causative and risk is likely influenced by genetic background. Lack of physical activity is a risk factor for type 2 diabetes and physical activity can reduce the risk of progressing to type 2 diabetes. Pathophysiology Normal glucose homeostasis is controlled by three interrelated processes. These processes include gluconeogenesis (glucose production that occurs in the liver), uptake and utilization of glucose by the peripheral tissues of the body, and insulin secretion by the pancreatic beta islet cells. The presence of glucose in the bloodstream triggers the production and release of insulin from the pancreas beta islet cells. The main function of insulin is to increase the rate of transport of glucose from the bloodstream into certain cells of the body, such as striated muscles, fibroblasts, and fat cells. It also is necessary for transport of amino acids, glycogen formation in the liver and skeletal muscles, triglyceride formation from glucose, nucleic acid synthesis, and protein synthesis. In individuals with prediabetes, a failure of pancreatic hormone release, failure of targeted tissues to respond to the insulin present or both leads to blood glucose rises to abnormally high levels. Diagnosis Prediabetes can be diagnosed with three different types of blood tests: Fasting blood sugar (glucose) level of: 110 to 125 mg/dL (6.1 mmol/L to 6.9 mmol/L) – WHO criteria 100 to 125 mg/dL (5.6 mmol/L to 6.9 mmol/L) – ADA criteria Glucose tolerance test: blood sugar level of 140 to 199 mg/dL (7.8 to 11.0 mM) 2 hours after ingesting a standardized 75 gram glucose solution Glycated hemoglobin (HbA1c) between 5.7 and 6.4 percent, i.e. 38.9 and 46.4 mmol/molLevels above these limits would justify a diagnosis for diabetes. Impaired fasting glucose Impaired fasting glycemia or impaired fasting glucose (IFG) refers to a condition in which the fasting blood glucose is elevated above what is considered normal levels but is not high enough to be classified as diabetes mellitus. It is considered a pre-diabetic state, associated with insulin resistance and increased risk of cardiovascular pathology, although of lesser risk than impaired glucose tolerance (IGT). IFG sometimes progresses to type 2 diabetes mellitus. Fasting blood glucose levels are in a continuum within a given population, with higher fasting glucose levels corresponding to a higher risk for complications caused by the high glucose levels. Some patients with impaired fasting glucose also may be diagnosed with impaired glucose tolerance, but many have normal responses to a glucose tolerance test. Fasting glucose is helpful in identifying prediabetes when positive but has a risk of false negatives.World Health Organization (WHO) criteria for impaired fasting glucose differs from the American Diabetes Association (ADA) criteria, because the normal range of glucose is defined differently by each. Fasting plasma glucose levels 100 mg/dL (5.5 mmol/L) and higher have been shown to increase complication rates significantly, however, WHO opted to keep its upper limit of normal at under 110 mg/dL for fear of causing too many people to be diagnosed as having impaired fasting glucose, whereas the ADA lowered the upper limit of normal to a fasting plasma glucose under 100 mg/dL. WHO criteria: fasting plasma glucose level from 6.1 mmol/L (110 mg/dL) to 6.9 mmol/L (125 mg/dL) ADA criteria: fasting plasma glucose level from 5.6 mmol/L (100 mg/dL) to 6.9 mmol/L (125 mg/dL) Impaired glucose tolerance Impaired glucose tolerance (IGT) is diagnosed with an oral glucose tolerance test. According to the criteria of the World Health Organization and the American Diabetes Association, impaired glucose tolerance is defined as: two-hour glucose levels of 140 to 199 mg per dL (7.8 to 11.0 mmol/L) on the 75-g oral glucose tolerance test. A patient is said to be under the condition of IGT when he/she has an intermediately raised glucose level after 2 hours, but less than the level that would qualify for type 2 diabetes mellitus. The fasting glucose may be either normal or mildly elevated.From 10 to 15 percent of adults in the United States have impaired glucose tolerance or impaired fasting glucose. Hemoglobin A1c Hemoglobin A1c is a measure of the percent of red blood cells that are glycated, or have a glucose molecule attached. This can be used as an indicator of blood glucose level over a longer period of time and is often used to diagnose prediabetes as well as diabetes. HbA1c may not accurately represent blood glucose levels and should not be used in certain medical conditions such as iron-deficiency anemia, Vitamin B12 and folate deficiency, pregnancy, hemolytic anemia, an enlarged spleen, and end-stage kidney failure. Fasting Insulin Hyperinsulinemia due to insulin resistance may occur in individuals with normal glucose levels and therefore is not diagnosed with usual tests. Hyperinsulinemia precedes prediabetes and diabetes that are characterized by hyperglycemia. Insulin resistance can be diagnosed by measures of plasma insulin, both fasting or during a glucose tolerance test. The use of fasting insulin to identify patients at risk has been proposed, but is currently not commonly used in clinical practice.The implications of hyperinsulinemia is the risk of comorbidities related to diabetes that may precede changes in blood glucose, including cardiovascular diseases. Screening Fasting plasma glucose screening should begin at age 30–45 and be repeated at least every three years. Earlier and more frequent screening should be conducted in at-risk individuals. The risk factors for which are listed below: Family history (parent or sibling) Dyslipidemia (triglycerides > 200 mg/dL or HDL < 35 mg/dL) Overweight or obesity (body mass index > 25 kg/m2) History of gestational diabetes or infant born with birth weight greater than 9 lb (4 kg) High risk ethnic group (such as of being of African American, Hispanic, Native American, Asian American or Pacific Islander heritage) Hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure > 90 mmHg) Prior fasting blood glucose > 99 mg/dL Known vascular disease Markers of insulin resistance (PCOS, acanthosis nigricans)The United States Preventative Services Task Force (USPSTF) recommends adults who are overweight/obese and aged 40–70 years old to get screened during visits to their regular physician. The American Diabetes Association (ADA) recommends normal testing repeated every three years and recommends a larger range of people get tested: anyone over the age of 45 regardless of risk; an adult of any age who is obese or overweight and has one or more risk factors, which includes hypertension, a first degree relative with diabetes, physical inactivity, high risk race/ethnicity, Asian Americans with BMI of ≥23 kg/m2, HDL < 35 mg/dL or TG > 250 mg/dL, women who have delivered child >9 lbs or with gestational diabetes, A1c ≥ 5.7%, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).In the UK, NICE guidelines suggest taking action to prevent diabetes for people with a body mass index (BMI) of 30. For people of Black African, African-Caribbean, South Asian and Chinese descent the recommendation to start prevention starts at the BMI of 27,5. A study based on a large sample of people in England suggest even lower BMIs for certain ethnic groups for the start of prevention, for example 24 in South Asian and 21 in Bangladeshi populations. Early detection and management Over half the people who are diagnosed with prediabetes eventually develop type 2 diabetes and once diagnosed with prediabetes, people experience a range of emotions: distress and fear; denial and downplay of risks; guilt and self-criticism; and self-compassion. While prediabetes is a reversible condition, it requires diet change and exercise, which may be more difficult for people diagnosed prediabetes because facing the risk of a chronic condition is associated with negative emotions, which further hinder the self-regulation that is required in reversing a prediabetes diagnosis. Still, without taking action, 37% of individuals with prediabetes will develop diabetes in only 4 years, and lifestyle intervention may decrease the percentage of prediabetic patients in whom diabetes develops to 20%. The National Diabetes Prevention Program (DPP) has a Center of Disease Control (CDC)-recognized lifestyle change program that showed prediabetic people following the structured program can cut their risk of developing type 2 diabetes by 58% (71% for people over 60 years old). Considering the possibility to recover from the prediabetic status but also this emotional struggle upon diagnosis, it is encouraged for higher risk patients to get tested early. Having an additional screening option in the dental setting may offset some of the emotional struggle because it is more regularly visited and therefore has the potential to initiate earlier recognition and intervention. Prediabetes screening in a dental setting Its been found that people will visit their dentist more regularly than their primary physician for checkups, so the dentists office becomes a very useful place for potentially checking for diabetes. For people who are unaware of their diabetes risk and fall into the non-White, obese, or ≥45 y old category, screening at the dentists would have the highest odds of getting identified as someone at risk. Studies have been done to evaluate the overall effectiveness and value of prediabetes testing in the dental setting, usually at dental schools. One study has looked at screening through dental visits followed up by intervention programs such as the commercial Weight Watchers and found it a cost-effective means to identify and treat affected people in the long term. Cost is a factor people at risk might need to consider, since, on average, people diagnosed with diabetes have approximately 2.3 times higher medical expenditure that what expenditures would be in its absence.A simple test may be instituted at the dentists office, in which an oral blood sample is taken during a normal visit to the dentists. This sample tests for glycated hemoglobin (HbA1c) levels; HbA1c gives healthcare professionals an idea of blood glucose levels and is the most reliable form of testing for diabetes in asymptomatic patients. Fasting and "acute perturbations" are not needed for HbA1c test and it reveals average glycemic control over 3-month period. HbA1c less than 5.6% is considered normal. Glucose status can also be tested through fasting blood sugar (FBS) and requires a blood sample after a patient has fasted for at least eight hours, so it might not be as convenient. Patients who have gotten oral blood samples taken say it feels as if part of a normal procedure, and dentists say it is convenient.In a study that analyzed data from 10,472 adults from 2013 to 2014 and 2015 to 2016, it was revealed that screening for risk of prediabetes in the dental setting has the potential to alert an estimated 22.36 million adults. Diabetes may be asymptomatic for a long time, but since it would be wasteful to test every patient at the dental office, utilizing known risk factors may guide who is ideal for testing. Since a history is already taken at a dental office, a few additional questions would help guide a dentist on narrowing down who the test is recommended for. For example, people with high BMI are at higher risk for diabetes. A study done by the School of Dentistry, Diabetes Research Centre, Mazandaran University of Medical Sciences in Sari, Iran found a relation between periodontitis and the prediabetic condition, and this could be another tool to help guide who might be recommended to take the test. Periodontal disease occurs when a number of anaerobic bacteria living on the tooth surface cause infections, which leads to a potentially sustained immune response. Diabetes is a type of condition in which infections are easier to get, and hyperglycemia contributes to the mechanism causing oral complications. Prevention The American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists (AACE) have developed lifestyle intervention guidelines for preventing the onset of type 2 diabetes: Healthy diet (a diet with limited refined carbohydrates, added sugars, trans fats, as well as limited intake of sodium and total calories) Physical fitness (30–45 minutes of cardiovascular exercise per day, 3–5 days a week) Weight loss by as little as 5–10 percent may have a significant impact on overall health Management There is evidence that prediabetes is a curable disease state. Although some drugs can delay the onset of diabetes, lifestyle modifications play a greater role in the prevention of diabetes. Intensive weight loss and lifestyle intervention, if sustained, may improve glucose tolerance substantially and prevent progression from IGT to type 2 diabetes. The Diabetes Prevention Program (DPP) study found a 16% reduction in diabetes risk for every kilogram of weight loss. Reducing weight by 7% through a low-fat diet and performing 150 minutes of exercise a week is the goal. The ADA guidelines recommend modest weight loss (5–10% body weight), moderate-intensity exercise (30 minutes daily), and smoking cessation.There are many dietary approaches that can reduce the risk of progression to diabetes. Most involve the reduction of added sugars and fats but there remains a lack of conclusive evidence proving the best approach.For patients with severe risk factors, prescription medication may be appropriate. This may be considered in patients for whom lifestyle therapy has failed, or is not sustainable, and who are at high-risk for developing type 2 diabetes. Metformin and acarbose help prevent the development of prediabetes, and also have a good safety profile. Evidence also supports thiazolidinediones but there are safety concerns, and data on newer agents such as GLP-1 receptor agonists, DPP4 inhibitors or meglitinides are lacking. Prognosis The progression to type 2 diabetes mellitus is not inevitable for those with prediabetes. The progression into diabetes mellitus from prediabetes is approximately 25% over three to five years. This increases to 50% risk of progressing to diabetes over 10 years. Diabetes is a leading cause of morbidity and mortality. Effects of the disease may affect larger blood vessels (e.g., atherosclerosis within the larger arteries of the cardiovascular system) or smaller blood vessels, as seen with damage to the retina of the eye, damage to the kidney, and damage to the nerves.Prediabetes is a risk factor for mortality and there is evidence of cardiovascular disease developing prior to a diagnosis of diabetes. Epidemiology Studies conducted from 1988 to 1994 indicated that of the total population of US in the age group 40–74 years, 34% had IFG, 15% had IGT, and 40% had prediabetes (IFG, IGT, or both). Eighteen million people (6% of the population) had type 2 diabetes in 2002.The incidence of diabetes is growing. In 2014, 29.1 million people or 9% of the US population had diabetes. In 2011–2012, the prevalence of diabetes in the U.S. using hemoglobin A1C, fasting plasma glucose or the two-hour plasma glucose definition was 14% for total diabetes, 9% for diagnosed diabetes, 5% for undiagnosed diabetes and 38% for prediabetes. See also Metabolic syndrome Diabetes Insulin resistance Cardiovascular disease References Further reading External links Diabetes.org
Cystic kidney disease	Cystic kidney disease refers to a wide range of hereditary, developmental, and acquired conditions and with the inclusion of neoplasms with cystic changes, over 40 classifications and subtypes have been identified. Depending on the disease classification, the presentation may be at birth, or much later into adult life. Cystic disease may involve one or both kidneys and may, or may not, occur in the presence of other anomalies. A higher incidence is found in males and prevalence increases with age. Renal cysts have been reported in more than 50% of patients over the age of 50. Typically, cysts grow up to 2.88 mm annually and may cause related pain and/or hemorrhage.Of the cystic kidney diseases, the most common is polycystic kidney disease with two sub-types: the less prevalent autosomal recessive and more prevalent autosomal dominant. Autosomal recessive polycystic kidney disease (ARPKD) is primarily diagnosed in infants and young children while autosomal dominant polycystic kidney disease (ADPKD) is most often diagnosed in adulthood.Another example of cystic kidney disease is Medullary sponge kidney. Types More Cystic Kidney Diseases Cystic kidney disease includes various conditions related to the formation of cysts in one or both kidneys. The most common subset is polycystic kidney disease (PKD) which is a genetic anomaly with two subsets, autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD). Consequently, causation can be genetic, developmental, or associated with systemic disease which can be acquired or malignant. Examples of acquired cystic kidney disease include simple cysts and medullary sponge kidney (MSK). Other types of genetic cystic kidney disease include juvenile nephronophthisis (JNPHP), medullary cystic kidney disease (MCKD), and glomerulocystic kidney disease (GCKD). Polycystic Kidney Disease PKD causes numerous cysts to grow in the kidneys. These cysts are filled with fluid and if they grow excessively, changing the shape of them and making them larger, leading to kidney damage. Mutations in genes PKD1 and PKD2 are responsible for autosomal dominant polycystic kidney disease (ADPKD), which is typically diagnosed in adulthood. Those genes encode for polycystic proteins and mutations regarding those genes are inherited and responsible for the disorder of autosomal dominant cystic kidney disease. In the United States, more than half a million people have PKD, making it the fourth leading cause of kidney failure. PKD affects all races and genders equally and those with PKD have a possibility of developing cysts in other organs such as liver, pancreas, spleen, ovaries, and large bowel. Usually, these latter cysts do not impose a problem. Half of patients have no manifestation of symptoms, but symptoms may include: hematuria, back or abdominal pain, or the development of hypertension. The disease is usually manifested before age 30, and 45% develop kidney failure by age 60. Mutation in the HDK1 gene is currently thought to be responsible for autosomal recessive polycystic kidney disease (ARPKD), which can be diagnosed in the womb, shortly after birth, and usually before 15 years of age. Cause The site of preference for cyst development is the renal tubule. After growth of a few millimeters has occurred, the cysts detach from the parent tubule, this detachment induced by excessive proliferation of tubular epithelium or excessive fluid secretions. Diagnosis Diagnosis includes imaging with ultrasound, CT and/or MRI. The least expensive, non-invasive, and most reliable method is ultrasonography but smaller cysts may escape detection, while the resolution of CT and MRI will enable smaller cysts to be captured. However, the increased complexity and expense of CT and MRI is usually reserved for higher risk situations. MRI can be used to monitor the development of cysts and growth of kidneys.Genetic test can be applicable to those who have a family history of PKD but is expensive and fails to detect PKD in 15% of cases where it is present. Antenatal scans Many forms of cystic kidney disease can be detected in children prior to birth. Abnormalities which only affect one kidney are unlikely to cause a problem with the healthy arrival of a baby. Abnormalities which affect both kidneys can have an effect on the babys amniotic fluid volume which can in turn lead to problems with lung development. Some forms of obstruction can be very hard to differentiate from cystic renal disease on early scans. Treatment The goal of treatment is to manage the disease and its symptoms, and to avoid or delay complications. Options include pain medication (except ibuprofen and other ‘non-steroidal anti-inflammatory agents (NSAID’s)’ which may worsen kidney function), low protein and sodium diet, diuretics, antibiotics to treat urinary tract infection, or interventions to drain cysts. In advanced cystic kidney disease with renal failure, renal transplant or dialysis may ultimately be necessary. Prognosis By late 70s, 50-75% of patients with CKD require renal replacement therapy, either dialysis or kidney transplant. The number and size of cysts and kidney volume are predictors for the progression of CKD and end-stage renal disease. PKD does not increase the risk for the development of renal cancer, but if such develops, it is more likely to be bilateral. The most probable cause of death is heart disease, ruptured cerebral aneurysm, or disseminated infection. Some factors that can affect life expectancy are mutated gene type, gender, the age of onset, high blood pressure, proteinuria, hematuria, UTI, hormones, pregnancies, and size of cysts. If risk factors are controlled and the disease is stabilized then the patients life expectancy can be prolonged greatly. References == External links ==
Psoas muscle abscess	An abscess in the psoas muscle of the abdomen may be caused by lumbar tuberculosis. Owing to the proximal attachments of the iliopsoas, such an abscess may drain inferiorly into the upper medial thigh and present as a swelling in the region. The sheath of the muscle arises from the lumbar vertebrae and the intervertebral discs between the vertebrae. The disc is more susceptible to infection, from tuberculosis and Salmonella discitis. The infection can spread into the psoas muscle sheath.Treatment may involve drainage and antibiotics. Additional images See also Femoral hernia Transient synovitis References == External links ==
Bloodstream infections	Bloodstream infections (BSIs), which include bacteremias when the infections are bacterial and fungemias when the infections are fungal, are infections present in the blood. Blood is normally a sterile environment, so the detection of microbes in the blood (most commonly accomplished by blood cultures) is always abnormal. A bloodstream infection is different from sepsis, which is the host response to bacteria.Bacteria can enter the bloodstream as a severe complication of infections (like pneumonia or meningitis), during surgery (especially when involving mucous membranes such as the gastrointestinal tract), or due to catheters and other foreign bodies entering the arteries or veins (including during intravenous drug abuse). Transient bacteremia can result after dental procedures or brushing of teeth.Bacteremia can have several important health consequences. The immune response to the bacteria can cause sepsis and septic shock, which has a high mortality rate. Bacteria can also spread via the blood to other parts of the body (which is called hematogenous spread), causing infections away from the original site of infection, such as endocarditis or osteomyelitis. Treatment for bacteremia is with antibiotics, and prevention with antibiotic prophylaxis can be given in high risk situations. Presentation Bacteremia is typically transient and is quickly removed from the blood by the immune system.Bacteremia frequently evokes a response from the immune system called sepsis, which consists of symptoms such as fever, chills, and hypotension. Severe immune responses to bacteremia may result in septic shock and multiple organ dysfunction syndrome, which are potentially fatal. Causes Bacteria can enter the bloodstream in a number of different ways. However, for each major classification of bacteria (gram negative, gram positive, or anaerobic) there are characteristic sources or routes of entry into the bloodstream that lead to bacteremia. Causes of bacteremia can additionally be divided into healthcare-associated (acquired during the process of receiving care in a healthcare facility) or community-acquired (acquired outside of a health facility, often prior to hospitalization). Gram positive bacteremia Gram positive bacteria are an increasingly important cause of bacteremia. Staphylococcus, streptococcus, and enterococcus species are the most important and most common species of gram-positive bacteria that can enter the bloodstream. These bacteria are normally found on the skin or in the gastrointestinal tract.Staphylococcus aureus is the most common cause of healthcare-associated bacteremia in North and South America and is also an important cause of community-acquired bacteremia. Skin ulceration or wounds, respiratory tract infections, and IV drug use are the most important causes of community-acquired staph aureus bacteremia. In healthcare settings, intravenous catheters, urinary tract catheters, and surgical procedures are the most common causes of staph aureus bacteremia.There are many different types of streptococcal species that can cause bacteremia. Group A streptococcus (GAS) typically causes bacteremia from skin and soft tissue infections. Group B streptococcus is an important cause of bacteremia in neonates, often immediately following birth. Viridans streptococci species are normal bacterial flora of the mouth. Viridans strep can cause temporary bacteremia after eating, toothbrushing, or flossing. More severe bacteremia can occur following dental procedures or in patients receiving chemotherapy. Finally, Streptococcus bovis is a common cause of bacteremia in patients with colon cancer.Enterococci are an important cause of healthcare-associated bacteremia. These bacteria commonly live in the gastrointestinal tract and female genital tract. Intravenous catheters, urinary tract infections and surgical wounds are all risk factors for developing bacteremia from enterococcal species. Resistant enterococcal species can cause bacteremia in patients who have had long hospital stays or frequent antibiotic use in the past (see antibiotic misuse). Gram negative bacteremia Gram negative bacterial species are responsible for approximately 24% of all cases of healthcare-associated bacteremia and 45% of all cases of community-acquired bacteremia. In general, gram negative bacteria enter the bloodstream from infections in the respiratory tract, genitourinary tract, gastrointestinal tract, or hepatobiliary system. Gram-negative bacteremia occurs more frequently in elderly populations (65 years or older) and is associated with higher morbidity and mortality in this population.E.coli is the most common cause of community-acquired bacteremia accounting for approximately 75% of cases. E.coli bacteremia is usually the result of a urinary tract infection. Other organisms that can cause community-acquired bacteremia include Pseudomonas aeruginosa, Klebsiella pneumoniae, and Proteus mirabilis. Salmonella infection, despite mainly only resulting in gastroenteritis in the developed world, is a common cause of bacteremia in Africa. It principally affects children who lack antibodies to Salmonella and HIV+ patients of all ages.Among healthcare-associated cases of bacteremia, gram negative organisms are an important cause of bacteremia in the ICU. Catheters in the veins, arteries, or urinary tract can all create a way for gram negative bacteria to enter the bloodstream. Surgical procedures of the genitourinary tract, intestinal tract, or hepatobiliary tract can also lead to gram negative bacteremia. Pseudomonas and Enterobacter species are the most important causes of gram negative bacteremia in the ICU. Bacteremia risk factors There are several risk factors that increase the likelihood of developing bacteremia from any type of bacteria. These include: HIV infection Diabetes Mellitus Chronic hemodialysis Solid organ transplant Stem cell transplant Treatment with glucocorticoids Liver failure Asplenia Mechanism Bacteremia can travel through the blood stream to distant sites in the body and cause infection (hematogenous spread). Hematogenous spread of bacteria is part of the pathophysiology of certain infections of the heart (endocarditis), structures around the brain (meningitis), and tuberculosis of the spine (Potts disease). Hematogenous spread of bacteria is responsible for many bone infections (osteomyelitis).Prosthetic cardiac implants (for example artificial heart valves) are especially vulnerable to infection from bacteremia. Prior to widespread use of vaccines, occult bacteremia was an important consideration in febrile children that appeared otherwise well. Diagnosis Bacteremia is most commonly diagnosed by blood culture, in which a sample of blood drawn from the vein by needle puncture is allowed to incubate with a medium that promotes bacterial growth. If bacteria are present in the bloodstream at the time the sample is obtained, the bacteria will multiply and can thereby be detected.Any bacteria that incidentally find their way to the culture medium will also multiply. For example, if the skin is not adequately cleaned before needle puncture, contamination of the blood sample with normal bacteria that live on the surface of the skin can occur. For this reason, blood cultures must be drawn with great attention to sterile process. The presence of certain bacteria in the blood culture, such as Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli almost never represent a contamination of the sample. On the other hand, contamination may be more highly suspected if organisms like Staphylococcus epidermidis or Cutibacterium acnes grow in the blood culture.Two blood cultures drawn from separate sites of the body are often sufficient to diagnose bacteremia. Two out of two cultures growing the same type of bacteria usually represents a real bacteremia, particularly if the organism that grows is not a common contaminant. One out of two positive cultures will usually prompt a repeat set of blood cultures to be drawn to confirm whether a contaminant or a real bacteremia is present. The patients skin is typically cleaned with an alcohol-based product prior to drawing blood to prevent contamination. Blood cultures may be repeated at intervals to determine if persistent — rather than transient — bacteremia is present.Prior to drawing blood cultures, a thorough patient history should be taken with particular regard to presence of both fevers and chills, other focal signs of infection such as in the skin or soft tissue, a state of immunosuppression, or any recent invasive procedures.Ultrasound of the heart is recommended in all those with bacteremia due to Staphylococcus aureus to rule out infectious endocarditis. Definition Bacteremia is the presence of bacteria in the bloodstream that are alive and capable of reproducing. It is a type of bloodstream infection. Bacteremia is defined as either a primary or secondary process. In primary bacteremia, bacteria have been directly introduced into the bloodstream. Injection drug use may lead to primary bacteremia. In the hospital setting, use of blood vessel catheters contaminated with bacteria may also lead to primary bacteremia. Secondary bacteremia occurs when bacteria have entered the body at another site, such as the cuts in the skin, or the mucous membranes of the lungs (respiratory tract), mouth or intestines (gastrointestinal tract), bladder (urinary tract), or genitals. Bacteria that have infected the body at these sites may then spread into the lymphatic system and gain access to the bloodstream, where further spread can occur.Bacteremia may also be defined by the timing of bacteria presence in the bloodstream: transient, intermittent, or persistent. In transient bacteremia, bacteria are present in the bloodstream for minutes to a few hours before being cleared from the body, and the result is typically harmless in healthy people. This can occur after manipulation of parts of the body normally colonized by bacteria, such as the mucosal surfaces of the mouth during tooth brushing, flossing, or dental procedures, or instrumentation of the bladder or colon. Intermittent bacteremia is characterized by periodic seeding of the same bacteria into the bloodstream by an existing infection elsewhere in the body, such as an abscess, pneumonia, or bone infection, followed by clearing of that bacteria from the bloodstream. This cycle will often repeat until the existing infection is successfully treated. Persistent bacteremia is characterized by the continuous presence of bacteria in the bloodstream. It is usually the result of an infected heart valve, a central line-associated bloodstream infection (CLABSI), an infected blood clot (suppurative thrombophlebitis), or an infected blood vessel graft. Persistent bacteremia can also occur as part of the infection process of typhoid fever, brucellosis, and bacterial meningitis. Left untreated, conditions causing persistent bacteremia can be potentially fatal.Bacteremia is clinically distinct from sepsis, which is a condition where the blood stream infection is associated with an inflammatory response from the body, often causing abnormalities in body temperature, heart rate, breathing rate, blood pressure, and white blood cell count. Treatment The presence of bacteria in the blood almost always requires treatment with antibiotics. This is because there are high mortality rates from progression to sepsis if antibiotics are delayed.The treatment of bacteremia should begin with empiric antibiotic coverage. Any patient presenting with signs or symptoms of bacteremia or a positive blood culture should be started on intravenous antibiotics. The choice of antibiotic is determined by the most likely source of infection and by the characteristic organisms that typically cause that infection. Other important considerations include the patients history of antibiotic use, the severity of the presenting symptoms, and any allergies to antibiotics. Empiric antibiotics should be narrowed, preferably to a single antibiotic, once the blood culture returns with a particular bacteria that has been isolated. Gram positive bacteremia The Infectious Disease Society of America (IDSA) recommends treating uncomplicated methicillin resistant staph aureus (MRSA) bacteremia with a 14-day course of intravenous vancomycin. Uncomplicated bacteremia is defined as having positive blood cultures for MRSA, but having no evidence of endocarditis, no implanted prostheses, negative blood cultures after 2–4 days of treatment, and signs of clinical improvement after 72 hrs.The antibiotic treatment of choice for streptococcal and enteroccal infections differs by species. However, it is important to look at the antibiotic resistance pattern for each species from the blood culture to better treat infections caused by resistant organisms. Gram negative bacteremia The treatment of gram negative bacteremia is also highly dependent on the causative organism. Empiric antibiotic therapy should be guided by the most likely source of infection and the patients past exposure to healthcare facilities. In particular, a recent history of exposure to a healthcare setting may necessitate the need for antibiotics with pseudomonas aeruginosa coverage or broader coverage for resistant organisms. Extended generation cephalosporins such as ceftriaxone or beta lactam/beta lactamase inhibitor antibiotics such as piperacillin-tazobactam are frequently used for the treatment of gram negative bacteremia. Catheter-associated infections For healthcare-associated bacteremia due to intravenous catheters, the IDSA has published guidelines for catheter removal. Short term catheters (in place <14 days) should be removed if bacteremia is caused by any gram negative bacteria, staph aureus, enterococci or mycobacteria. Long term catheters (>14 days) should be removed if the patient is developing signs or symptoms of sepsis or endocarditis, or if blood cultures remain positive for more than 72 hours. See also Antibiotic prophylaxis Dental antibiotic prophylaxis Fungemia Viremia References External links Bacteremia at Medscape eMedicine
Onyongnyong virus	The onyongnyong virus (ONNV) was first isolated by researchers at the Uganda Virus Research Institute in Entebbe, Uganda, during a large outbreak of a disease in 1959 that resembled dengue fever. ONNV is a togavirus (family Togaviridae), genus Alphavirus, is closely related to the chikungunya and Igbo Ora viruses, and is a member of the Semliki Forest antigenic complex. The name was given to the disease by the Acholi tribe during the 1959 outbreak. The name comes from the Nilotic language of Uganda and Sudan and means “weakening of the joints". The virus can infect humans and may cause disease. Signs and symptoms Common symptoms of infection with the virus are polyarthritis, rash and fever. Other symptoms include eye pain, chest pain, lymphadenitis and lethargy. The disease is self-limiting. No fatalities due to infection are known. Cause Strains ONNV has at least three major subtypes, or strains, the genomic sequences of which are currently available on genome databases. Transmission ONNV is transmitted by bites from an infected mosquito. It is the only virus whose primary vectors are anopheline mosquitoes (Anopheles funestus and Anopheles gambiae). Epidemiology There have been two epidemics of o’nyong’nyong fever. The first occurred from 1959 to 1962, spreading from Uganda to Kenya, Tanzania, Zaire (Democratic Republic of the Congo), Malawi and Mozambique, and affecting over two million people, one of the largest arbovirus epidemics ever recorded. The first virus isolates were obtained during this outbreak from mosquitoes and human blood samples collected from Gulu in northern Uganda in 1959.The second epidemic in 1996–1997 was confined to Uganda. The 35-year hiatus between the two outbreaks and evidence of an outbreak in 1904–1906 in Uganda indicate a 30–50 year cycle for epidemics.In 2013, ONNV was confirmed as the cause of disease in a 60-year-old German woman who became infected while traveling in East Africa. In 2015–2016 there was a minor outbreak in Uganda with 51 suspected cases.There has been a minor outbreak in Mombasa (Kenya) and the County Government of Mombasa issued a warning. A 2015 study indicated that ONNV is endemic in coastal East Africa, along with chikungunya virus. References == External links ==
Spondylopathy	Spondylopathies are disorders of the vertebrae. When involving inflammation, it can be called spondylitis. In contrast, a spondyloarthropathy is a condition involving the vertebral joints, but many conditions involve both spondylopathy and spondyloarthropathy. Examples include ankylosing spondylitis and spondylosis. See also Dorsopathies Spondyloarthropathy Spondylolisthesis Spondylosis Spondylitis Spondylolysis References == External links ==
Myeloid leukemia	Myeloid leukemia is a type of leukemia affecting myeloid tissue. Types include: Acute myeloid leukemia Chronic myelogenous leukemia Acute megakaryoblastic leukemia Blastic plasmacytoid dendritic cell neoplasm See also Hematological malignancies Myeloblast transient myeloproliferative disease == External links ==
Underweight	An underweight person is a person whose body weight is considered too low to be healthy. A person who is underweight is malnourished. Assessment The body mass index, a ratio of a persons weight to their height, has traditionally been used to assess the health of a person as it pertains to weight: under the cut-off point at a BMI of 18.5, a person is considered underweight. The calculation is either weight in kilograms divided by height in meters, squared, or weight in pounds times 703, divided by height in inches, squared. Another measure of underweight is through comparison to the average weight of a cohort of people of a similar age and height: people who are at least 15% to 20% below the average weight for the group are considered underweight.Body fat percentage has been suggested as another way to assess whether a person is underweight. Unlike the body mass index, which is a proxy measurement, the body fat percentage takes into account the difference in composition between adipose tissue (fat cells) and muscle tissue and their different roles in the body. The American Council on Exercise defines the amount of essential fat, below which a person is underweight, as 10–13% for women and 2–5% for men. The greater amount of essential body fat in women supports reproductive function. Prevalence Using the body mass index as a measure of weight-related health, with data from 2014, age-standardised global prevalence of underweight in women and men were 9.7% and 8.8%, respectively. These values were lower than what was reported for 1975 as 14.6% and 13,8%, respectively, indicating a worldwide reduction in the extent of undernutrition. Causes A person may be underweight due to genetics, improper metabolism of nutrients, lack of food (frequently due to poverty), drugs that affect appetite, illness (physical or mental) or the eating disorder anorexia nervosa.Being underweight is associated with certain medical conditions, including type 1 diabetes, hyperthyroidism, cancer, and tuberculosis. People with gastrointestinal or liver problems may be unable to absorb nutrients adequately. People with certain eating disorders can also be underweight due to one or more nutrient deficiencies or excessive exercise, which exacerbates nutrient deficiencies.A common belief is that healthy underweight individuals can ‘eat what they want’ and then burn it off either by high levels of activity or elevated metabolism. It has been shown however that individuals with BMI < 18.5 eat about 12% less calories than individuals with normal BMI (21.5 to 25) and they are 23% less physically active (by accelerometry). Problems Being underweight can be a symptom of an underlying condition, in which case it is secondary. Unexplained weight loss may require a professional medical diagnosis.Being underweight can also cause other conditions, in which case it is primary. Severely underweight individuals may have poor physical stamina and a weak immune system, leaving them open to infection. According to Robert E. Black of the Johns Hopkins School of Public Health (JHSPH), "Underweight status ... and micronutrient deficiencies also cause decreases in immune and non-immune host defenses, and should be classified as underlying causes of death if followed by infectious diseases that are the terminal associated causes." People who are malnourished raise special concerns, as not only gross caloric intake may be inadequate, but also intake and absorption of other vital nutrients, especially essential amino acids and micronutrients such as vitamins and minerals.In women, being severely underweight, as a result of an eating disorder or due to excessive strenuous exercise, can result in amenorrhea (absence of menstruation), infertility or complications during pregnancy if gestational weight gain is too low.Malnourishment can also cause anemia and hair loss. Being underweight is an established risk factor for osteoporosis, even for young people. This is seen in individuals suffering from relative energy deficiency in sport, formerly known as female athlete triad: when disordered eating or excessive exercise cause amenorrhea, hormone changes during ovulation leads to loss of bone mineral density. After this low bone mineral density causes the first spontaneous fractures, the damage is often irreversible. Although being underweight has been reported to increase mortality at rates comparable to that seen in morbidly obese people, the effect is much less drastic when restricted to non-smokers with no history of disease, suggesting that smoking and disease-related weight loss are the leading causes of the observed effect. Treatment Diet Underweight individuals may be advised to gain weight by increasing calorie intake. This can be done by eating a sufficient volume of sufficiently calorie-dense foods. Body weight may also be increased through the consumption of liquid nutritional supplements. Exercise Another way for underweight people to gain weight is by exercising, since muscle hypertrophy increases body mass. Weight lifting exercises are effective in helping to improve muscle tone as well as helping with weight gain. Weight lifting has also been shown to improve bone mineral density, which underweight people are more likely to lack.Exercise is catabolic, which results in a brief reduction in mass. However, during recovery, anabolic overcompensation causes the muscles to grow, which results in an overall increase in mass. This can happen through an increase in muscle proteins, or through enhanced storage of glycogen in muscles. Exercise can also help stimulate the appetite of a person who is not inclined to eat. Appetite stimulants Certain drugs may increase appetite either as their primary effect or as a side effect. Antidepressants, such as mirtazapine or amitriptyline, and antipsychotics, particularly chlorpromazine and haloperidol, as well as tetrahydrocannabinol (found in cannabis), all present an increase in appetite as a side effect. In states where it is approved, medicinal cannabis may be prescribed for severe appetite loss, such as that caused by cancer, AIDS, or severe levels of persistent anxiety. Other drugs or supplements which may increase appetite include antihistamines (such as diphenhydramine, promethazine or cyproheptadine). See also Essential nutrient List of phytochemicals in food Body image Emaciation Malnutrition Stunted growth References == External links ==
Ventricular fibrillation	Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the ventricles of the heart quiver. It is due to disorganized electrical activity. Ventricular fibrillation results in cardiac arrest with loss of consciousness and no pulse. This is followed by sudden cardiac death in the absence of treatment. Ventricular fibrillation is initially found in about 10% of people with cardiac arrest.Ventricular fibrillation can occur due to coronary heart disease, valvular heart disease, cardiomyopathy, Brugada syndrome, long QT syndrome, electric shock, or intracranial hemorrhage. Diagnosis is by an electrocardiogram (ECG) showing irregular unformed QRS complexes without any clear P waves. An important differential diagnosis is torsades de pointes.Treatment is with cardiopulmonary resuscitation (CPR) and defibrillation. Biphasic defibrillation may be better than monophasic. The medication epinephrine or amiodarone may be given if initial treatments are not effective. Rates of survival among those who are out of hospital when the arrhythmia is detected is about 17% while in hospital it is about 46%. Signs and symptoms Ventricular fibrillation is a cause of cardiac arrest. The ventricular muscle twitches randomly rather than contracting in a co-ordinated fashion (from the apex of the heart to the outflow of the ventricles), and so the ventricles fail to pump blood around the body – because of this, it is classified as a cardiac arrest rhythm, and patients in V-fib should be treated with cardiopulmonary resuscitation (CPR) and prompt defibrillation. Left untreated, ventricular fibrillation is rapidly fatal as the vital organs of the body, including the heart, are starved of oxygen, and as a result patients in this rhythm will not be conscious or responsive to stimuli. Prior to cardiac arrest, patients may complain of varying symptoms depending on the underlying cause. Patients may exhibit signs of agonal breathing, which to a layperson can look like normal spontaneous breathing, but is a sign of hypoperfusion of the brainstem.It has an appearance on electrocardiography of irregular electrical activity with no discernable pattern. It may be described as coarse or fine depending on its amplitude, or as progressing from coarse to fine V-fib. Coarse V-fib may be more responsive to defibrillation, while fine V-fib can mimic the appearance of asystole on a defibrillator or cardiac monitor set to a low gain. Some clinicians may attempt to defibrillate fine V-fib in the hope that it can be reverted to a cardiac rhythm compatible with life, whereas others will deliver CPR and sometimes drugs as described in the advanced cardiac life support protocols in an attempt to increase its amplitude and the odds of successful defibrillation. Causes Ventricular fibrillation has been described as "chaotic asynchronous fractionated activity of the heart" (Moe et al. 1964). A more complete definition is that ventricular fibrillation is a "turbulent, disorganized electrical activity of the heart in such a way that the recorded electrocardiographic deflections continuously change in shape, magnitude and direction".Ventricular fibrillation most commonly occurs within diseased hearts, and, in the vast majority of cases, is a manifestation of underlying ischemic heart disease. Ventricular fibrillation is also seen in those with cardiomyopathy, myocarditis, and other heart pathologies. In addition, it is seen with electrolyte imbalance, overdoses of cardiotoxic drugs, and following near drowning or major trauma. It is also notable that ventricular fibrillation occurs where there is no discernible heart pathology or other evident cause, the so-called idiopathic ventricular fibrillation.Idiopathic ventricular fibrillation occurs with a reputed incidence of approximately 1% of all cases of out-of-hospital arrest, as well as 3–9% of the cases of ventricular fibrillation unrelated to myocardial infarction, and 14% of all ventricular fibrillation resuscitations in patients under the age of 40. It follows then that, on the basis of the fact that ventricular fibrillation itself is common, idiopathic ventricular fibrillation accounts for an appreciable mortality. Recently described syndromes such as the Brugada Syndrome may give clues to the underlying mechanism of ventricular arrhythmias. In the Brugada syndrome, changes may be found in the resting ECG with evidence of right bundle branch block (RBBB) and ST elevation in the chest leads V1-V3, with an underlying propensity to sudden cardiac death.The relevance of this is that theories of the underlying pathophysiology and electrophysiology must account for the occurrence of fibrillation in the apparent "healthy" heart. It is evident that there are mechanisms at work that we do not fully appreciate and understand. Investigators are exploring new techniques of detecting and understanding the underlying mechanisms of sudden cardiac death in these patients without pathological evidence of underlying heart disease.Familial conditions that predispose individuals to developing ventricular fibrillation and sudden cardiac death are often the result of gene mutations that affect cellular transmembrane ion channels. For example, in Brugada Syndrome, sodium channels are affected. In certain forms of long QT syndrome, the potassium inward rectifier channel is affected.In 1899, it was also found that ventricular fibrillation was, typically, the ultimate cause of death when the electric chair was used. Pathophysiology Abnormal automaticity Automaticity is a measure of the propensity of a fiber to initiate an impulse spontaneously. The product of a hypoxic myocardium can be hyperirritable myocardial cells. These may then act as pacemakers. The ventricles are then being stimulated by more than one pacemaker. Scar and dying tissue is inexcitable, but around these areas usually lies a penumbra of hypoxic tissue that is excitable. Ventricular excitability may generate re-entry ventricular arrhythmia.Most myocardial cells with an associated increased propensity to arrhythmia development have an associated loss of membrane potential. That is, the maximum diastolic potential is less negative and therefore exists closer to the threshold potential. Cellular depolarisation can be due to a raised external concentration of potassium ions K+, a decreased intracellular concentration of sodium ions Na+, increased permeability to Na+, or a decreased permeability to K+. The ionic basic automaticity is the net gain of an intracellular positive charge during diastole in the presence of a voltage-dependent channel activated by potentials negative to –50 to –60 mV.Myocardial cells are exposed to different environments. Normal cells may be exposed to hyperkalaemia; abnormal cells may be perfused by normal environment. For example, with a healed myocardial infarction, abnormal cells can be exposed to an abnormal environment such as with a myocardial infarction with myocardial ischaemia. In conditions such as myocardial ischaemia, possible mechanism of arrhythmia generation include the resulting decreased internal K+ concentration, the increased external K+ concentration, norepinephrine release and acidosis. When myocardial cell are exposed to hyperkalemia, the maximum diastolic potential is depolarized as a result of the alteration of Ik1 potassium current, whose intensity and direction is strictly dependent on intracellular and extracellular potassium concentrations. With Ik1 suppressed, an hyperpolarizing effect is lost and therefore there can be activation of funny current even in myocardial cells (which is normally suppressed by the hyperpolarizing effect of coexisting potassium currents). This can lead to the instauration of automaticity in ischemic tissue. Re-entry The role of re-entry or circus motion was demonstrated separately by G. R. Mines and W. E. Garrey. Mines created a ring of excitable tissue by cutting the atria out of the ray fish. Garrey cut out a similar ring from the turtle ventricle. They were both able to show that, if a ring of excitable tissue was stimulated at a single point, the subsequent waves of depolarisation would pass around the ring. The waves eventually meet and cancel each other out, but, if an area of transient block occurred with a refractory period that blocked one wavefront and subsequently allowed the other to proceed retrogradely over the other path, then a self-sustaining circus movement phenomenon would result. For this to happen, however, it is necessary that there be some form of non-uniformity. In practice, this may be an area of ischemic or infarcted myocardium, or underlying scar tissue.It is possible to think of the advancing wave of depolarisation as a dipole with a head and a tail. The length of the refractory period and the time taken for the dipole to travel a certain distance—the propagation velocity—will determine whether such a circumstance will arise for re-entry to occur. Factors that promote re-entry would include a slow-propagation velocity, a short refractory period with a sufficient size of ring of conduction tissue. These would enable a dipole to reach an area that had been refractory and is now able to be depolarised with continuation of the wavefront.In clinical practice, therefore, factors that would lead to the right conditions to favour such re-entry mechanisms include increased heart size through hypertrophy or dilatation, drugs which alter the length of the refractory period and areas of cardiac disease. Therefore, the substrate of ventricular fibrillation is transient or permanent conduction block. Block due either to areas of damaged or refractory tissue leads to areas of myocardium for initiation and perpetuation of fibrillation through the phenomenon of re-entry. Triggered activity Triggered activity can occur due to the presence of afterdepolarisations. These are depolarising oscillations in the membrane voltage induced by preceding action potentials. These can occur before or after full repolarisation of the fiber and as such are termed either early (EADs) or delayed afterdepolarisations (DADs). All afterdepolarisations may not reach threshold potential, but, if they do, they can trigger another afterdepolarisation, and thus self-perpetuate. Power spectrum The distribution of frequency and power of a waveform can be expressed as a power spectrum in which the contribution of different waveform frequencies to the waveform under analysis is measured. This can be expressed as either the dominant or peak frequency, i.e., the frequency with the greatest power or the median frequency, which divides the spectrum in two halves.Frequency analysis has many other uses in medicine and in cardiology, including analysis of heart rate variability and assessment of cardiac function, as well as in imaging and acoustics. Histopathology Myofibre break-up, abbreviated MFB, is associated with ventricular fibrillation leading to death. Histomorphologically, MFB is characterized by fractures of the cardiac myofibres perpendicular to their long axis, with squaring of the myofibre nuclei. Treatment Defibrillation is the definitive treatment of ventricular fibrillation, whereby an electrical current is applied to the ventricular mass either directly or externally through pads or paddles, with the aim of depolarising enough of the myocardium for coordinated contractions to occur again. The use of this is often dictated around the world by Advanced Cardiac Life Support or Advanced Life Support algorithms, which is taught to medical practitioners including doctors, nurses and paramedics and also advocates the use of drugs, predominantly epinephrine, after every second unsuccessful attempt at defibrillation, as well as cardiopulmonary resuscitation (CPR) between defibrillation attempts. Though ALS/ACLS algorithms encourage the use of drugs, they state first and foremost that defibrillation should not be delayed for any other intervention and that adequate cardiopulmonary resuscitation be delivered with minimal interruption.The precordial thump is a manoeuver promoted as a mechanical alternative to defibrillation. Some advanced life support algorithms advocate its use once and only in the case of witnessed and monitored V-fib arrests as the likelihood of it successfully cardioverting a patient are small and this diminishes quickly in the first minute of onset.People who survive a "V-fib arrest" and who make a good recovery are often considered for an implantable cardioverter-defibrillator, which can quickly deliver this same life-saving defibrillation should another episode of ventricular fibrillation occur outside a hospital environment. Epidemiology Sudden cardiac arrest is the leading cause of death in the industrialised world. It exacts a significant mortality with approximately 70,000 to 90,000 sudden cardiac deaths each year in the United Kingdom, and survival rates are only 2%. The majority of these deaths are due to ventricular fibrillation secondary to myocardial infarction, or "heart attack". During ventricular fibrillation, cardiac output drops to zero, and, unless remedied promptly, death usually ensues within minutes. History Lyman Brewer suggests that the first recorded account of ventricular fibrillation dates as far back as 1500 BC, and can be found in the Ebers papyrus of ancient Egypt. An extract, recorded 3500 years ago, states: "When the heart is diseased, its work is imperfectly performed: the vessels proceeding from the heart become inactive, so that you cannot feel them … if the heart trembles, has little power and sinks, the disease is advanced and death is near." A book authored by Jo Miles suggests that it may even go back farther. Tests done on frozen remains found in the Himalayas seemed fairly conclusive that the first known case of ventricular fibrillation dates back to at least 2500 BC.Whether this is a description of ventricular fibrillation is debatable. The next recorded description occurs 3000 years later and is recorded by Vesalius, who described the appearance of "worm-like" movements of the heart in animals prior to death.The significance and clinical importance of these observations and descriptions possibly of ventricular fibrillation were not recognised until John Erichsen in 1842 described ventricular fibrillation following the ligation of a coronary artery (Erichsen JE 1842). Subsequent to this in 1850, fibrillation was described by Ludwig and Hoffa when they demonstrated the provocation of ventricular fibrillation in an animal by applying a "Faradic" (electrical) current to the heart.In 1874, Edmé Félix Alfred Vulpian coined the term mouvement fibrillaire, a term that he seems to have used to describe both atrial and ventricular fibrillation. John A. MacWilliam, a physiologist who had trained under Ludwig and who subsequently became Professor of Physiology at the University of Aberdeen, gave an accurate description of the arrhythmia in 1887. This definition still holds today, and is interesting in the fact that his studies and description predate the use of electrocardiography. His description is as follows: "The ventricular muscle is thrown into a state of irregular arrhythmic contraction, whilst there is a great fall in the arterial blood pressure, the ventricles become dilated with blood as the rapid quivering movement of their walls is insufficient to expel their contents; the muscular action partakes of the nature of a rapid incoordinate twitching of the muscular tissue … The cardiac pump is thrown out of gear, and the last of its vital energy is dissipated in the violent and the prolonged turmoil of fruitless activity in the ventricular walls." MacWilliam spent many years working on ventricular fibrillation and was one of the first to show that ventricular fibrillation could be terminated by a series of induction shocks through the heart.The first electrocardiogram recording of ventricular fibrillation was by August Hoffman in a paper published in 1912. At this time, two other researchers, George Ralph Mines and Garrey, working separately, produced work demonstrating the phenomenon of circus movement and re-entry as possible substrates for the generation of arrhythmias. This work was also accompanied by Lewis, who performed further outstanding work into the concept of "circus movement."Later milestones include the work by W. J. Kerr and W. L. Bender in 1922, who produced an electrocardiogram showing ventricular tachycardia evolving into ventricular fibrillation. The re-entry mechanism was also advocated by DeBoer, who showed that ventricular fibrillation could be induced in late systole with a single shock to a frog heart. The concept of "R on T ectopics" was further brought out by Katz in 1928. This was called the "vulnerable period" by Wiggers and Wegria in 1940, who brought to attention the concept of the danger of premature ventricular beats occurring on a T wave.Another definition of VF was produced by Wiggers in 1940. He described ventricular fibrillation as "an incoordinate type of contraction which, despite a high metabolic rate of the myocardium, produces no useful beats. As a result, the arterial pressure falls abruptly to very low levels, and death results within six to eight minutes from anemia [ischemia] of the brain and spinal cord".Spontaneous conversion of ventricular fibrillation to a more benign rhythm is rare in all but small animals. Defibrillation is the process that converts ventricular fibrillation to a more benign rhythm. This is usually by application of an electric shock to the myocardium and is discussed in detail in the relevant article. See also References External links Interactive models and information on ventricular fibrillation and other arrhythmias
Hypertensive encephalopathy	Hypertensive encephalopathy (HE) is general brain dysfunction due to significantly high blood pressure. Symptoms may include headache, vomiting, trouble with balance, and confusion. Onset is generally sudden. Complications can include seizures, posterior reversible encephalopathy syndrome, and bleeding in the back of the eye.In hypertensive encephalopathy, generally the blood pressure is greater than 200/130 mmHg. Occasionally it can occur at a BP as low as 160/100 mmHg. This can occur in kidney failure, those who rapidly stop blood pressure medication, pheochromocytoma, and people on a monoamine oxidase inhibitor (MAOI) who eat foods with tyramine. When it occurs in pregnancy it is known as eclampsia. The diagnosis requires ruling out other possible causes.The condition is generally treated with medications to relatively rapidly lower the blood pressure. This may be done with labetalol or sodium nitroprusside given by injection into a vein. In those who are pregnant, magnesium sulfate may be used. Other treatments may include anti-seizure medications.Hypertensive encephalopathy is uncommon. It is believed to occur more often in those without easy access to health care. The term was first used by Oppenheimer and Fishberg in 1928. It is classified as a type of hypertensive emergency. Signs and symptoms Hypertensive encephalopathy is most commonly encountered in young and middle-aged people who have hypertension. Overall, the condition is rare even among people with hypertension. Studies report that from 0.5 to 15% of people with malignant hypertension develop hypertensive encephalopathy. With the development of methods for detection and treatment of hypertension, hypertensive encephalopathy has been becoming more rare.Symptoms of hypertensive encephalopathy typically start to occur 12–48 hours after a sudden and sustained increase in blood pressure. The first manifestation of these symptoms is a severe headache. Headache occurs in greater than 75% of patients. The patient becomes restless. Alterations in consciousness may follow several hours later, which include impaired judgement and memory, confusion, somnolence and stupor. If the condition is not treated, these neurological symptoms may worsen and ultimately turn into a coma. Other symptoms may include increased irritability, vomiting, diplopia, seizures, twitching and myoclonus of the limbs. Alterations in vision (vision blurring, hemivisual field defects, color blindness, cortical blindness) are common. They occur in 4 out of 11 cases (Jellinek et al. 1964). Hemiparesis, intracerebral hemorrhage, aphasia may also occur, but they are less common. Pathogenesis Hypertensive encephalopathy is caused by an increase in blood pressure. Several conditions may evoke blood pressure elevation: acute nephritis, eclampsia, crises in chronic essential hypertension, sudden withdrawal of antihypertensive treatment. Additionally, hypertensive encephalopathy may occur in pheochromocytoma, Cushings syndrome, renal artery thrombosis.The impairment of cerebral blood flow that underlies hypertensive encephalopathy is still controversial. Normally, cerebral blood flow is maintained by an autoregulation mechanism that dilates arterioles in response to blood pressure decreases and constricts arterioles in response to blood pressure increases. This autoregulation falters when hypertension becomes excessive. According to the over-regulation conception, brain vessels spasm in response to acute hypertension, which results in cerebral ischemia and cytotoxic edema. According to the autoregulation breakthrough conception, cerebral arterioles are forced to dilate, leading to vasogenic edema.Cerebral edema can be generalized or focal. Brain ventricles are compressed, cortical gyri flattened. Diagnosis Diagnostic methods for hypertensive encephalopathy include physical examination, blood pressure measurement, blood sampling, ECG, EEG, chest X-ray, urinalysis, arterial blood gas analysis, and imaging of the head (CAT scan and/or MRI). Since decreasing blood pressure is essential, anti-hypertensive medication is administered without awaiting the results of the laboratory tests. Electroencephalographic examination detects the absence of alpha waves, signifying impaired consciousness. In people with visual disturbances, slow waves are detected in the occipital areas. Treatment The initial aim of treatment in hypertensive crises is to rapidly lower the diastolic pressure to about 100 to 105 mmHg; this goal should be achieved within two to six hours, with the maximum initial fall in BP not exceeding 25 percent of the presenting value. This level of BP control will allow gradual healing of the necrotizing vascular lesions. More aggressive hypotensive therapy is both unnecessary and may reduce the blood pressure below the autoregulatory range, possibly leading to ischemic events (such as stroke or coronary disease).Once the BP is controlled, the person should be switched to medication by mouth, with the diastolic pressure being gradually reduced to 85 to 90 mmHg over two to three months. The initial reduction to a diastolic pressure of approximately 100 mmHg is often associated with a modest worsening of renal function; this change, however, is typically transient as the vascular disease tends to resolve and renal perfusion improves over one to three months. Antihypertensive therapy should not be withheld in this setting unless there has been an excessive reduction in BP. A change in medication, however, is indicated if the decline in renal function is temporally related to therapy with an angiotensin (ACE) converting enzyme inhibitor or angiotensin II receptor blocker, which can interfere with renal autoregulation and produce acute kidney failure in patients with bilateral renal artery stenosis. (See "Renal effects of ACE inhibitors in hypertension".)ref Several parenteral antihypertensive agents are most often used in the initial treatment of malignant hypertension. Nitroprusside – an arteriolar and venous dilator, given as an intravenous infusion. Nitroprusside acts within seconds and has a duration of action of only two to five minutes. Thus, hypotension can be easily reversed by temporarily discontinuing the infusion, providing an advantage over the drugs listed below. However, the potential for cyanide toxicity limits the prolonged use of nitroprusside, particularly in patients with chronic kidney disease. Nicardipine – an arteriolar dilator, given as an intravenous infusion. Clevidipine – a short-acting dihydropyridine calcium channel blocker. It reduces blood pressure without affecting cardiac filling pressures or causing reflex tachycardia. Labetalol – an alpha- and beta-adrenergic blocker, given as an intravenous bolus or infusion. Bolus followed by infusion. Fenoldopam – a peripheral dopamine-1 receptor agonist, given as an intravenous infusion. Oral agents — A slower onset of action and an inability to control the degree of BP reduction has limited the use of oral antihypertensive agents in the therapy of hypertensive crises. They may, however, be useful when there is no rapid access to the parenteral medications described above. Both sublingual nifedipine and sublingual captopril can substantially lower the BP within 10 to 30 minutes in many patients. A more rapid response is seen when liquid nifedipine is swallowed.The major risk with oral agents is ischemic symptoms (e.g., angina pectoris, myocardial infarction, or stroke) due to an excessive and uncontrolled hypotensive response. Thus, their use should generally be avoided in the treatment of hypertensive crises if more controllable drugs are available. Prognosis Patients with hypertensive encephalopathy who are promptly treated usually recover without deficit. However, if treatment is not administered, the condition can lead to death. History The first descriptions of the condition date back to the early 1900s. In 1914, Volhard and Fahr distinguished a neurological disorder caused by acute hypertension from a uremic state. He described this condition a "pseudouremia". The term "hypertensive encephalopathy" was introduced by Oppenheimer and Fishberg in 1928 to describe the case of a patient with acute nephritis, severe hypertension, and cerebral symptoms.In the past, the term "hypertensive encephalopathy" has been applied to a range of neurological problems occurring in hypertensive patients, such as headache, dizziness cerebral hemorrhage and transient ischemic attacks. However, currently this term is narrowed down to a clinical condition produced by elevated blood pressure and which can be reversed by blood pressure reduction. References == External links ==
Chills	Chills is a feeling of coldness occurring during a high fever, but sometimes is also a common symptom which occurs alone in specific people. It occurs during fever due to the release of cytokines and prostaglandins as part of the inflammatory response, which increases the set point for body temperature in the hypothalamus. The increased set point causes the body temperature to rise (pyrexia), but also makes the patient feel cold or chills until the new set point is reached. Shivering also occurs along with chills because the patients body produces heat during muscle contraction in a physiological attempt to increase body temperature to the new set point. When it does not accompany a high fever, it is normally a light chill. Sometimes a chill of medium power and short duration may occur during a scare, especially in scares of fear, commonly interpreted like or confused by trembling. Severe chills with violent shivering are called rigors. Causes Chills are commonly caused by inflammatory diseases, such as influenza. It is also common in urinary tract infections. Malaria is one of the common reasons for chills and rigors. In malaria, the parasites enter the liver, grow there and then attack the red blood cells which causes rupture of these cells and release of a toxic substance hemozoin which causes chills recurring every 3 to 4 days. Sometimes they happen in specific people almost all the time, in a slight power, or it less commonly happens in a generally healthy person. See also Cold chill Goose bumps Night sweats References == External links ==
Hand	A hand is a prehensile, multi-fingered appendage located at the end of the forearm or forelimb of primates such as humans, chimpanzees, monkeys, and lemurs. A few other vertebrates such as the koala (which has two opposable thumbs on each "hand" and fingerprints extremely similar to human fingerprints) are often described as having "hands" instead of paws on their front limbs. The raccoon is usually described as having "hands" though opposable thumbs are lacking.Some evolutionary anatomists use the term hand to refer to the appendage of digits on the forelimb more generally—for example, in the context of whether the three digits of the bird hand involved the same homologous loss of two digits as in the dinosaur hand.The human hand usually has five digits: four fingers plus one thumb; these are often referred to collectively as five fingers, however, whereby the thumb is included as one of the fingers. It has 27 bones, not including the sesamoid bone, the number of which varies among people, 14 of which are the phalanges (proximal, intermediate and distal) of the fingers and thumb. The metacarpal bones connect the fingers and the carpal bones of the wrist. Each human hand has five metacarpals and eight carpal bones. Fingers contain some of the densest areas of nerve endings in the body, and are the richest source of tactile feedback. They also have the greatest positioning capability of the body; thus, the sense of touch is intimately associated with hands. Like other paired organs (eyes, feet, legs) each hand is dominantly controlled by the opposing brain hemisphere, so that handedness—the preferred hand choice for single-handed activities such as writing with a pencil, reflects individual brain functioning. Among humans, the hands play an important function in body language and sign language. Likewise, the ten digits of two hands and the twelve phalanges of four fingers (touchable by the thumb) have given rise to number systems and calculation techniques. Structure Many mammals and other animals have grasping appendages similar in form to a hand such as paws, claws, and talons, but these are not scientifically considered to be grasping hands. The scientific use of the term hand in this sense to distinguish the terminations of the front paws from the hind ones is an example of anthropomorphism. The only true grasping hands appear in the mammalian order of primates. Hands must also have opposable thumbs, as described later in the text. The hand is located at the distal end of each arm. Apes and monkeys are sometimes described as having four hands, because the toes are long and the hallux is opposable and looks more like a thumb, thus enabling the feet to be used as hands. The word "hand" is sometimes used by evolutionary anatomists to refer to the appendage of digits on the forelimb such as when researching the homology between the three digits of the bird hand and the dinosaur hand.An adult human males hand weighs about a pound. Areas Areas of the human hand include: The palm (Volar), which is the central region of the anterior part of the hand, located superficially to the metacarpus. The skin in this area contains dermal papillae to increase friction, such as are also present on the fingers and used for fingerprints. The opisthenar area (dorsal) is the corresponding area on the posterior part of the hand. The heel of the hand is the area anteriorly to the bases of the metacarpal bones, located in the proximal part of the palm. It is the area that sustains most pressure when using the palm of the hand for support, such as in handstand.There are five digits attached to the hand, notably with a nail fixed to the end in place of the normal claw. The four fingers can be folded over the palm which allows the grasping of objects. Each finger, starting with the one closest to the thumb, has a colloquial name to distinguish it from the others: index finger, pointer finger, forefinger, or 2nd digit middle finger or long finger or 3rd digit ring finger or 4th digit little finger, pinky finger, small finger, baby finger, or 5th digitThe thumb (connected to the first metacarpal bone and trapezium) is located on one of the sides, parallel to the arm. A reliable way of identifying human hands is from the presence of opposable thumbs. Opposable thumbs are identified by the ability to be brought opposite to the fingers, a muscle action known as opposition. Bones The skeleton of the human hand consists of 27 bones: the eight short carpal bones of the wrist are organized into a proximal row (scaphoid, lunate, triquetral and pisiform) which articulates with the bones of the forearm, and a distal row (trapezium, trapezoid, capitate and hamate), which articulates with the bases of the five metacarpal bones of the hand. The heads of the metacarpals will each in turn articulate with the bases of the proximal phalanx of the fingers and thumb. These articulations with the fingers are the metacarpophalangeal joints known as the knuckles. At the palmar aspect of the first metacarpophalangeal joints are small, almost spherical bones called the sesamoid bones. The fourteen phalanges make up the fingers and thumb, and are numbered I-V (thumb to little finger) when the hand is viewed from an anatomical position (palm up). The four fingers each consist of three phalanx bones: proximal, middle, and distal. The thumb only consists of a proximal and distal phalanx. Together with the phalanges of the fingers and thumb these metacarpal bones form five rays or poly-articulated chains. Because supination and pronation (rotation about the axis of the forearm) are added to the two axes of movements of the wrist, the ulna and radius are sometimes considered part of the skeleton of the hand. There are numerous sesamoid bones in the hand, small ossified nodes embedded in tendons; the exact number varies between people: whereas a pair of sesamoid bones are found at virtually all thumb metacarpophalangeal joints, sesamoid bones are also common at the interphalangeal joint of the thumb (72.9%) and at the metacarpophalangeal joints of the little finger (82.5%) and the index finger (48%). In rare cases, sesamoid bones have been found in all the metacarpophalangeal joints and all distal interphalangeal joints except that of the long finger. The articulations are: interphalangeal articulations of hand (the hinge joints between the bones of the digits) metacarpophalangeal joints (where the digits meet the palm) intercarpal articulations (where the palm meets the wrist) wrist (may also be viewed as belonging to the forearm). Arches The fixed and mobile parts of the hand adapt to various everyday tasks by forming bony arches: longitudinal arches (the rays formed by the finger bones and their associated metacarpal bones), transverse arches (formed by the carpal bones and distal ends of the metacarpal bones), and oblique arches (between the thumb and four fingers): Of the longitudinal arches or rays of the hand, that of the thumb is the most mobile (and the least longitudinal). While the ray formed by the little finger and its associated metacarpal bone still offers some mobility, the remaining rays are firmly rigid. The phalangeal joints of the index finger, however, offer some independence to its finger, due to the arrangement of its flexor and extension tendons.The carpal bones form two transversal rows, each forming an arch concave on the palmar side. Because the proximal arch simultaneously has to adapt to the articular surface of the radius and to the distal carpal row, it is by necessity flexible. In contrast, the capitate, the "keystone" of the distal arch, moves together with the metacarpal bones and the distal arch is therefore rigid. The stability of these arches is more dependent of the ligaments and capsules of the wrist than of the interlocking shapes of the carpal bones, and the wrist is therefore more stable in flexion than in extension. The distal carpal arch affects the function of the CMC joints and the hands, but not the function of the wrist or the proximal carpal arch. The ligaments that maintain the distal carpal arches are the transverse carpal ligament and the intercarpal ligaments (also oriented transversally). These ligaments also form the carpal tunnel and contribute to the deep and superficial palmar arches. Several muscle tendons attaching to the TCL and the distal carpals also contribute to maintaining the carpal arch.Compared to the carpal arches, the arch formed by the distal ends of the metacarpal bones is flexible due to the mobility of the peripheral metacarpals (thumb and little finger). As these two metacarpals approach each other, the palmar gutter deepens. The central-most metacarpal (middle finger) is the most rigid. It and its two neighbors are tied to the carpus by the interlocking shapes of the metacarpal bones. The thumb metacarpal only articulates with the trapezium and is therefore completely independent, while the fifth metacarpal (little finger) is semi-independent with the fourth metacarpal (ring finger) which forms a transitional element to the fifth metacarpal.Together with the thumb, the four fingers form four oblique arches, of which the arch of the index finger functionally is the most important, especially for precision grip, while the arch of the little finger contribute an important locking mechanism for power grip. The thumb is undoubtedly the "master digit" of the hand, giving value to all the other fingers. Together with the index and middle finger, it forms the dynamic tridactyl configuration responsible for most grips not requiring force. The ring and little fingers are more static, a reserve ready to interact with the palm when great force is needed. Muscles The muscles acting on the hand can be subdivided into two groups: the extrinsic and intrinsic muscle groups. The extrinsic muscle groups are the long flexors and extensors. They are called extrinsic because the muscle belly is located on the forearm. Intrinsic The intrinsic muscle groups are the thenar (thumb) and hypothenar (little finger) muscles; the interosseous muscles (four dorsally and three volarly) originating between the metacarpal bones; and the lumbrical muscles arising from the deep flexor (and are special because they have no bony origin) to insert on the dorsal extensor hood mechanism. Extrinsic The fingers have two long flexors, located on the underside of the forearm. They insert by tendons to the phalanges of the fingers. The deep flexor attaches to the distal phalanx, and the superficial flexor attaches to the middle phalanx. The flexors allow for the actual bending of the fingers. The thumb has one long flexor and a short flexor in the thenar muscle group. The human thumb also has other muscles in the thenar group (opponens and abductor brevis muscle), moving the thumb in opposition, making grasping possible. The extensors are located on the back of the forearm and are connected in a more complex way than the flexors to the dorsum of the fingers. The tendons unite with the interosseous and lumbrical muscles to form the extensorhood mechanism. The primary function of the extensors is to straighten out the digits. The thumb has two extensors in the forearm; the tendons of these form the anatomical snuff box. Also, the index finger and the little finger have an extra extensor used, for instance, for pointing. The extensors are situated within 6 separate compartments. The first four compartments are located in the grooves present on the dorsum of inferior side of radius while the 5th compartment is in between radius and ulna. The 6th compartment is in the groove on the dorsum of inferior side of ulna. Nerve supply The hand is innervated by the radial, median, and ulnar nerves. MotorThe radial nerve supplies the finger extensors and the thumb abductor, thus the muscles that extends at the wrist and metacarpophalangeal joints (knuckles); and that abducts and extends the thumb. The median nerve supplies the flexors of the wrist and digits, the abductors and opponens of the thumb, the first and second lumbrical. The ulnar nerve supplies the remaining intrinsic muscles of the hand.All muscles of the hand are innervated by the brachial plexus (C5–T1) and can be classified by innervation: SensoryThe radial nerve supplies the skin on the back of the hand from the thumb to the ring finger and the dorsal aspects of the index, middle, and half ring fingers as far as the proximal interphalangeal joints. The median nerve supplies the palmar side of the thumb, index, middle, and half ring fingers. Dorsal branches innervates the distal phalanges of the index, middle, and half ring fingers. The ulnar nerve supplies the ulnar third of the hand, both at the palm and the back of the hand, and the little and half ring fingers.There is a considerable variation to this general pattern, except for the little finger and volar surface of the index finger. For example, in some individuals, the ulnar nerve supplies the entire ring finger and the ulnar side of the middle finger, whilst, in others, the median nerve supplies the entire ring finger. Blood supply The hand is supplied with blood from two arteries, the ulnar artery and the radial artery. These arteries form three arches over the dorsal and palmar aspects of the hand, the dorsal carpal arch (across the back of the hand), the deep palmar arch, and the superficial palmar arch. Together these three arches and their anastomoses provide oxygenated blood to the palm, the fingers, and the thumb. The hand is drained by the dorsal venous network of the hand with deoxygenated blood leaving the hand via the cephalic vein and the basilic vein. Skin The glabrous (hairless) skin on the front of the hand, the palm, is relatively thick and can be bent along the hands flexure lines where the skin is tightly bound to the underlying tissue and bones. Compared to the rest of the bodys skin, the hands palms (as well as the soles of the feet) are usually lighter—and even much lighter in dark-skinned individuals, compared to the other side of the hand. Indeed, genes specifically expressed in the dermis of palmoplantar skin inhibit melanin production and thus the ability to tan, and promote the thickening of the stratum lucidum and stratum corneum layers of the epidermis. All parts of the skin involved in grasping are covered by papillary ridges (fingerprints) acting as friction pads. In contrast, the hairy skin on the dorsal side is thin, soft, and pliable, so that the skin can recoil when the fingers are stretched. On the dorsal side, the skin can be moved across the hand up to 3 cm (1.2 in); an important input the cutaneous mechanoreceptors.The web of the hand is a "fold of skin which connects the digits". These webs, located between each set of digits, are known as skin folds (interdigital folds or plica interdigitalis). They are defined as "one of the folds of skin, or rudimentary web, between the fingers and toes". Variation The ratio of the length of the index finger to the length of the ring finger in adults is affected by the level of exposure to male sex hormones of the embryo in utero. This digit ratio is below 1 for both sexes but it is lower in males than in females on average. Clinical significance A number of genetic disorders affect the hand. Polydactyly is the presence of more than the usual number of fingers. One of the disorders that can cause this is Catel-Manzke syndrome. The fingers may be fused in a disorder known as syndactyly. Or there may be an absence of one or more central fingers—a condition known as ectrodactyly. Additionally, some people are born without one or both hands (amelia). Hereditary multiple exostoses of the forearm—also known as hereditary multiple osteochondromas—is another cause of hand and forearm deformity in children and adults.There are several cutaneous conditions that can affect the hand including the nails. The autoimmune disease rheumatoid arthritis can affect the hand, particularly the joints of the fingers. Some conditions can be treated by hand surgery. These include carpal tunnel syndrome, a painful condition of the hand and fingers caused by compression of the median nerve, and Dupuytrens contracture, a condition in which fingers bend towards the palm and cannot be straightened. Similarly, injury to the ulnar nerve may result in a condition in which some of the fingers cannot be flexed. A common fracture of the hand is a scaphoid fracture—a fracture of the scaphoid bone, one of the carpal bones. This is the commonest carpal bone fracture and can be slow to heal due to a limited blood flow to the bone. There are various types of fracture to the base of the thumb; these are known as Rolando fractures, Bennets fracture, and Gamekeepers thumb. Another common fracture, known as Boxers fracture, is to the neck of a metacarpal. One can also have a broken finger. Evolution The prehensile hands and feet of primates evolved from the mobile hands of semi-arboreal tree shrews that lived about 60 million years ago. This development has been accompanied by important changes in the brain and the relocation of the eyes to the front of the face, together allowing the muscle control and stereoscopic vision necessary for controlled grasping. This grasping, also known as power grip, is supplemented by the precision grip between the thumb and the distal finger pads made possible by the opposable thumbs. Hominidae (great apes including humans) acquired an erect bipedal posture about 3.6 million years ago, which freed the hands from the task of locomotion and paved the way for the precision and range of motion in human hands. Functional analyses of the features unique to the hand of modern humans have shown that they are consistent with the stresses and requirements associated with the effective use of paleolithic stone tools. It is possible that the refinement of the bipedal posture in the earliest hominids evolved to facilitate the use of the trunk as leverage in accelerating the hand.While the human hand has unique anatomical features, including a longer thumb and fingers that can be controlled individually to a higher degree, the hands of other primates are anatomically similar and the dexterity of the human hand can not be explained solely on anatomical factors. The neural machinery underlying hand movements is a major contributing factor; primates have evolved direct connections between neurons in cortical motor areas and spinal motoneurons, giving the cerebral cortex monosynaptic control over the motoneurons of the hand muscles; placing the hands "closer" to the brain. The recent evolution of the human hand is thus a direct result of the development of the central nervous system, and the hand, therefore, is a direct tool of our consciousness—the main source of differentiated tactile sensations—and a precise working organ enabling gestures—the expressions of our personalities. There are nevertheless several primitive features left in the human hand, including pentadactyly (having five fingers), the hairless skin of the palm and fingers, and the os centrale found in human embryos, prosimians, and apes. Furthermore, the precursors of the intrinsic muscles of the hand are present in the earliest fishes, reflecting that the hand evolved from the pectoral fin and thus is much older than the arm in evolutionary terms.The proportions of the human hand are plesiomorphic (shared by both ancestors and extant primate species); the elongated thumbs and short hands more closely resemble the hand proportions of Miocene apes than those of extant primates. Humans did not evolve from knuckle-walking apes, and chimpanzees and gorillas independently acquired elongated metacarpals as part of their adaptation to their modes of locomotion. Several primitive hand features most likely present in the chimpanzee-human last common ancestor (CHLCA) and absent in modern humans are still present in the hands of Australopithecus, Paranthropus, and Homo floresiensis. This suggests that the derived changes in modern humans and Neanderthals did not evolve until 2.5 to 1.5 million years ago or after the appearance of the earliest Acheulian stone tools, and that these changes are associated with tool-related tasks beyond those observed in other hominins. The thumbs of Ardipithecus ramidus, an early hominin, are almost as robust as in humans, so this may be a primitive trait, while the palms of other extant higher primates are elongated to the extent that some of the thumbs original function has been lost (most notably in highly arboreal primates such as the spider monkey). In humans, the big toe is thus more derived than the thumb.There is a hypothesis suggesting the form of the modern human hand is especially conducive to the formation of a compact fist, presumably for fighting purposes. The fist is compact and thus effective as a weapon. It also provides protection for the fingers. However, this is not widely accepted to be one of the primary selective pressures acting on hand morphology throughout human evolution, with tool use and production being thought to be far more influential. Additional images See also References External links Hand anatomy (eMedicine) Film Board of Canada documentary Faces of the Hand "The Common Hand" article in the May 2012 National Geographic
Myelodysplastic syndrome	A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include feeling tired, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.Risk factors include previous chemotherapy or radiation therapy, exposure to certain chemicals such as tobacco smoke, pesticides, and benzene, and exposure to heavy metals such as mercury or lead. Problems with blood cell formation result in some combination of low red blood cell, platelet, and white blood cell counts. Some types have an increase in immature blood cells, called blasts, in the bone marrow or blood. The types of MDS are based on specific changes in the blood cells and bone marrow.Treatments may include supportive care, drug therapy, and hematopoietic stem cell transplantation. Supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics. Drug therapy may include the medications lenalidomide, antithymocyte globulin, and azacitidine. Certain people can be cured with chemotherapy followed by a stem-cell transplant from a donor.About seven per 100,000 people are affected, with about four per 100,000 people newly acquiring the condition each year. The typical age of onset is 70 years. The outlook depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells. The typical survival time following diagnosis is 2.5 years. The conditions were first recognized in the early 1900s. The current name came into use in 1976. Signs and symptoms Signs and symptoms are nonspecific and generally related to the blood cytopenias: Anemia (low RBC count or reduced hemoglobin) – chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain Neutropenia (low neutrophil count) – increased susceptibility to infection Thrombocytopenia (low platelet count) – increased susceptibility to bleeding and ecchymosis (bruising), as well as subcutaneous hemorrhaging resulting in purpura or petechiaeMany individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count: Neutropenia, anemia, and thrombocytopenia Splenomegaly or rarely hepatomegaly Abnormal granules in cells, abnormal nuclear shape and size Chromosome abnormality, including chromosomal translocations and abnormal chromosome numberAlthough some risk exists for developing acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. However, leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment. Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important factor in the persons medical history. Fever, weight loss and splenomegaly should point to a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) rather than pure myelodysplastic process. Cause Some people have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Xylene and benzene exposures have been associated with myelodysplasia. Vietnam veterans exposed to Agent Orange are at risk of developing MDS. A link may exist between the development of MDS "in atomic-bomb survivors 40 to 60 years after radiation exposure" (in this case, referring to people who were in close proximity to the dropping of the atomic bombs in Hiroshima and Nagasaki during World War II). Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia. Pathophysiology MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as radiation, benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late toxicity of cancer therapy (therapy associated MDS, t-MDS). MDS after exposure to radiation or alkylating agents such as busulfan, nitrosourea, or procarbazine, typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure to DNA topoisomerase II inhibitors occurs after a shorter latency of only 1–3 years and can have a 11q23 translocation. Other pre-existing bone-marrow disorders such as acquired aplastic anemia following immunosuppressive treatment and Fanconi anemia can evolve into MDS.MDS is thought to arise from mutations in the multipotent bone-marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and a significant increase in levels of apoptotic cell death occurs in bone-marrow cells. Clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone-marrow myeloblasts rises over a particular cutoff (20% for WHO and 30% for FAB), then transformation to acute myelogenous leukemia (AML) is said to have occurred. The progression of MDS to AML is a good example of the multistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into a cancer cell.Although recognition of leukemic transformation was historically important (see History), a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML, but rather from the cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion, MDS patients rarely experience injury from severe anemia. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). Long-term transfusion of packed red blood cells leads to iron overload. Genetics The recognition of epigenetic changes in DNA structure in MDS has explained the success of two (namely the hypomethylating agents 5-azacytidine and decitabine) of three (the third is lenalidomide) commercially available medications approved by the U.S. Food and Drug Administration to treat MDS. Proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth and cytopenias. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus, thereby restoring normal blood counts and retarding the progression of MDS to acute leukemia.Some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in MDS. 5q- syndrome Since at least 1974, the deletion in the long arm of chromosome 5 has been known to be associated with dysplastic abnormalities of hematopoietic stem cells. By 2005, lenalidomide, a chemotherapy drug, was recognized to be effective in MDS patients with the 5q- syndrome, and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low IPSS risk, and transfusion dependence respond best to lenalidomide. Typically, prognosis for these patients is favorable, with a 63-month median survival. Lenalidomide has dual action, by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion. Splicing factor mutations Mutations in splicing factors have been found in 40–80% of cases with myelodysplastic syndrome, particularly in those with ringed sideroblasts. IDH1 and IDH2 mutations Mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in 10–20% of patients with myelodysplastic syndrome, and confer a worsened prognosis in low-risk MDS. Because the incidence of IDH1/2 mutations increases as the disease malignancy increases, these findings together suggest that IDH1/2 mutations are important drivers of progression of MDS to a more malignant disease state. GATA2 deficiency GATA2 deficiency is a group of disorders caused by a defect, familial, or sporadic inactivating mutations, in one of the two GATA2 genes. These autosomal dominant mutations cause a reduction in the cellular levels of the genes product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymph-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are low and individuals develop over time hematological, immunological, lymphatic, or other presentations. Prominent among these presentations is MDS that often progresses to acute myelocytic leukemia, or less commonly, chronic myelomonocytic leukemia. Transient myeloproliferative disease Transient myeloproliferative disease is the abnormal proliferation of a clone of noncancerous megakaryoblasts in the liver and bone marrow. The disease is restricted to individuals with Down syndrome or genetic changes similar to those in Down syndrome, develops during pregnancy or shortly after birth, and resolves within 3 months, or in about 10% of cases, progresses to acute megakaryoblastic leukemia. Diagnosis The elimination of other causes of cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome, so differentiating MDS from anemia, thrombocytopenia, and leukopenia is important.A typical diagnostic investigation includes: Full blood count and examination of blood film: The blood film morphology can provide clues about hemolytic anemia, clumping of the platelets leading to spurious thrombocytopenia, or leukemia. Blood tests to eliminate other common causes of cytopenias such as lupus, hepatitis, B12, folate, or other vitamin deficiencies, kidney failure or heart failure, HIV, hemolytic anemia, monoclonal gammopathy: Age-appropriate cancer screening should be considered for all anemic patients. Bone marrow examination by a hematopathologist: This is required to establish the diagnosis since all hematopathologists consider dysplastic marrow the key feature of myelodysplasia. Cytogenetics or chromosomal studies: This is ideally performed on the bone marrow aspirate. Conventional cytogenetics require a fresh specimen since live cells are induced to enter metaphase to allow chromosomes to be seen. Interphase fluorescence in situ hybridization testing, usually ordered together with conventional cytogenetic testing, offers rapid detection of several chromosome abnormalities associated with MDS, including del 5q, −7, +8, and del 20q. Virtual karyotyping can be done for MDS, which uses computational tools to construct the karyogram from disrupted DNA. Virtual karyotyping does not require cell culture and has a dramatically higher resolution than conventional cytogenetics, but cannot detect balanced translocations. Flow cytometry is helpful to identify blasts, abnormal myeloid maturation, and establish the presence of any lymphoproliferative disorder in the marrow. Testing for copper deficiency should not be overlooked, as it can morphologically resemble MDS in bone-marrow biopsies.The features generally used to define an MDS are blood cytopenias, ineffective hematopoiesis, dyserythropoiesis, dysgranulopoiesis, dysmegakaropoiesis, and increased myeloblasts. Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by: Granulocytic series: Hypersegmented neutrophils (also seen in vit B12/folate deficiency) Hyposegmented neutrophils (pseudo Pelger-Huet) Hypogranular neutrophils or pseudo Chediak-Higashi (large azurophilic granules) Auer rods – automatically RAEB II (if blast count < 5% in the peripheral blood and < 10% in the bone marrow aspirate); also note Auer rods may be seen in mature neutrophils in AML with translocation t(8;21) Dimorphic granules (basophilic and eosinophilic granules) within eosinophils Erythroid series: Binucleated erythroid precursors and karyorrhexis Erythroid nuclear budding Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias) Loss of e-cadherin in normoblasts is a sign of aberrancy. PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin-fixed bone-marrow biopsy). Note: one can see PAS vacuolar positivity in L1 and L2 blasts (FAB classification; the L1 and L2 nomenclature is not used in the WHO classification) Ringed sideroblasts (10 or more iron granules encircling one-third or more of the nucleus) seen on Perls Prussian blue iron stain (>15% ringed sideroblasts when counted among red cell precursors for refractory anemia with ring sideroblasts) Megakaryocytic series (can be the most subjective): Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation) Hypersegmented (osteoclastic appearing) megakaryocytes Ballooning of the platelets (seen with interference contrast microscopy)Other stains can help in special cases (PAS and naphthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy. On the bone-marrow biopsy, high-grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors, which are islands of immature precursors cells (myeloblasts and promyelocytes) localized to the center of the intertrabecular space rather than adjacent to the trabeculae or surrounding arterioles. This morphology can be difficult to differentiate from treated leukemia and recovering immature normal marrow elements. Also, topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands. Differential diagnosis Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also, congenital diseases such as congenital dyserythropoietic anemia (CDA I through IV) have been recognized, Pearsons syndrome (sideroblastic anemia), Jordans anomaly – vacuolization in all cell lines may be seen in Chanarin-Dorfman syndrome, aminolevulinic acid enzyme deficiency and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines; however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity, and other poisons.All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes, and platelets or their progenitor cells, megakaryocytes). Classification World Health Organization In the late 1990s, a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others. In 2008, the WHO developed a new classification scheme that is based more on genetic findings, but morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy are still the screening tests used to decide which classification is best and which cytogenetic aberrations may be related.The list of dysplastic syndromes under the new WHO system includes: Note : not all physicians concur with this reclassification, because the underlying pathology of this disease is not well understood. Myelodysplastic syndrome unclassified The WHO has proposed a criterion for diagnosis and classification of MDS that may apply to most cases. However, occasional cases are difficult to classify into defined categories because of one or more unusual features: Rare cases with less than 5% blast will present with Auer rods. These cases usually have the features of RAMD. Occasionally, cases of MDS present with isolated neutropenia or thrombocytopenia without anemia and with dysplastic changes confined to the single lineage. The terms refractory neutropenia and refractory thrombocytopenia have sometimes been used to describe these cases. A diagnosis of MDS in patients with neutropenia or thrombocytopenia without anemia should be made with caution. Patients with RA or RAEB occasionally present with leukocytosis or thrombocytosis instead of the usual cytopenia. Management The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to AML. The IPSS scoring system can help triage patients for more aggressive treatment (i.e. bone marrow transplant) as well as help determine the best timing of this therapy. Supportive care with blood products and hematopoietic growth factors (e.g. erythropoietin) is the mainstay of therapy. The regulatory environment for the use of erythropoietins is evolving, according to a recent US Medicare National coverage determination. However, no comment on the use of hematopoietic growth factors for MDS was made in that document.Agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS: 5-azacytidine: 21-month median survival Decitabine: Complete response rate reported as high as 43%. A phase I study has shown efficacy in AML when decitabine is combined with valproic acid. Lenalidomide: Effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype of MDS Decitabine/cedazuridine (Inqovi) is a fixed-dosed combination medication for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).Chemotherapy with the hypomethylating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML. Lenalidomide was approved by the FDA in December 2005 only for use in the 5q- syndrome. In the United States, treatment of MDS with lenalidomide costs about $9,200 per month. The chemotherapy may be supported by other drugs like all-trans retinoic acid (ATRA), however the evidence of benefit is not clear.HLA-matched allogeneic stem cell transplantation, particularly in younger (i.e. less than 40 years of age) and more severely affected patients, offers the potential for curative therapy. The success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tend to have a more favorable outcome with transplantation. Iron levels Iron overload can develop in MDS as a result of the RBC transfusions, which are a major part of the supportive care for anemic MDS patients. Although the specific therapies patients receive may alleviate the RBC transfusion need in some cases, many MDS patients may not respond to these treatments, thus may develop secondary hemochromatosis due to iron overload from repeated RBC transfusions. Patients requiring relatively large numbers of RBC transfusions can experience the adverse effect of chronic iron overload on their liver, heart, and endocrine functions. For patients requiring many RBC transfusions, serum ferritin levels, number of RBC transfusions received, and associated organ dysfunction (heart, liver, and pancreas) should be monitored to determine iron levels. Monitoring serum ferritin may also be useful, aiming to decrease ferritin levels to < 1000 µg/L.Currently, two iron chelators are available in the US, deferoxamine for intravenous use and deferasirox for oral use. These options now provide potentially useful drugs for treating the iron overload problem. A third chelating agent is available in Europe, deferiprone, for oral use, but is not available in the US.Clinical trials in MDS patients are ongoing, with iron chelating agents to address the question of whether iron chelation alters the natural history of patients with MDS who are transfusion dependent. Reversal of some of the consequences of iron overload in MDS by iron chelation therapy has been shown. Both the MDS Foundation and the National Comprehensive Cancer Network MDS Guidelines Panel have recommended that chelation therapy be considered to decrease iron overload in selected MDS patients. Evidence also suggests a potential value exists to iron chelation in patients who will undergo a stem-cell transplant. Although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction in some patients), recently a safety warning by the FDA and Novartis was added to deferasirox treatment guidelines. Following postmarketing use of deferasirox, rare cases of acute kidney failure or liver failure occurred, some resulting in death. Due to this, patients should be closely monitored on deferasirox therapy prior to the start of therapy and regularly thereafter. Prognosis The outlook in MDS is variable, with about 30% of patients progressing to refractory AML. The median survival time varies from years to months, depending on type. Stem-cell transplantation offers possible cure, with survival rates of 50% at 3 years, although older patients do poorly.Indicators of a good prognosis: Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (< 20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; and in vitro marrow culture with a nonleukemic growth pattern Indicators of a poor prognosis: Advanced age; severe neutropenia or thrombocytopenia; high blast count in the bone marrow (20–29%) or blasts in the blood; Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section; completely or mostly abnormal karyotypes, or complex marrow chromosome abnormalities and in vitro bone marrow culture with a leukemic growth pattern Karyotype prognostic factors: Good: normal, -Y, del(5q), del(20q) Intermediate or variable: +8, other single or double anomalies Poor: complex (>3 chromosomal aberrations); chromosome 7 anomaliesThe IPSS is the most commonly used tool in MDS to predict long-term outcome.Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or virtual karyotype. The best prognosis is seen with RA and RARS, where some nontransplant patients live more than a decade (typical is on the order of 3–5 years, although long-term remission is possible if a bone-marrow transplant is successful). The worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. About one-quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated diseases. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997. This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias. Genetic markers Although not yet formally incorporated in the generally accepted classification systems, molecular profiling of myelodysplastic syndrome genomes has increased the understanding of prognostic molecular factors for this disease. For example, in low-risk MDS, IDH1 and IDH2 mutations are associated with significantly worsened survival. Epidemiology The exact number of people with MDS is not known because it can go undiagnosed and no tracking of the syndrome is mandated. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The number of new cases each year is probably increasing as the average age of the population increases, and some authors propose that the number of new cases in those over 70 may be as high as 15 per 100,000 per year.The typical age at diagnosis of MDS is between 60 and 75 years; a few people are younger than 50, and diagnoses are rare in children. Males are slightly more commonly affected than females. History Since the early 20th century, some people with acute myelogenous leukemia were begun to be recognized to have a preceding period of anemia and abnormal blood cell production. These conditions were lumped together with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS. Michael Brecker Roald Dahl Nora Ephron Joe Farrell Pat Hingle John Kirby (attorney) Joe Morgan (Cincinnati Reds player) Paul Motian James W. Nance Robin Roberts (newscaster) Carl Sagan Susan Sontag Fred Willard French-American-British (FAB) classification In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. This French-American-British classification was published in 1976, and revised in 1982. It was used by pathologists and clinicians for almost 20 years. Cases were classified into five categories: (A table comparing these is available from the Cleveland Clinic.) See also Chloroma Myeloproliferative syndrome Clonal hematopoiesis References External links Myelodysplastic syndrome at Curlie Fenaux, P., et al. (2014). Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up † Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis,
Myelodysplastic syndrome	treatment and follow-up. Annals of Oncology 25(suppl 3): iii57–iii69.
Dolichocephaly	Dolichocephaly (derived from the Ancient Greek δολιχός long and κεφαλή head) is a condition where the head is longer than would be expected, relative to its width. In humans, scaphocephaly is a form of dolichocephaly. Dolichocephalic dogs (such as German Shepherds) have elongated noses. This makes them vulnerable to fungal diseases of the nose such as aspergillosis. In humans the anterior–posterior diameter (length) of dolichocephaly head is more than the transverse diameter (width).It can be present in cases of Sensenbrenner syndrome, Crouzon syndrome, Sotos syndrome, CMFTD as well as Marfan syndrome. See also Brachycephaly Cephalic index Plagiocephaly References == External links ==
Hour	An hour (symbol: h; also abbreviated hr) is a unit of time conventionally reckoned as 1⁄24 of a day and scientifically reckoned between 3,599 and 3,601 seconds, depending on the speed of Earths rotation. There are 60 minutes in an hour, and 24 hours in a day. The hour was initially established in the ancient Near East as a variable measure of 1⁄12 of the night or daytime. Such seasonal, temporal, or unequal hours varied by season and latitude. Equal or equinoctial hours were taken as 1⁄24 of the day as measured from noon to noon; the minor seasonal variations of this unit were eventually smoothed by making it 1⁄24 of the mean solar day. Since this unit was not constant due to long term variations in the Earths rotation, the hour was finally separated from the Earths rotation and defined in terms of the atomic or physical second. In the modern metric system, hours are an accepted unit of time defined as 3,600 atomic seconds. However, on rare occasions an hour may incorporate a positive or negative leap second, making it last 3,599 or 3,601 seconds, in order to keep it within 0.9 seconds of UT1, which is based on measurements of the mean solar day. Name Hour is a development of the Anglo-Norman houre and Middle English ure, first attested in the 13th century.It displaced tide tīd, "time" and stound stund, span of time. The Anglo-Norman term was a borrowing of Old French ure, a variant of ore, which derived from Latin hōra and Greek hṓrā (ὥρα). Like Old English tīd and stund, hṓrā was originally a vaguer word for any span of time, including seasons and years. Its Proto-Indo-European root has been reconstructed as yeh₁- ("year, summer"), making hour distantly cognate with year. The time of day is typically expressed in English in terms of hours. Whole hours on a 12-hour clock are expressed using the contracted phrase oclock, from the older of the clock. (10 am and 10 pm are both read as "ten oclock".) Hours on a 24-hour clock ("military time") are expressed as "hundred" or "hundred hours". (1000 is read "ten hundred" or "ten hundred hours"; 10 pm would be "twenty-two hundred".) Fifteen and thirty minutes past the hour is expressed as "a quarter past" or "after" and "half past", respectively, from their fraction of the hour. Fifteen minutes before the hour may be expressed as "a quarter to", "of", "till", or "before" the hour. (9:45 may be read "nine forty-five" or "a quarter till ten".) History Antiquity The ancient Greeks kept time differently from the way we do today. Instead of dividing the time between one midnight and the next into 24 equal hours, they divided the time from sunrise to sunset into 12 "seasonal hours" (their actual duration depending on season), and the time from sunset to the next sunrise again in 12 "seasonal hours". Initially, only the day was divided into 12 seasonal hours and the night into 3 or 4 night watches.By the Hellenistic period the night was also divided into 12 hours. The day-and-night (νυχθήμερον) was probably first divided into twenty-four hours by Hipparchus of Nicaea. The Greek astronomer Andronicus of Cyrrhus oversaw the construction of a horologion called the Tower of the Winds in Athens during the first century BCE. This structure tracked a 24-hour day using both sundials and mechanical hour indicators.The canonical hours were introduced to early Christianity from Second Temple Judaism. By AD 60, the Didache recommends disciples to pray the Lords Prayer three times a day; this practice found its way into the canonical hours as well. By the second and third centuries, such Church Fathers as Clement of Alexandria, Origen, and Tertullian wrote of the practice of Morning and Evening Prayer, and of the prayers at the third, sixth and ninth hours. In the early church, during the night before every feast, a vigil was kept. The word "Vigils", at first applied to the Night Office, comes from a Latin source, namely the Vigiliae or nocturnal watches or guards of the soldiers. The night from six oclock in the evening to six oclock in the morning was divided into four watches or vigils of three hours each, the first, the second, the third, and the fourth vigil.The Horae were originally personifications of seasonal aspects of nature, not of the time of day. The list of twelve Horae representing the twelve hours of the day is recorded only in Late Antiquity, by Nonnus. The first and twelfth of the Horae were added to the original set of ten: Auge (first light) Anatole (sunrise)] Mousike (morning hour of music and study) Gymnastike (morning hour of exercise) Nymphe (morning hour of ablutions) Mesembria (noon) Sponde (libations poured after lunch) Elete (prayer) Akte (eating and pleasure) Hesperis (start of evening) Dysis (sunset) Arktos (night sky) Middle Ages Medieval astronomers such as al-Biruni and Sacrobosco, divided the hour into 60 minutes, each of 60 seconds; this derives from Babylonian astronomy, where the corresponding terms denoted the time required for the Suns apparent motion through the ecliptic to describe one minute or second of arc, respectively. In present terms, the Babylonian degree of time was thus four minutes long, the "minute" of time was thus four seconds long and the "second" 1/15 of a second.) In medieval Europe, the Roman hours continued to be marked on sundials but the more important units of time were the canonical hours of the Orthodox and Catholic Church. During daylight, these followed the pattern set by the three-hour bells of the Roman markets, which were succeeded by the bells of local churches. They rang prime at about 6 am, terce at about 9 am, sext at noon, nones at about 3 pm, and vespers at either 6 pm or sunset. Matins and lauds precede these irregularly in the morning hours; compline follows them irregularly before sleep; and the midnight office follows that. Vatican II ordered their reformation for the Catholic Church in 1963, though they continue to be observed in the Orthodox churches. When mechanical clocks began to be used to show hours of daylight or nighttime, their period needed to be changed every morning and evening (for example, by changing the length of their pendula). The use of 24 hours for the entire day meant hours varied much less and the clocks needed to be adjusted only a few times a month. Modernity The minor irregularities of the apparent solar day were smoothed by measuring time using the mean solar day, using the Suns movement along the celestial equator rather than along the ecliptic. The irregularities of this time system were so minor that most clocks reckoning such hours did not need adjustment. However, scientific measurements eventually became precise enough to note the effect of tidal deceleration of the Earth by the Moon, which gradually lengthens the Earths days. During the French Revolution, a general decimalisation of measures was enacted, including decimal time between 1793 and 1795. Under its provisions, the French hour (French: heure) was 1⁄10 of the day and divided formally into 100 decimal minutes (minute décimale) and informally into 10 tenths (décime). This hour was only briefly in official use, being repealed by the same 1795 legislation that first established the metric system. The metric system bases its measurements of time upon the second, defined since 1952 in terms of the Earths rotation in AD 1900. Its hours are a secondary unit computed as precisely 3,600 seconds. However, an hour of Coordinated Universal Time (UTC), used as the basis of most civil time, has lasted 3,601 seconds 27 times since 1972 in order to keep it within 0.9 seconds of universal time, which is based on measurements of the mean solar day at 0° longitude. The addition of these seconds accommodates the very gradual slowing of the rotation of the Earth. In modern life, the ubiquity of clocks and other timekeeping devices means that segmentation of days according to their hours is commonplace. Most forms of employment, whether wage or salaried labour, involve compensation based upon measured or expected hours worked. The fight for an eight-hour day was a part of labour movements around the world. Informal rush hours and happy hours cover the times of day when commuting slows down due to congestion or alcoholic drinks being available at discounted prices. The hour record for the greatest distance travelled by a cyclist within the span of an hour is one of cyclings greatest honours. Counting hours Many different ways of counting the hours have been used. Because sunrise, sunset, and, to a lesser extent, noon, are the conspicuous points in the day, starting to count at these times was, for most people in most early societies, much easier than starting at midnight. However, with accurate clocks and modern astronomical equipment (and the telegraph or similar means to transfer a time signal in a split-second), this issue is much less relevant. Astrolabes, sundials, and astronomical clocks sometimes show the hour length and count using some of these older definitions and counting methods. Counting from dawn In ancient and medieval cultures, the counting of hours generally started with sunrise. Before the widespread use of artificial light, societies were more concerned with the division between night and day, and daily routines often began when light was sufficient."Babylonian hours" divide the day and night into 24 equal hours, reckoned from the time of sunrise. They are so named from the false belief of ancient authors that the Babylonians divided the day into 24 parts, beginning at sunrise. In fact, they divided the day into 12 parts (called kaspu or "double hours") or into 60 equal parts. Unequal hours Sunrise marked the beginning of the first hour, the middle of the day was at the end of the sixth hour and sunset at the end of the twelfth hour. This meant that the duration of hours varied with the season. In the Northern hemisphere, particularly in the more northerly latitudes, summer daytime hours were longer than winter daytime hours, each being one twelfth of the time between sunrise and sunset. These variable-length hours were variously known as temporal, unequal, or seasonal hours and were in use until the appearance of the mechanical clock, which furthered the adoption of equal length hours.This is also the system used in Jewish law and frequently called "Talmudic hour" (Shaa Zemanit) in a variety of texts. The Talmudic hour is one twelfth of time elapsed from sunrise to sunset, day hours therefore being longer than night hours in the summer; in winter they reverse. The Indic day began at sunrise. The term hora was used to indicate an hour. The time was measured based on the length of the shadow at day time. A hora translated to 2.5 pe. There are 60 pe per day, 60 minutes per pe and 60 kshana (snap of a finger or instant) per minute. Pe was measured with a bowl with a hole placed in still water. Time taken for this graduated bowl was one pe. Kings usually had an officer in charge of this clock. Counting from sunset In so-called "Italian time", "Italian hours", or "old Czech time", the first hour started with the sunset Angelus bell (or at the end of dusk, i.e., half an hour after sunset, depending on local custom and geographical latitude). The hours were numbered from 1 to 24. For example, in Lugano, the sun rose in December during the 14th hour and noon was during the 19th hour; in June the sun rose during the 7th hour and noon was in the 15th hour. Sunset was always at the end of the 24th hour. The clocks in church towers struck only from 1 to 12, thus only during night or early morning hours. This manner of counting hours had the advantage that everyone could easily know how much time they had to finish their days work without artificial light. It was already widely used in Italy by the 14th century and lasted until the mid-18th century; it was officially abolished in 1755, or in some regions customary until the mid-19th century.The system of Italian hours can be seen on a number of clocks in Europe, where the dial is numbered from 1 to 24 in either Roman or Arabic numerals. The St Marks Clock in Venice, and the Orloj in Prague are famous examples. It was also used in Poland and Bohemia until the 17th century. The Islamic day begins at sunset. The first prayer of the day (maghrib) is to be performed between just after sunset and the end of twilight. Until 1968 Saudi Arabia used the system of counting 24 equal hours with the first hour starting at sunset. Counting from noon For many centuries, up to 1925, astronomers counted the hours and days from noon, because it was the easiest solar event to measure accurately. An advantage of this method (used in the Julian Date system, in which a new Julian Day begins at noon) is that the date doesnt change during a single nights observing. Counting from midnight In the modern 12-hour clock, counting the hours starts at midnight and restarts at noon. Hours are numbered 12, 1, 2, ..., 11. Solar noon is always close to 12 noon (ignoring artificial adjustments due to time zones and daylight saving time), differing according to the equation of time by as much as fifteen minutes either way. At the equinoxes sunrise is around 6 a.m. (Latin: ante meridiem, before noon), and sunset around 6 p.m. (Latin: post meridiem, after noon). In the modern 24-hour clock, counting the hours starts at midnight, and hours are numbered from 0 to 23. Solar noon is always close to 12:00, again differing according to the equation of time. At the equinoxes sunrise is around 06:00, and sunset around 18:00. History of timekeeping in other cultures Egypt The ancient Egyptians began dividing the night into wnwt at some time before the compilation of the Dynasty V Pyramid Texts in the 24th century BC. By 2150 BC (Dynasty IX), diagrams of stars inside Egyptian coffin lids—variously known as "diagonal calendars" or "star clocks"—attest that there were exactly 12 of these. Clagett writes that it is "certain" this duodecimal division of the night followed the adoption of the Egyptian civil calendar, usually placed c. 2800 BC on the basis of analyses of the Sothic cycle, but a lunar calendar presumably long predated this and also would have had twelve months in each of its years. The coffin diagrams show that the Egyptians took note of the heliacal risings of 36 stars or constellations (now known as "decans"), one for each of the ten-day "weeks" of their civil calendar. (12 sets of alternate "triangle decans" were used for the 5 epagomenal days between years.) Each night, the rising of eleven of these decans were noted, separating the night into twelve divisions whose middle terms would have lasted about 40 minutes each. (Another seven stars were noted by the Egyptians during the twilight and predawn periods, although they were not important for the hour divisions.) The original decans used by the Egyptians would have fallen noticeably out of their proper places over a span of several centuries. By the time of Amenhotep III (c. 1350 BC), the priests at Karnak were using water clocks to determine the hours. These were filled to the brim at sunset and the hour determined by comparing the water level against one of its twelve gauges, one for each month of the year. During the New Kingdom, another system of decans was used, made up of 24 stars over the course of the year and 12 within any one night. The later division of the day into 12 hours was accomplished by sundials marked with ten equal divisions. The morning and evening periods when the sundials failed to note time were observed as the first and last hours.The Egyptian hours were closely connected both with the priesthood of the gods and with their divine services. By the New Kingdom, each hour was conceived as a specific region of the sky or underworld through which Ras solar barge travelled. Protective deities were assigned to each and were used as the names of the hours. As the protectors and resurrectors of the sun, the goddesses of the night hours were considered to hold power over all lifespans and thus became part of Egyptian funerary rituals. Two fire-spitting cobras were said to guard the gates of each hour of the underworld, and Wadjet and the rearing cobra (uraeus) were also sometimes referenced as wnwt from their role protecting the dead through these gates. The Egyptian word for astronomer, used as a synonym for priest, was wnwty, "one of the wnwt", as it were "one of the hours". The earliest forms of wnwt include one or three stars, with the later solar hours including the determinative hieroglyph for "sun". East Asia Ancient China divided its day into 100 "marks" (Chinese: 刻, oc kʰək, p kè) running from midnight to midnight. The system is said to have been used since remote antiquity, credited to the legendary Yellow Emperor, but is first attested in Han-era water clocks and in the 2nd-century history of that dynasty. It was measured with sundials and water clocks. Into the Eastern Han, the Chinese measured their day schematically, adding the 20-ke difference between the solstices evenly throughout the year, one every nine days. During the night, time was more commonly reckoned during the night by the "watches" (Chinese: 更, oc kæŋ, p gēng) of the guard, which were reckoned as a fifth of the time from sunset to sunrise.Imperial China continued to use ke and geng but also began to divide the day into 12 "double hours" (t 時, s 时, oc də, p shí, lit. "time[s]") named after the earthly branches and sometimes also known by the name of the corresponding animal of the Chinese zodiac. The first shi originally ran from 11 pm to 1 am but was reckoned as starting at midnight by the time of the History of Song, compiled during the early Yuan. These apparently began to be used during the Eastern Han that preceded the Three Kingdoms era, but the sections that would have covered them are missing from their official histories; they first appear in official use in the Tang-era Book of Sui. Variations of all these units were subsequently adopted by Japan and the other countries of the Sinosphere. The 12 shi supposedly began to be divided into 24 hours under the Tang, although they are first attested in the Ming-era Book of Yuan. In that work, the hours were known by the same earthly branches as the shi, with the first half noted as its "starting" and the second as "completed" or "proper" shi. In modern China, these are instead simply numbered and described as "little shi". The modern ke is now used to count quarter-hours, rather than a separate unit. As with the Egyptian night and daytime hours, the division of the day into twelve shi has been credited to the example set by the rough number of lunar cycles in a solar year, although the 12-year Jovian orbital cycle was more important to traditional Chinese and Babylonian reckoning of the zodiac. Southeast Asia In Thailand, Laos, and Cambodia, the traditional system of noting hours is the six-hour clock. This reckons each of a days 24 hours apart from noon as part of a fourth of the day. 7 am was the first hour of the first half of daytime; 1 pm the first hour of the latter half of daytime; 7 pm the first hour of the first half of nighttime; and 1 am the first hour of the latter half of nighttime. This system existed in the Ayutthaya Kingdom, deriving its current phrasing from the practice of publicly announcing the daytime hours with a gong and the nighttime hours with a drum. It was abolished in Laos and Cambodia during their French occupation and is uncommon there now. The Thai system remains in informal use in the form codified in 1901 by King Chulalongkorn. India The Vedas and Puranas employed units of time based on the sidereal day (nakṣatra ahorātram). This was variously divided into 30 muhūtras of 48 minutes each or 60 dandas or nadís of 24 minutes each. The solar day was later similarly divided into 60 ghaṭikás of about the same duration, each divided in turn into 60 vinadis. The Sinhalese followed a similar system but called their sixtieth of a day a peya. Derived measures air changes per hour (ACH), a measure of the replacements of air within a defined space used for indoor air quality ampere hour (Ah), a measure of electrical charge used in electrochemistry BTU-hour, a measure of power used in the power industry and for air conditioners and heaters credit hour, a measure of an academic courses contracted instructional time per week for a semester horsepower-hour (hph), a measure of energy used in the railroad industry hour angle, a measure of the angle between the meridian plane and the hour circle passing through a certain point used in the equatorial coordinate system kilometres per hour (km/h), a measure of land speed kilowatt-hour (kWh), a measure of energy commonly used as an electrical billing unit knot (kn), a measure of nautical miles per hour, used for maritime and aerial speed man-hour, the amount of work performed by the average worker in one hour, used in productivity analysis metre per hour (m/h), a measure of slow speeds mile per hour (mph), a measure of land speed passengers per hour per direction (p/h/d), a measure of the capacity of public transportation systems pound per hour (PPH), a measure of mass flow used for engines fuel flow work or working hour, a measure of working time used in various regulations, such as those distinguishing part- and full-time employment and those limiting truck drivers working hours or hours of service See also Liturgy of the Hours Horology Horae, the deified hours of ancient Greece and Rome Hexadecimal hour, a proposed unit lasting 1 h 30 min Decimal hour or deciday, a French Revolutionary unit lasting 2 h 24 min Golden Hour & Blue Hour in photography Metric time Notes References Bibliography Further reading Gerhard Dohrn-van Rossum (1996). History of the Hour: Clocks and Modern Temporal Orders. University of Chicago Press. ISBN 978-0-226-15510-4. Christopher Walker (ed.), Astronomy before the Telescope. London: British Museum Press, 1996. External links World time zones Accurate time vs. PC Clock Difference
Shortness of breath	Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity", and recommends evaluating dyspnea by assessing the intensity of its distinct sensations, the degree of distress and discomfort involved, and its burden or impact on the patients activities of daily living. Distinct sensations include effort/work to breathe, chest tightness or pain, and "air hunger" (the feeling of not enough oxygen). The tripod position is often assumed to be a sign. Dyspnea is a normal symptom of heavy physical exertion but becomes pathological if it occurs in unexpected situations, when resting or during light exertion. In 85% of cases it is due to asthma, pneumonia, cardiac ischemia, interstitial lung disease, congestive heart failure, chronic obstructive pulmonary disease, or psychogenic causes, such as panic disorder and anxiety. The best treatment to relieve or even remove shortness of breath typically depends on the underlying cause. Definition Dyspnea, in medical terms, is "shortness of breath". The American Thoracic Society defines dyspnea as: "A subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity." Other definitions also describe it as "difficulty in breathing", "disordered or inadequate breathing", "uncomfortable awareness of breathing", and as the experience of "breathlessness" (which may be either acute or chronic). Differential diagnosis While shortness of breath is generally caused by disorders of the cardiac or respiratory system, others such as the neurological, musculoskeletal, endocrine, hematologic, and psychiatric systems may be the cause. DiagnosisPro, an online medical expert system, listed 497 distinct causes in October 2010. The most common cardiovascular causes are acute myocardial infarction and congestive heart failure while common pulmonary causes include chronic obstructive pulmonary disease, asthma, pneumothorax, pulmonary edema and pneumonia. On a pathophysiological basis the causes can be divided into: (1) an increased awareness of normal breathing such as during an anxiety attack, (2) an increase in the work of breathing and (3) an abnormality in the ventilatory or respiratory system.The tempo of onset and the duration of dyspnea are useful in knowing the etiology of dyspnea. Acute shortness of breath is usually connected with sudden physiological changes, such as laryngeal edema, bronchospasm, myocardial infarction, pulmonary embolism, or pneumothorax. Patients with COPD and idiopathic pulmonary fibrosis (IPF) have a mild onset and gradual progression of dyspnea on exertion, punctuated by acute exacerbations of shortness of breath. In contrast, most asthmatics do not have daily symptoms, but have intermittent episodes of dyspnea, cough, and chest tightness that are usually associated with specific triggers, such as an upper respiratory tract infection or exposure to allergens. Acute coronary syndrome Acute coronary syndrome frequently presents with retrosternal chest discomfort and difficulty catching the breath. It however may atypically present with shortness of breath alone. Risk factors include old age, smoking, hypertension, hyperlipidemia, and diabetes. An electrocardiogram and cardiac enzymes are important both for diagnosis and directing treatment. Treatment involves measures to decrease the oxygen requirement of the heart and efforts to increase blood flow. COVID-19 People that have been infected by COVID-19 may have symptoms such as a fever, dry cough, loss of smell and taste, and in moderate to severe cases, shortness of breath. Congestive heart failure Congestive heart failure frequently presents with shortness of breath with exertion, orthopnea, and paroxysmal nocturnal dyspnea. It affects between 1–2% of the general United States population and occurs in 10% of those over 65 years old. Risk factors for acute decompensation include high dietary salt intake, medication noncompliance, cardiac ischemia, abnormal heart rhythms, kidney failure, pulmonary emboli, hypertension, and infections. Treatment efforts are directed towards decreasing lung congestion. Chronic obstructive pulmonary disease People with chronic obstructive pulmonary disease (COPD), most commonly emphysema or chronic bronchitis, frequently have chronic shortness of breath and a chronic productive cough. An acute exacerbation presents with increased shortness of breath and sputum production. COPD is a risk factor for pneumonia; thus this condition should be ruled out. In an acute exacerbation treatment is with a combination of anticholinergics, beta2-adrenoceptor agonists, steroids and possibly positive pressure ventilation. Asthma Asthma is the most common reason for presenting to the emergency room with shortness of breath. It is the most common lung disease in both developing and developed countries affecting about 5% of the population. Other symptoms include wheezing, tightness in the chest, and a non productive cough. Inhaled corticosteroids are the preferred treatment for children, however these drugs can reduce the growth rate. Acute symptoms are treated with short-acting bronchodilators. Pneumothorax Pneumothorax presents typically with pleuritic chest pain of acute onset and shortness of breath not improved with oxygen. Physical findings may include absent breath sounds on one side of the chest, jugular venous distension, and tracheal deviation. Pneumonia The symptoms of pneumonia are fever, productive cough, shortness of breath, and pleuritic chest pain. Inspiratory crackles may be heard on exam. A chest x-ray can be useful to differentiate pneumonia from congestive heart failure. As the cause is usually a bacterial infection, antibiotics are typically used for treatment. Pulmonary embolism Pulmonary embolism classically presents with an acute onset of shortness of breath. Other presenting symptoms include pleuritic chest pain, cough, hemoptysis, and fever. Risk factors include deep vein thrombosis, recent surgery, cancer, and previous thromboembolism. It must always be considered in those with acute onset of shortness of breath owing to its high risk of mortality. Diagnosis, however, may be difficult and Wells Score is often used to assess the clinical probability. Treatment, depending on severity of symptoms, typically starts with anticoagulants; the presence of ominous signs (low blood pressure) may warrant the use of thrombolytic drugs. Anemia Anemia that develops gradually usually presents with exertional dyspnea, fatigue, weakness, and tachycardia. It may lead to heart failure. Anaemia is often a cause of dyspnea. Menstruation, particularly if excessive, can contribute to anaemia and to consequential dyspnea in women. Headaches are also a symptom of dyspnea in patients with anaemia. Some patients report a numb sensation in their head, and others have reported blurred vision caused by hypotension behind the eye due to a lack of oxygen and pressure; these patients have also reported severe head pains, many of which lead to permanent brain damage. Symptoms can include loss of concentration, focus, fatigue, language faculty impairment and memory loss. Cancer Shortness of breath is common in people with cancer and may be caused by numerous different factors. In people with advanced cancer, acute shortness of periods of time with severe shortness of breath may occur, along with a more continuous feeling of breathlessness. Other Other important or common causes of shortness of breath include cardiac tamponade, anaphylaxis, interstitial lung disease, panic attacks, and pulmonary hypertension. Also, around 2/3 of women experience shortness of breath as a part of a normal pregnancy.Cardiac tamponade presents with dyspnea, tachycardia, elevated jugular venous pressure, and pulsus paradoxus. The gold standard for diagnosis is ultrasound.Anaphylaxis typically begins over a few minutes in a person with a previous history of the same. Other symptoms include urticaria, throat swelling, and gastrointestinal upset. The primary treatment is epinephrine.Interstitial lung disease presents with gradual onset of shortness of breath typically with a history of a predisposing environmental exposure. Shortness of breath is often the only symptom in those with tachydysrhythmias.Panic attacks typically present with hyperventilation, sweating, and numbness. They are however a diagnosis of exclusion.Neurological conditions such as spinal cord injury, phrenic nerve injuries, Guillain–Barré syndrome, amyotrophic lateral sclerosis, multiple sclerosis and muscular dystrophy can all cause an individual to experience shortness of breath. Shortness of breath can also occur as a result of vocal cord dysfunction (VCD).Sarcoidosis is an inflammatory disease of unknown etiology that generally presents with dry cough, fatigue, and shortness of breath, although multiple organ systems may be affected, with involvement of sites such as the eyes, the skin and the joints. Pathophysiology Different physiological pathways may lead to shortness of breath including via ASIC chemoreceptors, mechanoreceptors, and lung receptors.It is thought that three main components contribute to dyspnea: afferent signals, efferent signals, and central information processing. It is believed the central processing in the brain compares the afferent and efferent signals; and dyspnea results when a "mismatch" occurs between the two: such as when the need for ventilation (afferent signaling) is not being met by physical breathing (efferent signaling).Afferent signals are sensory neuronal signals that ascend to the brain. Afferent neurons significant in dyspnea arise from a large number of sources including the carotid bodies, medulla, lungs, and chest wall. Chemoreceptors in the carotid bodies and medulla supply information regarding the blood gas levels of O2, CO2 and H+. In the lungs, juxtacapillary (J) receptors are sensitive to pulmonary interstitial edema, while stretch receptors signal bronchoconstriction. Muscle spindles in the chest wall signal the stretch and tension of the respiratory muscles. Thus, poor ventilation leading to hypercapnia, left heart failure leading to interstitial edema (impairing gas exchange), asthma causing bronchoconstriction (limiting airflow) and muscle fatigue leading to ineffective respiratory muscle action could all contribute to a feeling of dyspnea.Efferent signals are the motor neuronal signals descending to the respiratory muscles. The most important respiratory muscle is the diaphragm. Other respiratory muscles include the external and internal intercostal muscles, the abdominal muscles and the accessory breathing muscles.As the brain receives its plentiful supply of afferent information relating to ventilation, it is able to compare it to the current level of respiration as determined by the efferent signals. If the level of respiration is inappropriate for the bodys status then dyspnea might occur. There is also a psychological component to dyspnea, as some people may become aware of their breathing in such circumstances but not experience the typical distress of dyspnea. Diagnosis The initial approach to evaluation begins by assessment of the airway, breathing, and circulation followed by a medical history and physical examination. Signs and symptoms that represent significant severity include hypotension, hypoxemia, tracheal deviation, altered mental status, unstable dysrhythmia, stridor, intercostal indrawing, cyanosis, tripod positioning, pronounced use of accessory muscles (sternocleidomastoid, scalenes) and absent breath sounds.A number of scales may be used to quantify the degree of shortness of breath. It may be subjectively rated on a scale from 1 to 10 with descriptors associated with the number (The Modified Borg Scale). The MRC breathlessness scale suggests five grades of dyspnea based on the circumstances and severity in which it arises. Blood tests A number of labs may be helpful in determining the cause of shortness of breath. D-dimer, while useful to rule out a pulmonary embolism in those who are at low risk, is not of much value if it is positive, as it may be positive in a number of conditions that lead to shortness of breath. A low level of brain natriuretic peptide is useful in ruling out congestive heart failure; however, a high level, while supportive of the diagnosis, could also be due to advanced age, kidney failure, acute coronary syndrome, or a large pulmonary embolism. Imaging A chest x-ray is useful to confirm or rule out a pneumothorax, pulmonary edema, or pneumonia. Spiral computed tomography with intravenous radiocontrast is the imaging study of choice to evaluate for pulmonary embolism. Treatment The primary treatment of shortness of breath is directed at its underlying cause. Extra supplemental oxygen is effective in those with hypoxia; however, this has no effect in those with normal blood oxygen saturations. Physiotherapy Individuals can benefit from a variety of physical therapy interventions. Persons with neurological/neuromuscular abnormalities may have breathing difficulties due to weak or paralyzed intercostal, abdominal and/or other muscles needed for ventilation. Some physical therapy interventions for this population include active assisted cough techniques, volume augmentation such as breath stacking, education about body position and ventilation patterns and movement strategies to facilitate breathing. Pulmonary rehabilitation may alleviate symptoms in some people, such as those with COPD, but will not cure the underlying disease. Fan therapy to the face has been shown to relieve shortness of breath in patients with a variety of advanced illnesses including cancer. The mechanism of action is thought to be stimulation of the trigeminal nerve. Palliative medicine Systemic immediate release opioids are beneficial in emergently reducing the symptom severity of shortness of breath due to both cancer and non cancer causes; long-acting/sustained-release opioids are also used to prevent/continue treatment of dyspnea in palliative setting. There is a lack of evidence to recommend midazolam, nebulised opioids, the use of gas mixtures, or cognitive-behavioral therapy yet. Non-pharmacological techniques Non-pharmacological interventions provide key tools for the management of breathlessness. Potentially beneficial approaches include active management of psychosocial issues (anxiety, depression, etc.), and implementation of self-management strategies, such as physical and mental relaxation techniques, pacing techniques, energy conservation techniques, learning exercises to control breathing, and education. The use of a fan may possibly be beneficial. Cognitive behavioural therapy may also be helpful. Pharmacological treatment For people with severe, chronic, or uncontrollable breathlessness, non-pharmacological approaches to treating breathlessness may be combined with medication. For people who have cancer that is causing the breathlessness, medications that have been suggested include opioids, benzodiazepines, oxygen, and steroids. Results of recent systematic reviews and meta-analyses found opioids were not necessarily associated with more effectiveness in treatment for patients with advanced cancer.Ensuring that the balance between side effects and adverse effects from medications and potential improvements from medications needs to be carefully considered before prescribing medication. The use of systematic corticosteriods in palliative care for people with cancer is common, however the effectiveness and potential adverse effects of this approach in adults with cancer has not been well studied. Epidemiology Shortness of breath is the primary reason 3.5% of people present to the emergency department in the United States. Of these individuals, approximately 51% are admitted to the hospital and 13% are dead within a year. Some studies have suggested that up to 27% of hospitalized people develop dyspnea, while in dying patients 75% will experience it. Acute shortness of breath is the most common reason people requiring palliative care visit an emergency department. Up to 70% of adults with advanced cancer also experience dyspnoea. Etymology and pronunciation English dyspnea comes from Latin dyspnoea, from Greek dyspnoia, from dyspnoos, which literally means "disordered breathing". Its combining forms (dys- + -pnea) are familiar from other medical words, such as dysfunction (dys- + function) and apnea (a- + -pnea). The most common pronunciation in medical English is disp-NEE-ə, with the p expressed and the stress on the /niː/ syllable. But pronunciations with a silent p in pn (as also in pneumo-) are common ( or ), as are those with the stress on the first syllable ( or ). In English, the various -pnea-suffixed words commonly used in medicine do not follow one clear pattern as to whether the /niː/ syllable or the one preceding it is stressed; the p is usually expressed but is sometimes silent depending on the word. The following collation or list shows the preponderance of how major dictionaries pronounce and transcribe them (less-used variants are omitted): See also List of terms of lung size and activity Bronchospasm Orthopnea References External links Shortness Of Breath (Dyspnea)StatPearls
Rheumatoid nodule	A rheumatoid nodule is a lump of tissue, or an area of swelling, that appear on the exterior of the skin usually around the olecranon (tip of the elbow) or the interphalangeal joints (finger knuckles), but can appear in other areas. There are four different types of rheumatoid nodules: subcutaneous rheumatoid nodules, cardiac nodules, pulmonary nodules, and central nervous systems nodules. These nodules occur almost exclusively in association with rheumatoid arthritis. Very rarely do rheumatoid nodules occur as rheumatoid nodulosis (multiple nodules on the hands or other areas) in the absence of rheumatoid arthritis. Rheumatoid nodules can also appear in other areas of the body other than the skin. Less commonly they occur in the lining of the lung or other internal organs. The occurrence of nodules in the lung of miners exposed to silica dust was known as Caplan’s syndrome. Rarely, the nodules occur at diverse sites on body (e.g. upper eyelid, distal region of the soles of the feet, vulva and internally in the gallbladder, lung, heart valves, larynx, and spine).Rheumatoid nodules can vary in size from 2 mm to 5 cm and are usually rather firm to the touch. Quite often they are associated with synovial pockets or bursae. About 5% of people with rheumatoid arthritis have such nodules within two years of disease onset, and the cumulative prevalence is about 20 to 30%. Risk factors of developing rheumatoid nodules include as smoking and trauma to small vessels.In the majority of the time, nodules are not painful or disabling in any way. They are usually more of an unsightly nuisance. However, rheumatoid nodules can become painful when infection or ulcers occur on the skin of the nodule. Some nodules can actually disappear over time, but other times, they can grow larger making prediction of nodular size difficult to predict.Treatment also can be quite difficult, but surgical removal and injection of corticosteroids have both shown good results towards the treatment for rheumatoid nodules. Pathophysiology Although the exact process is unknown, there are a few hypotheses for the generation of rheumatoid nodules. It has been observed that rheumatoid nodules frequently form over extensor sites and areas vulnerable to trauma. The trauma causes inflammatory particles to build up and leads to a secondary inflammatory response which ultimately causes fibrin release and necrosis. Another hypothesis suggests that the inflammation of blood vessels activates complement components, which leads to the deposit of rheumatoid factors and fibrin.The rheumatoid nodule is the most common cutaneous manifestation of rheumatoid arthritis (RA). Rheumatoid arthritis involves chronic inflammation of synovial membranes, which leads to degradation of articular cartilage and the juxta-articular bone. Inflammation is caused by T cells, B cells and monocytes when endothelial cells are activated. Neovascularization, or the growth of new blood vessels, serves as an additional marker for rheumatoid arthritis. A hyperplastic synovial lining layer can be caused by the expansion of synovial fibroblast and macrophage cells. This expansion of the synovial membrane, sometimes referred to as "pannus," can lead to bony erosions and cartilage degradation at the site of the cartilage-bone junction in the periarticular bone.It is important to note that the cause of rheumatoid arthritis is unknown. It is speculated that genetic and environmental factors can both contribute to the development of rheumatoid arthritis. Gene loci and antigens, such as HLA class II antigens, have been seen as closely associated with rheumatoid arthritis. Environmental risk factors include smoking, periodontitis, viral infections and gut, mouth and lung microbiomes. Researchers have noted that Prevotella species, which are expanded in the gastrointestinal tract in early RA, and Porphyromonas gingivalis, which is associated with periodontitis, may have a role in pathogenesis. Pathology Histological examination of nodules shows that they consist of a shell of fibrous tissue surrounding a center of fibrinoid necrosis. Pea-sized nodules have one centre. Larger nodules tend to be multilocular, with many separate shells or with connections between the necrotic centers. Individual necrotic centers may contain a cleft or several centers of necrosis may all open on to a large bursal pocket containing synovial fluid. The boundary between the necrotic center and the outer fibrous shell is made up of the characteristic feature of the nodule, which is known as a cellular palisade. The palisade is a densely packed layer of macrophages and fibroblasts which tend to be arranged radially, like the seeds of a kiwifruit or fig. Further out into the fibrous shell there is a zone that contains T cells and plasma cells in association with blood vessels. The histology of pulmonary nodules are similar to that of subcutaneous nodules, with central necrosis surrounded by palisading macrophages and inflammatory infiltrate. Risk Factors Rheumatoid nodules develop if a person currently has rheumatoid arthritis. However, not all people with rheumatoid arthritis develop rheumatoid nodules. Some risk factors for rheumatoid nodules for people with rheumatoid arthritis may include: Smoking (strong association) Elevated levels of serum rheumatoid factors HLA-DRB1 gene (weak association) Trauma to small vessels Having severe rheumatoid arthritis Taking Methotrexate over other arthritis drugs Diagnosis Differential diagnosis of rheumatoid nodules can be classified from localization, depth pathology, age of onset, persistence, rheumatoid factor, concomitant joint disease, and bone erosions. Diagnosis is typically determined clinically by a rheumatologist. Rheumatoid arthritis associated rheumatoid nodules are typically subcutaneous and occur at extensor sites. The onset typically starts in adulthood and presents with rheumatoid factors and bone erosions, and concomitant joint diseases. The pathology is characterized by central necrosis, palisading mononuclear cells, and perivascular lymphocytic infiltrations.Rheumatoid nodulosis is characterized by multiple subcutaneous nodules presenting with rheumatoid factors but an absence of joint complaints. The nodules are typically small and concentrated on the extensor sites of the hands and feet, sometimes accompanied by bone erosions. The onset typically starts in adulthood with a pathology similar to rheumatoid arthritis associated rheumatoid nodules.Benign rheumatoid nodules are often not associated with rheumatoid factors or concomitant joint diseases. They are typically found on the feet, scalp, and pretibial regions. Frequently seen in children before the age of 18, the pathology is similar to that of rheumatoid arthritis associated rheumatoid nodules. The nodules are non-tender and undergo rapid growth, but also resolve spontaneously. A similar presentation occurring more intracutaneously (superficial) is known as granuloma annulare.Rheumatic fever nodules are typically associated with acute rheumatic fever in children. They are not accompanied by rheumatoid factors or bone erosions, but are associated with concomitant joint diseases. No larger than the size of peas, they are typically found at extensor sites and processus spinosi of the vertebrae. The pathology is characterized by central necrosis and little histiocytic/lymphocytic infiltration. Prevalence There are 4 different types of rheumatoid nodules: subcutaneous rheumatoid nodules, cardiac nodules, pulmonary nodules and central nervous system nodules. Subcutaneous rheumatoid nodules According to a study done by the BARFOT study group, 7% of individuals diagnosed with rheumatoid arthritis reported the presence of subcutaneous rheumatoid nodules upon initial diagnosis. And about 30-40% of all those diagnosed with rheumatoid arthritis reported developing these nodules throughout the course of the disease. Subcutaneous rheumatoid nodules is correlated with the increased risk of cardiovascular and respiratory disease, and those with detected subcutaneous rheumatoid nodules should be assessed for cardiovascular and respiratory risk factors.Cardiac nodules Rheumatoid nodules may also form in the heart. Specifically, it could develop in the myocardium, pericardium, and other valvular structures, and these nodules can be discovered through echocardiograms. There are little studies with minimal data on the development of cardiac nodules in association with rheumatoid arthritis, but the general consensus is that such occurrences is relatively rare. Pulmonary Nodules The reported prevalence of pulmonary nodules has varying depending on the method of detection. In a 1984 study done on lung biopsies in rheumatoid arthritis, the reported prevalence was about 32% in a sample size of 40 individuals. However, another clinical study utilizing a different method of detection; plain film radiographs of the chest; showed that only 2 out of 516 people (~0.4%) diagnosed with rheumatoid arthritis developed pulmonary nodules. Additionally, other clinical studies have reported increased pulmonary nodule growth following treatments with methotrexate, leflunomide, and etanercept.Central nervous system nodules Like cardiac nodules, nodules developing in the central nervous system is also relatively rare. Most reports of nodule growth on the central nervous system also presented with severe stages of erosive joint diseases. Generally, these nodules can be detected through MRI and confirmed through biopsies. As of right now, there are no known mediations that have been reported in reducing nodules in the central nervous systems. Prevention There are no methods as of right now to completely prevent the development of rheumatoid nodules, but for those diagnosed with rheumatoid arthritis, proper management of the disease could reduce the risk of nodule formation. Additionally, proper medication adherence, smoking cessation, increasing physical activity, and keeping up with doctor appointments are just some lifestyle changes that could "prevent" nodules. Treatment Treatment for rheumatoid nodules may be tricky as some treatments for rheumatoid arthritis can act against the nodules. Common drug therapies for rheumatoid arthritis may show no benefits towards the treatment for rheumatoid nodules. Common drug therapies, such as anti TNF treatment or other immunosuppressive drugs, for rheumatoid arthritis has shown little effect on the nodules. In fact, it has been shown that Methotrexate, a drug often used in rheumatoid arthritis, is actually correlated with the increased risk of nodule formation. Because rheumatoid nodules also cause pain or nerve entrapment, treatment for these symptoms with nonsteroidal anti-inflammatory drugs may be sufficient. Other drug therapies, such as corticosteroids, have shown to decrease nodular size, however, it can increase the risk of infection as well. Local corticosteroid injections seems to be the most studied treatment for rheumatoid nodules as of now. Surgery to have the nodule removed is another option that can be done to treat rheumatoid nodules. However, usually these are usually only indicated in the case of eroding/ necrotising skin. See also Rheumatoid nodulosis Rheumatoid arthritis References == External links ==
Tularemia	Tularemia, also known as rabbit fever, is an infectious disease caused by the bacterium Francisella tularensis. Symptoms may include fever, skin ulcers, and enlarged lymph nodes. Occasionally, a form that results in pneumonia or a throat infection may occur.The bacterium is typically spread by ticks, deer flies, or contact with infected animals. It may also be spread by drinking contaminated water or breathing in contaminated dust. It does not spread directly between people. Diagnosis is by blood tests or cultures of the infected site.Prevention is by using insect repellent, wearing long pants, rapidly removing ticks, and not disturbing dead animals. Treatment is typically with the antibiotic streptomycin. Gentamicin, doxycycline, or ciprofloxacin may also be used.Between the 1970s and 2015, around 200 cases were reported in the United States a year. Males are affected more often than females. It occurs most frequently in the young and the middle aged. In the United States, most cases occur in the summer. The disease is named after Tulare County, California, where the disease was discovered in 1911. A number of other animals, such as rabbits, may also be infected. Signs and symptoms Depending on the site of infection, tularemia has six characteristic clinical variants: ulceroglandular (the most common type representing 75% of all forms), glandular, oropharyngeal, pneumonic, oculoglandular, and typhoidal.The incubation period for tularemia is one to 14 days; most human infections become apparent after three to five days. In most susceptible mammals, the clinical signs include fever, lethargy, loss of appetite, signs of sepsis, and possibly death. Nonhuman mammals rarely develop the skin lesions seen in people. Subclinical infections are common, and animals often develop specific antibodies to the organism. Fever is moderate or very high, and tularemia bacilli can be isolated from blood cultures at this stage. The face and eyes redden and become inflamed. Inflammation spreads to the lymph nodes, which enlarge and may suppurate (mimicking bubonic plague). Lymph node involvement is accompanied by a high fever. Cause Tularemia is caused by the bacteria Francisella tularensis which is typically spread by ticks, deer flies, and contact with infected animals. Bacteria The bacteria can penetrate into the body through damaged skin, mucous membranes, and inhalation. Humans are most often infected by tick/deer fly bite or through handling an infected animal. Ingesting infected water, soil, or food can also cause infection. Hunters are at a higher risk for this disease because of the potential of inhaling the bacteria during the skinning process. It has been contracted from inhaling particles from an infected rabbit ground up in a lawnmower (see below). Tularemia is not spread directly from person to person. Humans can also be infected through bioterrorism attempts.Francisella tularensis can live both within and outside the cells of the animal it infects, meaning it is a facultative intracellular bacterium. It primarily infects macrophages, a type of white blood cell, and thus is able to evade the immune system. The course of disease involves the spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system. The course of disease is different depending on the route of exposure. Mortality in untreated (before the antibiotic era) patients has been as high as 50% in the pneumoniac and typhoidal forms of the disease, which however account for less than 10% of cases. Spread The most common way the disease is spread is via arthropod vectors. Ticks involved include Amblyomma, Dermacentor, Haemaphysalis, and Ixodes. Rodents, rabbits, and hares often serve as reservoir hosts, but waterborne infection accounts for 5 to 10% of all tularemia in the United States. Tularemia can also be transmitted by biting flies, particularly the deer fly Chrysops discalis. Individual flies can remain infectious for 14 days and ticks for over two years. Tularemia may also be spread by direct contact with contaminated animals or material, by ingestion of poorly cooked flesh of infected animals or contaminated water, or by inhalation of contaminated dust. Diagnosis Pathology In lymph node biopsies, the typical histopathologic pattern is characterized by geographic areas of necrosis with neutrophils and necrotizing granulomas. The pattern is non specific and similar to other infectious lymphadenopathies.The laboratorial isolation of F. tularensis requires special media such as buffered charcoal yeast extract agar. It cannot be isolated in the routine culture media because of the need for sulfhydryl group donors (such as cysteine). The microbiologist must be informed when tularemia is suspected not only to include the special media for appropriate isolation, but also to ensure that safety precautions are taken to avoid contamination of laboratory personnel. Serological tests (detection of antibodies in the serum of the patients) are available and widely used. Cross reactivity with Brucella can confuse interpretation of the results, so diagnosis should not rely only on serology. Molecular methods such as PCR are available in reference laboratories. Prevention There are no safe, available, approved vaccines against tularemia. However, vaccination research and development continues, with live attenuated vaccines being the most thoroughly researched and most likely candidate for approval. Sub-unit vaccine candidates, such as killed-whole cell vaccines, are also under investigation, however research has not reached a state of public use.Optimal preventative practices include limiting direct exposure when handling potentially infected animals by wearing gloves and face masks (importantly when skinning deceased animals). Treatment If infection occurs or is suspected, treatment is generally with the antibiotics streptomycin or Gentamicin. Doxycycline was previously used. Gentamicin may be easier to obtain than streptomycin. There is also tentative evidence to support the use of quinolone antibiotics. Prognosis Since the invention of antibiotics, the rate of death associated with tularemia has decreased from 60% to less than 4%. Epidemiology Tularemia is most common in the Northern Hemisphere, including North America and parts of Europe and Asia. It occurs between 30º and 71º north latitude.In the United States, although records show that tularemia was never particularly common, incidence rates continued to drop over the course of the 20th century. Between 1990 and 2000, the rate dropped to less than 1 per one million, meaning the disease is extremely rare in the United States today.In Europe, tularemia is generally rare, though outbreaks with hundreds of cases occur every few years in neighboring Finland and Sweden. In Sweden over a period from 1984 to 2012 a total of 4,830 cases of tularemia occurred (most of the infections were acquired within the country). About 1.86 cases per 100,000 persons occur each year with higher rates in those between 55 and 70. Outbreaks From May to October 2000, an outbreak of tularemia in Marthas Vineyard, Massachusetts, resulted in one fatality, and brought the interest of the United States Centers for Disease Control and Prevention (CDC) as a potential investigative ground for aerosolised Francisella tularensis. For a time, Marthas Vineyard was identified as the only place in the world where documented cases of tularemia resulted from lawn mowing. However, in May 2015 a resident of Lafayette, Colorado, died from aerosolised F. tularensis, which was also connected to lawn mowing, highlighting this new vector of risk. An outbreak of tularemia occurred in Kosovo in 1999–2000.In 2004, three researchers at Boston Medical Center, in Massachusetts, were accidentally infected with F. tularensis, after apparently failing to follow safety procedures.In 2005, small amounts of F. tularensis were detected in the National Mall area of Washington, D.C., the morning after an antiwar demonstration on September 24, 2005. Biohazard sensors were triggered at six locations surrounding the Mall. While thousands of people were potentially exposed, no infections were reported. The detected bacteria likely originated from a natural source, not from a bioterror attempt.In 2005, an outbreak occurred in Germany amongst participants in a hare hunt. About 27 people came into contact with contaminated blood and meat after the hunt. Ten of the exposed, aged 11 to 73, developed tularemia. One of these died due to complications caused by chronic heart disease.Tularemia is endemic in the Gori region of the Eurasian country of Georgia. The last outbreak was in 2006. The disease is also endemic on the uninhabited Pakri Islands off the northern coast of Estonia. Used for bombing practice by Soviet forces, chemical and bacteriological weapons may have been dropped on these islands.In July 2007, an outbreak was reported in the Spanish autonomous region of Castile and León and traced to the plague of voles infesting the region. Another outbreak had taken place ten years before in the same area.In January 2011, researchers searching for brucellosis among feral pig populations in Texas discovered widespread tularemia infection or evidence of past infection in feral hog populations of at least two Texas counties, even though tularemia is not normally associated with pigs at all. Precautions were recommended for those who hunt, dress, or prepare feral hogs. Since feral hogs roam over large distances, concern exists that tularemia may spread or already be present in feral hogs over a wide geographic area.In November 2011, it was found in Tasmania. Reports claimed it to be the first in the Southern Hemisphere. However, the causative organism was documented to have been isolated from a foot wound in the Northern Territory in 2003.In 2014, at least five cases of tularemia were reported in Colorado and at least three more cases in early 2015, including one death as a result of lawn mowing, as noted above. In the summer of 2015, a popular hiking area just north of Boulder was identified as a site of animal infection and signs were posted to warn hikers. History The tularemia bacterium was first isolated by G.W. McCoy of the United States Public Health Service plague lab and reported in 1912. Scientists determined tularemia could be dangerous to humans; a human being may catch the infection after contacting an infected animal. The ailment soon became associated with hunters, cooks and agricultural workers. Biological weapon The Centers for Disease Control and Prevention (CDC) regard F. tularensis as a viable biological warfare agent, and it has been included in the biological warfare programs of the United States, Soviet Union and Japan at various times. A former Soviet biological weapons scientist, Ken Alibek, has alleged that an outbreak of tularemia among German soldiers shortly before the Battle of Stalingrad was due to the release of F. tularensis by Soviet forces. Others who have studied the pathogen "propose that an outbreak resulting from natural causes is more likely". In the United States, practical research into using rabbit fever as a biological warfare agent took place in 1954 at Pine Bluff Arsenal, Arkansas, an extension of the Fort Detrick program. It was viewed as an attractive agent because: it is easy to aerosolize it is highly infective; between 10 and 50 bacteria are sufficient to infect victims it is nonpersistent and easy to decontaminate (unlike anthrax) it is highly incapacitating to infected persons it has comparatively low lethality, which is useful where enemy soldiers are in proximity to noncombatants, e.g. civiliansThe Schu S4 strain was standardized as "Agent UL" for use in the United States M143 bursting spherical bomblet. It was a lethal biological warfare agent with an anticipated fatality rate of 40 to 60%. The rate-of-action was around three days, with a duration-of-action of one to three weeks (treated) and two to three months (untreated), with frequent relapses. UL was streptomycin resistant. The aerobiological stability of UL was a major concern, being sensitive to sunlight, and losing virulence over time after release. When the 425 strain was standardized as "agent JT" (an incapacitant rather than lethal agent), the Schu S4 strains symbol was changed again to SR.Both wet and dry types of F. tularensis (identified by the codes TT and ZZ) were examined during the "Red Cloud" tests, which took place from November 1966 to February 1967 in the Tanana Valley, Alaska. Other animals Cats and dogs can acquire the disease from the bite of a tick or flea that has fed on an infected host, such as a rabbit or rodent. For treatment of infected cats, antibiotics are the preferred treatment, including tetracycline, chloramphenicol or streptomycin. Long treatment courses may be necessary as relapses are common. References External links Tularemia at Curlie
Exfoliation	Exfoliation can refer to: Exfoliation (botany), the loss of leaves (or, in some cases, pieces of bark) from a plant Exfoliation (cosmetology), a cosmetic technique that aims to remove dead skin from the body and face Exfoliation (geology), a process resulting in parallel fractures in the surface of rock Exfoliation corrosion (metallurgy), a severe type of intergranular corrosion Exfoliation - Intercalation (chemistry), the complete separation of the layers of a material Exfoliation syndrome, an eye disease See also Exfoliative dermatitis, sometimes known as erythroderma, a skin disease process involving redness and scaling of most or all of the sufferers skin, with various causes
Endocrine disease	Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology. Types of disease Broadly speaking, endocrine disorders may be subdivided into three groups: Endocrine gland hypofunction/hyposecretion (leading to hormone deficiency) Endocrine gland hyperfunction/hypersecretion (leading to hormone excess) Tumours (benign or malignant) of endocrine glandsEndocrine disorders are often quite complex, involving a mixed picture of hyposecretion and hypersecretion because of the feedback mechanisms involved in the endocrine system. For example, most forms of hyperthyroidism are associated with an excess of thyroid hormone and a low level of thyroid stimulating hormone. List of diseases Glucose homeostasis disorders Diabetes Type 1 Diabetes Type 2 Diabetes Gestational Diabetes Mature Onset Diabetes of the Young Hypoglycemia Idiopathic hypoglycemia Insulinoma Glucagonoma Thyroid disorders Goitre Hyperthyroidism Graves-Basedow disease Toxic multinodular goitre Hypothyroidism Thyroiditis Hashimotos thyroiditis Thyroid cancer Thyroid hormone resistance Calcium homeostasis disorders and Metabolic bone disease Parathyroid gland disorders Primary hyperparathyroidism Secondary hyperparathyroidism Tertiary hyperparathyroidism Hypoparathyroidism Pseudohypoparathyroidism Osteoporosis Osteitis deformans (Pagets disease of bone) Rickets Osteomalacia Pituitary gland disorders Posterior pituitary Diabetes insipidus Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Anterior pituitary Hypopituitarism (or Panhypopituitarism) Pituitary tumors Pituitary adenomas Prolactinoma (or Hyperprolactinemia) Acromegaly, gigantism, dwarfism Cushings disease Sex hormone disorders Disorders of sex development or intersex disorders Hermaphroditism Gonadal dysgenesis Androgen insensitivity syndromes Hypogonadism (Gonadotropin deficiency) Inherited (genetic and chromosomal) disorders Kallmann syndrome Klinefelter syndrome Turner syndrome Acquired disorders Ovarian failure (also known as Premature Menopause) Testicular failure Disorders of Puberty Delayed puberty Precocious puberty Menstrual function or fertility disorders Amenorrhea Polycystic ovary syndrome Tumours of the endocrine glands not mentioned elsewhere Multiple endocrine neoplasia MEN type 1 MEN type 2a MEN type 2b Carcinoid syndrome See also separate organs Autoimmune polyendocrine syndromes Incidentaloma - an unexpected finding on diagnostic imaging, often of endocrine glands Endocrine emergencies In endocrinology, medical emergencies include diabetic ketoacidosis, hyperosmolar hyperglycemic state, hypoglycemic coma, acute adrenocortical insufficiency, phaeochromocytoma crisis, hypercalcemic crisis, thyroid storm, myxoedema coma and pituitary apoplexy.Emergencies arising from decompensated pheochromocytomas or parathyroid adenomas are sometimes referred for emergency resection when aggressive medical therapies fail to control the patients state, however the surgical risks are significant, especially blood pressure lability and the possibility of cardiovascular collapse after resection (due to a brutal drop in respectively catecholamines and calcium, which must be compensated with gradual normalization). It remains debated when emergency surgery is appropriate as opposed to urgent or elective surgery after continued attempts to stabilize the patient, notably in view of newer and more efficient medications and protocols. See also List of MeSH codes (C19) List of ICD-9 codes 240-279: Endocrine, nutritional and metabolic diseases, and immunity disorders References External links Endocrine+system+diseases at the US National Library of Medicine Medical Subject Headings (MeSH) MedlinePlus Overview endocrinediseases
Micromastia	Micromastia (also called hypomastia, breast aplasia, breast hypoplasia, or mammary hypoplasia) is a medical term describing the postpubertal underdevelopment of a womans breast tissue. Just as it is impossible to define normal breast size, there is no objective definition of micromastia. Breast development is commonly asymmetric and one or both breasts may be small. This condition may be a congenital defect associated with underlying abnormalities of the pectoral muscle (as in Polands syndrome), related to trauma (typically surgery or radiotherapy) or it may be a more subjective aesthetic description. Self perceived micromastia involves a discrepancy between a persons body image, and her internalized images of appropriate or desirable breast size and shape. Societal ideals over breast size vary over time, but there exist many conceived ideas involving breasts and sexual attractiveness and identity across different cultures. Causes Micromastia can be congenital or acquired disorder and may be unilateral or bilateral. Congenital causes include ulnar–mammary syndrome (caused by mutations in the TBX3 gene), Poland syndrome, Turner syndrome, and congenital adrenal hyperplasia. There is also a case report of familial hypoplasia of the nipples and athelia associated with mammary hypoplasia that was described in a father and his daughters. Acquired causes of micromastia include irradiation in infancy and childhood and surgical removal of prepubertal breast bud. Treatment The procedure to remedy micromastia is breast enlargement, most commonly augmentation mammoplasty using breast implants. Other techniques available involve using muscle flap-based reconstructive surgery techniques (latissimus dorsi and rectus abdominis muscles), microsurgical reconstruction, or fat grafting. Another potential treatment is hormonal breast enhancement, such as with estrogens. See also Amastia Amazia Breast atrophy Breast reconstruction Tuberous breasts References == External links ==
Tanapox	Tanapox (a virus from the genus Yatapoxvirus) was first seen among individuals in the flood plain of the Tana River in Kenya during two epidemics (1957 and 1962) of acute febrile illness accompanied by localized skin lesions. Signs and symptoms The incubation period in human cases remains unknown, but in a person who underwent voluntary inoculation, erythema and central thickening appear by the fourth day. Most patients present a mild pre-eruptive fever that lasts 3–4 days, severe headaches and backaches, and often itching at the site where the skin lesion develops.There is initially a small nodule, without any central abrasion. This small nodule soon becomes papular and gradually enlarges to reach a maximum diameter of about 15 mm by the end of the second week of infection. The draining lymph nodes are also enlarged and tender from about the fifth day following the appearance of the skin lesion. The lesion remains mostly nodular but, ulcerates during the third week and then gradually heals within five to six weeks, leaving a scar. In Kenya, the lesions were almost always solitary and were found on the upper arm, face, neck, and truck. Conversely, in Zaire, 22% of patients had multiple lesions, usually two or three. The maximum number of lesions seen in one patient was ten. In the case of Zairian patients, the lesions were mostly found on the lower limbs, with a couple of patients reporting lesions on the upper limbs, trunk, and head. Histopathology Tanapox virus in humans produces increased thickening of the epidermis with extensive degeneration of the prickle cell layer. The cytoplasm of the swollen epidermal cells is filled with large, pleomorphic, eosinophilic B-type inclusion bodies. Nuclei of infected cells are also swollen, with chromatin being concentrated at the nuclear periphery. Epidemiology Human tanapox has been mostly documented in Kenya and Zaire, but it is believed to occur much more widely throughout tropical Africa. All age groups and both sexes appear to be affected by this virus. During the Kenyan epidemics of 1957 and 1962, cases of tanapox were reported more frequently among persons who worked or played close to the river. As a result of this, researchers concluded that tanapox is most likely a zoonosis. However, neither the reservoir host nor the mode of transmission from wild animal to human is known. It is hypothesized that tanapox virus may be transferred from monkeys or another reservoir host to humans by infected arthropods that act as mechanical vectors. Only one case of human to human transmission has been reported. References Definition of Tanapox from MedicineNet.com == External links ==
Itch	Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response patterns are different. Pain creates a withdrawal reflex, whereas itch leads to a scratch reflex.Unmyelinated nerve fibers for itch and pain both originate in the skin; however, information for them is conveyed centrally in two distinct systems that both use the same nerve bundle and spinothalamic tract. Classification Most commonly, an itch is felt in one place. If it is felt all over the body, then it is called generalized itch or generalized pruritus.If the sensation of itching persists for six weeks or longer, then it is called chronic itch or chronic pruritus. Chronic idiopathic pruritus or essential pruritus is a rare form of itch that persists for longer than six weeks, and for which no clear cause can be identified. Signs and symptoms Pain and itch have very different behavioral response patterns. Pain elicits a withdrawal reflex, which leads to retraction and therefore a reaction trying to protect an endangered part of the body. Itch in contrast creates a scratch reflex, which draws one to the affected skin site. Itch generates stimulus of a foreign object underneath or upon the skin and also the urge to remove it. For example, responding to a local itch sensation is an effective way to remove insects from ones skin. Scratching has traditionally been regarded as a way to relieve oneself by reducing the annoying itch sensation. However, there are hedonic aspects to scratching, as one would find noxious scratching highly pleasurable. This can be problematic with chronic itch patients, such as ones with atopic dermatitis, who may scratch affected spots until they no longer produce a pleasant or painful sensation, instead of when the itch sensation disappears. It has been hypothesized that motivational aspects of scratching include the frontal brain areas of reward and decision making. These aspects might therefore contribute to the compulsive nature of itch and scratching. Contagious itch Events of "contagious itch" are very common occurrences. Even a discussion on the topic of itch can give one the desire to scratch. Itch is likely to be more than a localized phenomenon in the place one scratches. Results from a study showed that itching and scratching were induced purely by visual stimuli in a public lecture on itching. The sensation of pain can also be induced in a similar fashion, often by listening to a description of an injury, or viewing an injury itself. There is little detailed data on central activation for contagious itching, but it is hypothesized that a human mirror neuron system exists in which one imitates certain motor actions when they view others performing the same action. A similar hypothesis has been used to explain the cause of contagious yawning. Itch inhibition due to pain Studies done in the last decade have shown that itch can be inhibited by many other forms of painful stimuli, such as noxious heat, physical rubbing/scratching, noxious chemicals, and electric shock. Causes Infections Body louse, found in substandard living conditions Cutaneous larva migrans, a skin disease Head lice, if limited to the neck and scalp Herpes, a viral disease Insect bites, such as those from mosquitos or chiggers Pubic lice, if limited to the genital area Scabies, especially when several other persons in close contact also itch Shaving, which may irritate the skin Swimmers itch, a short-term immune reaction Varicella – i.e. chickenpox, prevalent among young children and highly contagious Tungiasis, ectoparasite of skin Environmental and allergic Allergic reaction to contact with specific chemicals, such as urushiol, derived from poison ivy or poison oak, or Balsam of Peru, found in many foods and fragrances. Certain allergens may be diagnosed in a patch test. Foreign objects on the skin are the most common cause of non-pathological itching. Photodermatitis – sunlight reacts with chemicals in the skin, leading to the formation of irritant metabolites. Urticaria (also called hives) usually causes itching. Skin disorders Dandruff; an unusually large amount of flaking is associated with this sensation. Punctate palmoplantar keratoderma, a group of disorders characterized by abnormal thickening of the palms and soles. Skin conditions (such as psoriasis, eczema, seborrhoeic dermatitis, sunburn, athletes foot, and hidradenitis suppurativa). Most are of an inflammatory nature. Scab healing, scar growth, and the development or emergence of moles, pimples, and ingrown hairs from below the epidermis. Xerosis: dry skin, frequently seen in the winter and also associated with older age, frequent bathing in hot showers or baths, and high-temperature and low-humidity environments. Other medical disorders Diabetes mellitus, a group of metabolic diseases in which a person has high blood sugar Hyperparathyroidism, overactivity of the parathyroid glands resulting in excess production of parathyroid hormone (PTH) Iron deficiency anemia, a common anemia (low red blood cell or hemoglobin levels) Cholestasis, where bile acids leaking into the serum activate peripheral opioid receptors, resulting in the characteristic generalized, severe itching Malignancy or internal cancer, such as lymphoma or Hodgkins disease Polycythemia, which can cause generalized itching due to increased histamines Psychiatric disease ("psychogenic itch", as may be seen in delusional parasitosis) Thyroid illness Uraemia – the itching sensation this causes is known as uremic pruritus Medication Drugs (such as opioids) that activate histamine (H1) receptors or trigger histamine release Chloroquine, a drug used in the treatment and prevention of malaria Bile acid congeners such as obeticholic acid Related to pregnancy Gestational pemphigoid, a dermatosis of pregnancy Intrahepatic cholestasis of pregnancy, a medical condition in which cholestasis occurs Pruritic urticarial papules and plaques of pregnancy (PUPPP), a chronic hives-like rash Other Menopause, or changes in hormonal balances associated with aging Terminal illness Mechanism Itch can originate in the peripheral nervous system (dermal or neuropathic) or in the central nervous system (neuropathic, neurogenic, or psychogenic). Dermal/pruritoceptive Itch originating in the skin is known as pruritoceptive, and can be induced by a variety of stimuli, including mechanical, chemical, thermal, and electrical stimulation. The primary afferent neurons responsible for histamine-induced itch are unmyelinated C-fibres.Two major classes of human C-fibre nociceptors exist: mechano-responsive nociceptors and mechano-insensitive nociceptors. Mechano-responsive nociceptors have been shown in studies to respond to mostly pain, and mechano-insensitive receptors respond mostly to itch induced by histamine. However, it does not explain mechanically induced itch or itch produced without a flare reaction that involves no histamine. Therefore, it is possible that pruritoceptive nerve fibres have different classes of fibres, which is unclear in current research.Studies have been done to show that itch receptors are found only on the top two skin layers, the epidermis and the epidermal/dermal transition layers. Shelley and Arthur verified the depth by injecting individual itch powder (Mucuna pruriens) spicules and noting that maximal sensitivity occurred at the basal cell layer or the innermost layer of the epidermis. Surgical removal of those skin layers removed the ability for a patient to perceive itch. Itch is never felt in muscle or joints, which strongly suggests that deep tissue probably does not contain itch signaling apparatuses.Itch is often classified as that which is histamine mediated (histaminergic) and nonhistaminergic. Sensitivity to pruritic stimuli is evenly distributed across the skin and has a clear spot distribution with similar density to that of pain. The different substances that elicit itch upon intracutaneous injection (injection within the skin) elicit only pain when injected subcutaneously (beneath the skin).Itch is readily abolished in skin areas treated with nociceptor excitotoxin capsaicin but remains unchanged in skin areas rendered touch insensitive by pretreatment with anti-inflammatory saponins. Although experimentally induced itch can still be perceived under a complete A-fiber conduction block, it is significantly diminished. Overall, itch sensation is mediated by A-delta and C nociceptors located in the uppermost layer of the skin. Molecular diversity of itch transmitting primary afferents Using single-cell mRNA sequencing, sensory-modality specific primary afferent have been molecularly defined into clusters based on gene expression patterns. Here, 11 sub clusters were detected; NF1-3, transmitting innocuous nociceptive information; NF4-5, which transmit proprioceptive information; NP1-3, transmitting itch information; PEP1-2, nociceptive information and TH, which is involved in pleasant touch, The pruriceptive NP1-3 were shown to express genes related to histaminergic and non-histaminergic signaling, where NF1 expresses genes responding to lysophosphatidic acid (Lpar3 and Lpar5), NP2 chloroquine-responsive genes (Mrgpra3 and Mrgprx1), whereas NP3 expresses neuropeptides Nppb and Sst as well as genes involved in inflammatory itch (Il31ra, Osmr and Crystrl2). The histamine receptor gene Hrh1 was found in NP2 and NP3, suggesting that histaminergic itch is transmitted by both these pruriceptive sub clusters. The spinal itch pathway After the pruriceptive primary afferent has been activated, the signal is transmitted from the skin into the spinal dorsal horn. In this area, a number of interneurons will either be inhibited or activated to promote activation of projection neurons, mediating the puriceptive signal to the brain. The GRP-GRPR interneuron system has been found to be important for mediating both histaminergic and non-histaminergic itch, where the GRP neurons activate GRPR neurons to promote itch Neuropathic Neuropathic itch can originate at any point along the afferent pathway as a result of damage of the nervous system. They could include diseases or disorders in the central nervous system or peripheral nervous system. Examples of neuropathic itch in origin are notalgia paresthetica, brachioradial pruritus, brain tumors, multiple sclerosis, peripheral neuropathy, and nerve irritation. Neurogenic Neurogenic itch, which is itch induced centrally but with no neural damage, is mostly associated with increased accumulation of exogenous opioids and possibly synthetic opioids. Psychogenic Itch is also associated with some symptoms of psychiatric disorders such as tactile hallucinations, delusions of parasitosis, or obsessive-compulsive disorders (as in OCD-related neurotic scratching). Peripheral sensitization Inflammatory mediators—such as bradykinin, serotonin (5-HT) and prostaglandins—released during a painful or pruritic inflammatory condition not only activate pruriceptors but also cause acute sensitization of the nociceptors. In addition, expression of neuro growth factors (NGF) can cause structural changes in nociceptors, such as sprouting. NGF is high in injured or inflamed tissue. Increased NGF is also found in atopic dermatitis, a hereditary and non-contagious skin disease with chronic inflammation. NGF is known to up-regulate neuropeptides, especially substance P. Substance P has been found to have an important role in inducing pain; however, there is no confirmation that substance P directly causes acute sensitization. Instead, substance P may contribute to itch by increasing neuronal sensitization and may affect release of mast cells, which contain many granules rich in histamine, during long-term interaction. Central sensitization Noxious input to the spinal cord is known to produce central sensitization, which consists of allodynia, exaggeration of pain, and punctuate hyperalgesia, extreme sensitivity to pain. Two types of mechanical hyperalgesia can occur: 1) touch that is normally painless in the uninjured surroundings of a cut or tear can trigger painful sensations (touch-evoked hyperalgesia), and 2) a slightly painful pin prick stimulation is perceived as more painful around a focused area of inflammation (punctuate hyperalgesia). Touch-evoked hyperalgesia requires continuous firing of primary afferent nociceptors, and punctuate hyperalgesia does not require continuous firing which means it can persist for hours after a trauma and can be stronger than normally experienced. In addition, it was found that patients with neuropathic pain, histamine ionophoresis resulted in a sensation of burning pain rather than itch, which would be induced in normal healthy patients. This shows that there is spinal hypersensitivity to C-fiber input in chronic pain. Treatment A variety of over-the-counter and prescription anti-itch drugs are available. Some plant products have been found to be effective anti-pruritics, others not. Non-chemical remedies include cooling, warming, soft stimulation. Topical antipruritics in the form of creams and sprays are often available over-the-counter. Oral anti-itch drugs also exist and are usually prescription drugs. The active ingredients usually belong to the following classes: Antihistamines, such as diphenhydramine (Benadryl) Corticosteroids, such as hydrocortisone topical cream; see topical steroid Counterirritants, such as mint oil, menthol, or camphor Crotamiton (trade name Eurax) is an antipruritic agent available as a cream or lotion, often used to treat scabies. Its mechanism of action remains unknown. Local anesthetics, such as benzocaine topical cream (Lanacane)Phototherapy is helpful for severe itching, especially if caused by kidney failure. The common type of light used is UVB.Sometimes scratching relieves isolated itches, hence the existence of devices such as the back scratcher. Often, however, scratching only offers temporary relief and can intensify itching, even causing further damage to the skin, dubbed the "itch-scratch cycle".The mainstay of therapy for dry skin is maintaining adequate skin moisture and topical emollients. No studies have been conducted to investigate the effectiveness of emollient creams, cooling lotions, topical corticosteroids, topical antidepressants, systemic antihistamines, systemic antidepressants, systemic anticonvulsants, and phototherapy on chronic itchiness of unknown origin. The effectiveness of therapeutic options for people who are terminally ill with malignant cancer is not known. History In 1660, German physician Samuel Hafenreffer introduced the definition of pruritus (itch). Epidemiology Approximately 280 million people globally, 4% of the population, have difficulty with itchiness. This is comparable to the 2–3% of the population who have psoriasis. See also Feeling, a perceptual state of conscious experience. Formication, a sensation that resembles that of small insects crawling on or under the skin Pruritus ani (also known as anusitis), irritation of skin at the exit of the rectum (anus), causing the desire to scratch Referred itch, a phenomenon in which a stimulus applied in one region of the body is felt as an itch or irritation in a different part of the body Itching powder, a powder or powder-like substance that induces itching when applied onto human skin. References == Further reading ==
Air embolism	An air embolism, also known as a gas embolism, is a blood vessel blockage caused by one or more bubbles of air or other gas in the circulatory system. Air can be introduced into the circulation during surgical procedures, lung over-expansion injury, decompression, and a few other causes. Air embolisms may also occur in the xylem of vascular plants, especially when suffering from water stress. Divers can develop arterial gas embolisms as a consequence of lung over-expansion injuries. Breathing gas introduced into the venous system of the lungs due to pulmonary barotrauma will not be trapped in the alveolar capillaries, and will consequently be circulated to the rest of the body through the systemic arteries, with a high risk of embolism. Inert gas bubbles arising from decompression are generally formed in the venous side of the systemic circulation, where inert gas concentrations are highest, these bubbles are generally trapped in the capillaries of the lungs where they will usually be eliminated without causing symptoms. If they are shunted to the systemic circulation through a patent foramen ovale they can travel to and lodge in the brain where they can cause stroke, the coronary capillaries where they can cause myocardial ischaemia or other tissues, where the consequences are usually less critical. The first aid treatment is to administer oxygen at the highest practicable concentration, treat for shock and transport to a hospital where therapeutic recompression and hyperbaric oxygen therapy are the definitive treatment. Signs and symptoms In surgery Symptoms include: Hypotension Shortness of breath In divers Symptoms of arterial gas embolism include: Loss of consciousness Cessation of breathing Vertigo Convulsions Tremors Loss of coordination Loss of control of bodily functions Numbness Paralysis Extreme fatigue Weakness in the extremities Areas of abnormal sensation Visual abnormalities Hearing abnormalities Personality changes Cognitive impairment Nausea or vomiting Bloody sputum Symptoms of other consequences of lung overexpansion such as pneumothorax, subcutaneous or mediastinal emphysema may also be present. Causes Interventional procedures Interventional radiology procedures, cardiac, and neurosurgical procedures can predispose to air embolism. Besides, increasing use of pump injectors for contrast delivery, and percutaneous intervention to the lungs also increases the risk of air embolism. Decompression illness Gas embolism is a diving disorder experienced by underwater divers who breathe gases at ambient pressure, and can happen in two distinct ways: Pulmonary barotrauma: Air bubbles can enter the bloodstream as a result of gross trauma to the lining of the lung following a rapid ascent while holding the breath; the air held within the lung expands to the point where the tissues tear (pulmonary barotrauma). This is easy to do as the lungs give little warning through pain until they do burst. The diver will usually arrive at the surface in pain and distress and may froth or spit blood. A pulmonary barotrauma is usually obvious and may present quite differently from decompression sickness. Decompression sickness: Inert gas bubbles form in the bloodstream if the gas dissolved in the blood under pressure during the dive is not allowed sufficient time to be eliminated in solution on ascent. The symptoms may be subtle and not immediately noticeable, and may develop for some time after surfacing. Ventilator induced pulmonary barotrauma Trauma to the lung can also cause an air embolism. This may happen after a patient is placed on a ventilator and air is forced into an injured vein or artery, causing sudden death. Breath-holding while ascending from scuba diving may also force lung air into pulmonary arteries or veins in a similar manner, due to the pressure difference. Direct injection Air can be injected directly into a vein or artery accidentally during clinical procedures. Misuse of a syringe to meticulously remove air from the vascular tubing of a hemodialysis circuit can allow air into the vascular system. Venous air embolism is a rare complication of diagnostic and therapeutic procedures requiring catheterization of a vein or artery. If a significant embolism occurs, the cardiovascular, pulmonary, or central nervous system may be affected. Interventions to remove or mitigate the embolism may include procedures to reduce bubble size, or withdrawal of air from the right atrium.The lethal dose for humans is considered theoretically between 3 and 5 ml per kg. It is estimated that 300-500 ml of gas introduced at a rate of 100 ml per sec would prove fatal. Mechanism Air embolism can occur whenever a blood vessel is open and a pressure gradient exists favoring entry of gas. Because the circulatory pressure in most arteries and veins is greater than atmospheric pressure, an air embolus does not often happen when a blood vessel is injured. In the veins above the heart, such as in the head and neck, the venous pressure may be less than atmospheric and an injury may let air in. This is one reason why surgeons must be particularly careful when operating on the brain, and why the head of the bed is tilted down when inserting or removing a central venous catheter from the jugular or subclavian veins.When air enters the veins, it travels to the right side of the heart, and then to the lungs. This can cause the vessels of the lung to constrict, raising the pressure in the right side of the heart. If the pressure rises high enough in a patient who is one of the 20% to 30% of the population with a patent foramen ovale, the gas bubble can then travel to the left side of the heart, and on to the brain or coronary arteries. Such bubbles are responsible for the most serious of gas embolic symptoms. Venous or pulmonary air embolism occurs when air enters the systemic veins and is transported to the right side of the heart and from there into the pulmonary arteries, where it may lodge, blocking or reducing blood flow. Gas in the venous circulation can cause cardiac problems by obstructing the pulmonary circulation or forming an air-lock which raises central venous pressure and reduces pulmonary and systemic arterial pressures. Experiments on animals show that the amount of gas necessary for this to happen is quite variable. Human case reports suggest that injecting more than 100 mL of air into the venous system at rates greater than 100 mL/s can be fatal. Very large and symptomatic amounts of venous air emboli may also occur in rapid decompression in severe diving or decompression accidents, where they may interfere with circulation in the lungs and result in respiratory distress and hypoxia.Gas embolism in a systemic artery, termed arterial gas embolism (AGE), is a more serious matter than in a vein, because a gas bubble in an artery may directly stop blood flow to an area fed by the artery. The symptoms of AGE depend on the area of blood flow, and may be those of stroke for a cerebral arterial gas embolism (CAGE) or heart attack if the heart is affected. The amount of arterial gas embolism that causes symptoms depends on location — 2 mL of air in the cerebral circulation can be fatal, while 0.5 mL of air into a coronary artery can cause cardiac arrest. Prevention and screening If a patent foramen ovale (PFO) is suspected, an examination by echocardiography may be performed to diagnose the defect. In this test, very fine bubbles are introduced into a patients vein by agitating saline in a syringe to produce the bubbles, then injecting them into an arm vein. A few seconds later, these bubbles may be clearly seen in the ultrasound image, as they travel through the patients right atrium and ventricle. At this time, bubbles may be observed directly crossing a septal defect, or else a patent foramen ovale may be opened temporarily by asking the patient to perform the Valsalva maneuver while the bubbles are crossing through the right heart – an action which will open the foramen flap and show bubbles passing into the left heart. Such bubbles are too small to cause harm in the test, but such a diagnosis may alert the patient to possible problems which may occur from larger bubbles, formed during activities like underwater diving, where bubbles may grow during decompression. A PFO test may be recommended for divers intending to expose themselves to relatively high decompression stress in deep technical diving. Diagnosis As a general rule, any diver who has breathed gas under pressure at any depth who surfaces unconscious, loses consciousness soon after surfacing, or displays neurological symptoms within about 10 minutes of surfacing should be assumed to be experiencing arterial gas embolism.Symptoms of arterial gas embolism may be present but masked by environmental effects such as hypothermia, or pain from other obvious causes. Neurological examination is recommended when there is suspicion of lung overexpansion injury. Symptoms of decompression sickness may be very similar to, and confused with, symptoms of arterial gas embolism, however, treatment is basically the same. Discrimination between gas embolism and decompression sickness may be difficult for injured divers, and both may occur simultaneously. Dive history may eliminate decompression sickness in many cases, and the presence of symptoms of other lung overexpansion injury would raise the probability of gas embolism. Treatment A large bubble of air in the heart (as can follow certain traumas in which air freely gains access to large veins) will present with a constant "machinery" murmur. It is important to promptly place the patient in Trendelenburg position (head down) and on their left side (left lateral decubitus position). The Trendelendburg position keeps a left-ventricular air bubble away from the coronary artery ostia (which are near the aortic valve) so that air bubbles do not enter and occlude the coronary arteries (which would cause a heart attack). Left lateral decubitus positioning helps to trap air in the non-dependent segment of the right ventricle (where it is more likely to remain instead of progressing into the pulmonary artery and occluding it). The left lateral decubitus position also prevents the air from passing through a potentially patent foramen ovale (present in as many as 30% of adults) and entering the left ventricle, from which it could then embolise to distal arteries (potentially causing occlusive symptoms such as stroke).Administration of high percentage oxygen is recommended for both venous and arterial air embolism. This is intended to counteract ischaemia and accelerate bubble size reduction.For venous air embolism the Trendelenburg or left lateral positioning of a patient with an air-lock obstruction of the right ventricle may move the air bubble in the ventricle and allow blood flow under the bubble.Hyperbaric therapy with 100% oxygen is recommended for patients presenting clinical features of arterial air embolism, as it accelerates removal of nitrogen from the bubbles by solution and improves tissue oxygenation. This is recommended particularly for cases of cardiopulmonary or neurological involvement. Early treatment has greatest benefits, but it can be effective as late as 30 hours after the injury. Treatment of divers Oxygen first aid treatment is useful for suspected gas embolism casualties or divers who have made fast ascents or missed decompression stops. Most fully closed-circuit rebreathers can deliver sustained high concentrations of oxygen-rich breathing gas and could be used as an alternative to pure open-circuit oxygen resuscitators. However pure oxygen from an oxygen cylinder through a Non-rebreather mask is the optimal way to deliver oxygen to a decompression illness patient. Recompression is the most effective, though slow, treatment of gas embolism in divers. Normally this is carried out in a recompression chamber. As pressure increases, the solubility of a gas increases, which reduces bubble size by accelerating absorption of the gas into the surrounding blood and tissues. Additionally, the volumes of the gas bubbles decrease in inverse proportion to the ambient pressure as described by Boyles law. In the hyperbaric chamber the patient may breathe 100% oxygen, at ambient pressures up to a depth equivalent of 18 msw. Under hyperbaric conditions, oxygen diffuses into the bubbles, displacing the nitrogen from the bubble and into solution in the blood. Oxygen bubbles are more easily tolerated. Diffusion of oxygen into the blood and tissues under hyperbaric conditions supports areas of the body which are deprived of blood flow when arteries are blocked by gas bubbles. This helps to reduce ischemic injury. The effects of hyperbaric oxygen also counteract the damage that can occur with reperfusion of previously ischemic areas; this damage is mediated by leukocytes (a type of white blood cell). Complications High incidence of relapse after hyperbaric oxygen treatment due to delayed cerebral edema. Epidemiology In terms of the epidemiology of air embolisms one finds that the intraoperative period to have the highest incidence. For example, VAE (vascular air embolism) in neurological cases ranges up to 80%, and OBGYN surgeries incidence can climb to 97% for VAE. In divers the incidence rate is 7/100,000 per dive. In society and culture Direct injection air embolism was one of the methods used by Belgian murderer Ivo Poppe to kill some of his victims (the other method being valium).William Davis, formerly a nurse in Texas, was convicted in October 2021 of murdering four and injuring two patients by injecting air into their arterial lines following heart surgery. During opening arguments for sentencing, prosecutors told the court that they would present evidence of an additional three murders and three attempted murders.Dorothy L. Sayers made use of direct injection air embolism as a murder method in her 1927 Lord Peter Wimsey mystery novel Unnatural Death (published in the US in 1928 as The Dawson Pedigree), although her description was subsequently criticised as implausible on account of the injection site and volume.Air embolism was the method used by an insane nurse to euthanize seven terminally ill patients in the episode "Amazing Grace" of the TV series Shadow Chasers.Near the end of young adult novel Catching Fire, as well as its film adaptation, protagonist Katniss Everdeen grabs a syringe and fills it with air, with the intention of killing Peeta Mellark quickly via air embolism. In plants Air embolisms generally occur in the xylem of vascular plants because a fall in hydraulic pressure results in cavitation. Falling hydraulic pressure occurs as a result of water stress or physical damage. A number of physiological adaptations serve to prevent cavitation and to recover from it. The cavitation may be prevented from spreading by the narrow pores in the walls between vessel elements. The plant xylem sap may be able to detour around the cavitation through interconnections. Water loss may be reduced by closing off leaf stomata to reduce transpiration, or some plants produce positive xylem pressure from the roots. When xylem pressure increases, the cavitation gases may redissolve. See also Ebullism – Formation of gas bubbles in bodily fluids due to reduced environmental pressure References External links Arterial Gas Embolism
X-linked ichthyosis	X-linked ichthyosis (abbreviated XLI) is a skin condition caused by the hereditary deficiency of the steroid sulfatase (STS) enzyme that affects 1 in 2000 to 1 in 6000 males. XLI manifests with dry, scaly skin and is due to deletions or mutations in the STS gene. XLI can also occur in the context of larger deletions causing contiguous gene syndromes. Treatment is largely aimed at alleviating the skin symptoms. The term is from the Ancient Greek ichthys meaning fish. Signs and symptoms The major symptoms of XLI include scaling of the skin, particularly on the neck, trunk, and lower extremities. The extensor surfaces are typically the most severely affected areas. The >4 mm diameter scales adhere to the underlying skin and can be dark brown or gray in color. Symptoms may subside during the summer. Associated medical conditions Aside from the skin scaling, XLI is not typically associated with other major medical problems. Atrial fibrillation or atrial flutter may affect up to 1 in 10 males with XLI. Heart rhythm abnormalities in individuals with XLI tend to co-occur with disorders of the gastrointestinal tract, and are likely to result from steroid sulfatase deficiency. Corneal opacities may be present but do not affect vision. Cryptorchidism is reported in some individuals. Individuals with XLI appear at increased risk of developmental disorders such as autism and Attention Deficit Hyperactivity Disorder and some affected individuals exhibit mood problems Mood problems in XLI appear to be most influenced by stigma or bullying associated with the skin condition, and by difficulties with treating the skin condition. Individuals with XLI can exhibit intellectual disability, although this is thought to be due to deletions encompassing neighboring genes (e.g. VCX) in addition to STS.Female carriers generally do not experience any of these problems but can have difficulty during childbirth, as the STS expressed in the placenta plays a role in normal labor. Female carriers may also be at slightly increased risk of developing mental health problems following childbirth For these reasons carriers should ensure their obstetrician is aware of the condition. Genetics The STS gene is located on the X chromosome at band Xp22.3. Thus, the syndrome is an X-linked condition, and it affects males and females differently. The 23rd pair of chromosomes is typically termed the "sex chromosomes". Females have two X chromosomes and males have one X and one Y chromosome. Therefore, in normal individuals, males carry a single copy of the STS gene and females carry two copies. This gene partially escapes X-inactivation and females normally express higher amounts of the STS enzyme than males.XLI can occur through new deletions or mutations of the STS gene but is more commonly inherited from a carrier mother. A hemizygous deletion or mutation of the STS gene in a male results in complete absence of enzyme activity, while a female carrier of a mutation or deletion is heterozygous and still has a normal copy of the STS gene. Female carriers of an STS deletion or mutation still express the STS enzyme, although with decreased enzyme activity.For this reason, XLI most commonly affects males, although individuals with numeric abnormalities of the sex chromosomes (45,X and 47,XXY) who also carry STS deletions or mutations would be exceptions to this rule.In addition, a female could be affected if she were the offspring of an affected male and a carrier female and inherited a deletion or mutation of the STS gene on both X chromosomes. Genetic counseling issues Since the majority of cases appear to occur through transmission of an STS deletion from a carrier mother, enzyme testing or DNA testing should be performed in the mother of any newly diagnosed simplex case (i.e. the first case in a family). In the case of an extended family with many affected individuals, carrier status can often be assigned based on pedigree analysis. Males with XLI will transmit the X chromosome harboring the STS deletion or mutation to each of his female offspring, who will therefore be an obligate carrier. However, all male offspring will be unaffected, since they receive their fathers Y chromosome. Female carriers of an STS deletion or mutation have a 50% chance with each pregnancy of transmitting it to an offspring. Thus, each male offspring has a 50% chance of being affected by XLI, while each female offspring has a 50% chance of being a carrier for this condition. Any individual that inherits the mothers normal copy of the STS gene will be unaffected and will have an extremely low chance of having a child affected with this condition.Due to random segregation of the chromosomes during gametogenesis, each pregnancy will be subject to the same probabilities, regardless of the number of previously affected or unaffected offspring. The above recurrence risks are based on the assumption that an affected male or carrier female will have children with an unaffected or non-carrier individual. The risks of having affected offspring would clearly increase in the case of a union between a male with XLI and a carrier female. Physiology/biochemistry The STS enzyme (EC 3.1.6.2), also referred to as Arylsulfatase C, is expressed throughout the body, with highest expression in the skin, liver, lymph nodes, and placenta, and lower expression in breast tissue and brain STS catalyzes the hydrolysis of sulfated steroids, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS), to non-sulfated steroids estradiol and androstenediol, respectively. Prenatally, the enzyme is involved in placental estrogen production. The enzyme is also involved in adrenal steroid production as well as conversion of sulfated steroids in other tissues.There seems to be a particularly important role for the enzyme in skin. Deficiency of the enzyme leads to the characteristic dry and scaly skin seen in ichthyosis. Recent research indicates that the skin abnormalities seen in XLI may be due to accumulation of cholesterol sulfate in the outer epidermis, leading to abnormal barrier function and corneocyte retention. Diagnosis XLI can be suspected based on clinical findings, although symptoms can take varying amounts of time to become evident, from a few hours after birth, up to a year in milder cases. The diagnosis is usually made by a dermatologist, who also typically formulates the treatment plan (see below). STS enzyme deficiency is confirmed using a clinically available biochemical assay. Carrier detection can be performed in mothers of affected sons using this test (see Genetics, below). Molecular testing for DNA deletions or mutations is also offered, and can be particularly useful in the evaluation of individuals with associated medical conditions (see below). Prenatal diagnosis is possible using either biochemical or molecular tests. However, the use of prenatal diagnosis for genetic conditions that are considered to be generally benign raises serious ethical considerations and requires detailed genetic counseling. Treatment Because XLI is caused by a gene mutation or deletion, there is no "cure." One of the aims of treatment is to reduce scaling by removing the excess, flaky scales, and keep the skin hydrated. This can be achieved using a variety of topical creams. Other treatments involve Keratolytic agents such as Ammonium lactate (Lac-Hydrin) are used to facilitate the release of retained corneocytes. oral isotretinoin acitretin The topical receptor-selective retinoid tazarotene Research is ongoing with regard to the use of gene therapy to treat XLI. Timber Pharmaceuticals is planning on conducting a phase 3 trial of its investigational topical isotretinoin product in the second quarter of 2022 for the treatment of congential ichthyosis. History In the 1960s, recessive x-linked ichthyosis was distinguished clinically from other ichthyoses.: 486 : 561 See also Ichthyosis Carvajal syndrome References == External links ==
Electrocution	Electrocution is death or severe injury caused by electric shock from electric current passing through the body. The word is derived from "electro" and "execution", but it is also used for accidental death.The term "electrocution" was coined in 1889 in the US just before the first use of the electric chair and originally referred to only electrical execution and not other electrical deaths. However, since no English word was available for non-judicial deaths due to electric shock, the word "electrocution" eventually took over as a description of all circumstances of electrical death from the new commercial electricity. Origins In the Netherlands in 1746 Pieter van Musschenbroeks lab assistant, Andreas Cuneus, received an extreme shock while working with a leyden jar, the first recorded injury from man-made electricity. By the mid-19th century high-voltage electrical systems came into use to power arc lighting for theatrical stage lighting and lighthouses leading to the first recorded accidental death in 1879 when a stage carpenter in Lyon, France, touched a 250-volt wire.The spread of arc light–based street lighting systems (which at the time ran at a voltage above 3,000 volts) after 1880 led to many people dying from coming in contact with these high-voltage lines, a strange new phenomenon which seemed to kill instantaneously without leaving a mark on the victim. This would lead to execution by electricity in the electric chair in the early 1890s as an official method of capital punishment in the U.S. state of New York, thought to be a more humane alternative to hanging. After an 1881 death in Buffalo, New York, caused by a high-voltage arc lighting system, Alfred P. Southwick sought to develop this phenomenon into a way to execute condemned criminals. Southwick, a dentist, based his device on the dental chair.The next nine years saw a promotion by Southwick, the New York state Gerry commission (which included Southwick) recommending execution by electricity, a June 4, 1888 law making it the state form of execution on January 2, 1889, and a further state committee of doctors and lawyers to finalize the details of the method used.The adoption of the electric chair became mixed up in the "war of currents" between Thomas Edisons direct current system and industrialist George Westinghouses alternating current system in 1889 when noted anti-AC activist Harold P. Brown became a consultant to the committee. Brown pushed, with the assistance and sometimes collusion of Edison Electric and Westinghouses chief AC rival, the Thomson-Houston Electric Company, for the successful adoption of alternating current to power the chair, an attempt to portray AC as a public menace and the "executioners current". Etymology In May 1889 the state of New York sentenced its first criminal, a street merchant named William Kemmler, to be executed in their new form of capital punishment. Tabloid newspapers, trying to describe this new form of electrical execution, started settling on "electrocution," a portmanteau word derived from "electro" and "execution". It was not the only choice of word people were considering. The New York Times editorial column noted words such as "Westinghoused" (after the Westinghouse Electric alternating current equipment that was to be used), "Gerrycide" (after Elbridge Thomas Gerry, who headed the New York death penalty commission that suggested adopting the electric chair), and "Browned" (after anti-AC activist Harold P. Brown). Thomas Edison preferred the words dynamort, ampermort and electromort. The New York Times hated the word electrocution, describing it as being pushed forward by "pretentious ignoramuses". Medical aspects Fish & Geddes state: "Contact with 20 mA of current can be fatal".The health hazard of an electric current flowing through the body depends on the amount of current and the length of time for which it flows, not merely on the voltage. However, a high voltage is required to produce a high current through the body. This is due to the relatively high resistance of skin when dry, requiring a high voltage to pass through. The severity of a shock also depends on whether the path of the current includes a vital organ. Death can occur from any shock that carries enough sustained current to stop the heart. Low currents (70–700 mA) usually trigger fibrillation in the heart, which is reversible via defibrillator but is nearly always fatal without help. Currents as low as 30 mA AC or 300–500 mA DC applied to the body surface can cause fibrillation. Large currents (> 1 A) cause permanent damage via burns and cellular damage. References Bibliography Brandon, Craig (2009). The Electric Chair: An Unnatural American History. McFarland. ISBN 978-0786444939. Moran, Richard (2007). Executioners Current: Thomas Edison, George Westinghouse, and the Invention of the Electric Chair. New York: Knopf Doubleday Publishing Group. ISBN 978-0-37572-446-6.
Sedative	A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but the majority of them affect the neurotransmitter gamma-aminobutyric acid (GABA). In spite of the fact that each sedative acts in its own way, most produce relaxing effects by increasing GABA activity.This group is related to hypnotics. The term sedative describes drugs that serve to calm or relieve anxiety, whereas the term hypnotic describes drugs whose main purpose is to initiate, sustain, or lengthen sleep. Because these two functions frequently overlap, and because drugs in this class generally produce dose-dependent effects (ranging from anxiolysis to loss of consciousness) they are often referred to collectively as sedative-hypnotic drugs.Sedatives can be used to produce an overly-calming effect (alcohol being the most common sedating drug). In the event of an overdose or if combined with another sedative, many of these drugs can cause deep unconsciousness and even death. Terminology There is some overlap between the terms "sedative" and "hypnotic". Advances in pharmacology have permitted more specific targeting of receptors, and greater selectivity of agents, which necessitates greater precision when describing these agents and their effects: Anxiolytic refers specifically to the effect upon anxiety. (However, some benzodiazepines can be all three: sedatives, hypnotics, and anxiolytics). Tranquilizer can refer to anxiolytics or antipsychotics. Soporific and sleeping pill are near-synonyms for hypnotics. The term "chemical cosh" The term "chemical cosh" (a club) is sometimes used popularly for a strong sedative, particularly for: widespread dispensation of antipsychotic drugs in residential care to make people with dementia easier to manage. use of methylphenidate to calm children with attention deficit hyperactivity disorder, though paradoxically this drug is known to be a stimulant. See also Antipsychotic controversy Types of sedatives Therapeutic use Doctors and veterinarians often administer sedatives to patients in order to dull the patients anxiety related to painful or anxiety-provoking procedures. Although sedatives do not relieve pain in themselves, they can be a useful adjunct to analgesics in preparing patients for surgery, and are commonly given to patients before they are anaesthetized, or before other highly uncomfortable and invasive procedures like cardiac catheterization, colonoscopy or MRI. Risks Sedative dependence Some sedatives can cause psychological and physical dependence when taken regularly over a period of time, even at therapeutic doses. Dependent users may get withdrawal symptoms ranging from restlessness and insomnia to convulsions and death. When users become psychologically dependent, they feel as if they need the drug to function, although physical dependence does not necessarily occur, particularly with a short course of use. In both types of dependences, finding and using the sedative becomes the focus in life. Both physical and psychological dependence can be treated with therapy. Misuse Many sedatives can be misused, but barbiturates and benzodiazepines are responsible for most of the problems with sedative use due to their widespread recreational or non-medical use. People who have difficulty dealing with stress, anxiety or sleeplessness may overuse or become dependent on sedatives. Some heroin users may take them either to supplement their drug or to substitute for it. Stimulant users may take sedatives to calm excessive jitteriness. Others take sedatives recreationally to relax and forget their worries. Barbiturate overdose is a factor in nearly one-third of all reported drug-related deaths. These include suicides and accidental drug poisonings. Accidental deaths sometimes occur when a drowsy, confused user repeats doses, or when sedatives are taken with alcohol. A study from the United States found that in 2011, sedatives and hypnotics were a leading source of adverse drug events (ADEs) seen in the hospital setting: Approximately 2.8% of all ADEs present on admission and 4.4% of ADEs that originated during a hospital stay were caused by a sedative or hypnotic drug. A second study noted that a total of 70,982 sedative exposures were reported to U.S. poison control centers in 1998, of which 2310 (3.2%) resulted in major toxicity and 89 (0.1%) resulted in death. About half of all the people admitted to emergency rooms in the U.S. as a result of nonmedical use of sedatives have a legitimate prescription for the drug, but have taken an excessive dose or combined it with alcohol or other drugs.There are also serious paradoxical reactions that may occur in conjunction with the use of sedatives that lead to unexpected results in some individuals. Malcolm Lader at the Institute of Psychiatry in London estimates the incidence of these adverse reactions at about 5%, even in short-term use of the drugs. The paradoxical reactions may consist of depression, with or without suicidal tendencies, phobias, aggressiveness, violent behavior and symptoms sometimes misdiagnosed as psychosis. Dangers of combining sedatives and alcohol Sedatives and alcohol are sometimes combined recreationally or carelessly. Since alcohol is a strong depressant that slows brain function and depresses respiration, the two substances compound each others actions and this combination can prove fatal. Worsening of psychiatric symptoms The long-term use of benzodiazepines may have a similar effect on the brain as alcohol, and are also implicated in depression, anxiety, posttraumatic stress disorder (PTSD), mania, psychosis, sleep disorders, sexual dysfunction, delirium, and neurocognitive disorders (including benzodiazepine-induced persisting dementia which persists even after the medications are stopped). As with alcohol, the effects of benzodiazepine on neurochemistry, such as decreased levels of serotonin and norepinephrine, are believed to be responsible for their effects on mood and anxiety. Additionally, benzodiazepines can indirectly cause or worsen other psychiatric symptoms (e.g., mood, anxiety, psychosis, irritability) by worsening sleep (i.e., benzodiazepine-induced sleep disorder). Like alcohol, benzodiazepines are commonly used to treat insomnia in the short-term (both prescribed and self-medicated), but worsen sleep in the long-term. While benzodiazepines can put people to sleep, they disrupt sleep architecture: decreasing sleep time, delaying time to REM sleep, and decreasing deep slow-wave sleep (the most restorative part of sleep for both energy and mood). Dementia Sedatives and hypnotics should be avoided in people with dementia, according to the medication appropriateness tool for co‐morbid health conditions in dementia criteria. The use of these medications can further impede cognitive function for people with dementia, who are also more sensitive to side effects of medications. Amnesia Sedatives can sometimes leave the patient with long-term or short-term amnesia. Lorazepam is one such pharmacological agent that can cause anterograde amnesia. Intensive care unit patients who receive higher doses over longer periods, typically via IV drip, are more likely to experience such side effects. Additionally, the prolonged use of tranquilizers increases the risk of obsessive and compulsive disorder, where the person becomes unaware whether he has performed a scheduled activity or not, he may also repetitively perform tasks and still re-performs the same task trying to make-up for continuous doubts. Remembering names that were earlier known becomes an issue such that the memory loss becomes apparent. Disinhibition and crime Sedatives — most commonly alcohol but also GHB, Flunitrazepam (Rohypnol), and to a lesser extent, temazepam (Restoril), and midazolam (Versed) — have been reported for their use as date rape drugs (also called a Mickey) and being administered to unsuspecting patrons in bars or guests at parties to reduce the intended victims defenses. These drugs are also used for robbing people. Statistical overviews suggest that the use of sedative-spiked drinks for robbing people is actually much more common than their use for rape. Cases of criminals taking rohypnol themselves before they commit crimes have also been reported, as the loss of inhibitions from the drug may increase their confidence to commit the offence, and the amnesia produced by the drug makes it difficult for police to interrogate them if they are caught. See also Hypnotic Antidepressants Benzodiazepine withdrawal syndrome Tranquilizer Tranquilizer gun Notes References Further reading Tone, Andrea. The Age of Anxiety: A History of Americas Turbulent Affair with Tranquilizers (Basic Books, 2009) 288 pp.; ISBN 978-0-465-08658-0 excerpty and text search
Parapsoriasis	Parapsoriasis refers to one of a group of skin disorders that are characterized primarily by their resemblance to psoriasis (red, scaly lesions), rather than by their underlying cause. Neoplasms can develop from parapsoriasis. For example, it can develop into cutaneous T-cell lymphoma. The word "parapsoriasis" was formed in 1902. Classification The parapsoriasis groups, described and debated for nearly a century, has spawned a confusing nomenclature. There are some authors who prefer to limit the term "parapsoriasis" to large- and small-plaque variants only. However, the following classification scheme is now generally accepted:: 450 Large-plaque parapsoriasis Small-plaque parapsoriasis Pityriasis lichenoides Pityriasis lichenoides chronica Pityriasis lichenoides et varioliformis acuta Lymphomatoid papulosis See also Poikiloderma vasculare atrophicans List of cutaneous conditions References == External links ==
Atrioventricular block	Atrioventricular block (AV block) is a type of heart block that occurs when the electrical signal traveling from the atria, or the upper chambers of the heart, to ventricles, or the lower chambers of the heart, is impaired. Normally, the sinoatrial node (SA node) produces an electrical signal to control the heart rate. The signal travels from the SA node to the ventricles through the atrioventricular node (AV node). In an AV block, this electrical signal is either delayed or completely blocked. When the signal is completely blocked, the ventricles produce their own electrical signal to control the heart rate. The heart rate produced by the ventricles is much slower than that produced by the SA node.Some AV blocks are benign, or normal, in certain people, such as in athletes or children. Other blocks are pathologic, or abnormal, and have several causes, including ischemia, infarction, fibrosis, and drugs. Classification There are three types, or degrees, of AV block: (1) first-degree, (2) second-degree, and (3) third-degree, with third-degree being the most severe. An ECG is used to differentiate between the different types of AV blocks. However, one important consideration when diagnosing AV blocks from ECGs is the possibility of pseudo- AV blocks which are due to concealed junctional extrasystoles. It is important to diagnose AV-blocks precisely because unnecessary pacemaker placement in patients with pseudo-AV blocks can worsen symptoms and create complications. First-degree atrioventricular block First-degree AV block occurs when there is a delay, but not disruption, as the electrical signal moves between the atrium and the ventricles through the AV node. On ECG, this is defined by a PR interval greater than 200 msec. Additionally, there are no dropped, or skipped, beats. Second-degree atrioventricular block Second-degree AV block occurs when the electrical signal between the atria and ventricles is even more impaired than in a first-degree AV block. In a second-degree AV block, the impairment results in a failure to conduct an impulse, which causes a skipped beat. Mobitz I Mobitz I is characterized by a progressive yet reversible block of the AV node. On ECG, this is defined by progressive prolongation of the PR interval, with a resulting dropped beat (the PR interval gets longer and longer until a beat is finally dropped, or skipped).Some patients are asymptomatic; those who have symptoms respond to treatment effectively. There is a low risk of a Mobitz I AV block leading to heart attack and complete heart block. Mobitz II Mobitz II is caused by a sudden, unexpected failure of the His-Purkinje cells to conduct the electrical impulse. On ECG, the PR interval is unchanged from beat to beat, but there is a sudden failure to conduct the signal to the ventricles, and resulting in random skipped beat.The risks and possible effects of Mobitz II are much more severe than Mobitz I in that it can lead to severe heart attack. Third-degree atrioventricular block Third-degree AV block occurs when the signal between the atria and ventricles is completely blocked, and there is no communication between the two. None of the signals from the upper chambers makes it to the lower chambers. On ECG, there is no relationship between P waves and QRS complexes, meaning the P waves and QRS complexes are not in a 1:1 ratio.Third-degree AV block is the most severe of the AV blocks. Persons with third-degree AV block need emergency treatment including but not limited to a pacemaker. Etiology There are many causes of AV block, ranging from a normal variant among people to the result of a heart attack.First-degree AV block and Mobitz I second-degree block are often thought to be just normal, benign, conditions in people, and do not often result from a severe underlying condition.Mobitz II second-degree block and third-degree AV block are not normal variants and are associated with an underlying condition. Common causes include ischemia (lack of blood flow and oxygen to the heart muscle) or progressive fibrosis (excessive scaring) of the heart. It is also possible that a high degree block can result after cardiac surgery during which the surgeon was in close proximity to the electrical conduction system and accidentally injured it. Reversible causes of Mobitz II and third-degree heart block include untreated Lyme disease, hypothyroidism, hyperkalemia (high levels of potassium), and drug toxicity. Drugs that slow the conduction of the electrical signal through AV node, such as beta-blockers, digoxin, calcium channel blockers, and amiodarone, can cause heart block if they are taken in excessive amounts, or the levels in the blood get too high. Anatomy The synchronized contraction of the heart occurs through a well-coordinated electrical signal pathway. The initial electrical signal originates from the SA node located in the upper portion of the right atrium. The electrical signal then travels through both the right and left atrium and causes the two atria to contract at the same time. This simultaneous contraction results in the P wave seen in an ECG tracing.The electrical signal then travels to the AV node located on the lower portion of the interatrial septum. At the AV node there is a delay in the electrical signal, which allows the atria to contract and blood to flow from the atria to the ventricles. This delay accounts for the ECG period between the P wave and the QRS complex, and creates the PR interval. From the AV nodes, the electrical signal travels through Bundle of His and divides into the right bundle and left bundle, which are located within the interventricular septum. Finally, the electrical signal travels into the Purkinje fibers. The division of the signal into a right and left bundle and then into the Purkinje fibers allows for a simultaneous depolarization and contraction of the right and left ventricles. The contraction of the ventricles results in the QRS complex seen on an ECG tracing. After contraction, the ventricles must repolarize, or reset themselves, in order to allow for a second depolarization and contraction. The repolarization creates the T wave in the ECG tracing. Diagnosis An electrocardiogram, or ECG, is used to differentiate between the different types of AV block. In AV block, there is a disruption between the signal traveling from the atria to the ventricles. This results in abnormalities in the PR interval, as well as the relationship between P waves and QRS complexes on the ECG tracing. If the patient is symptomatic from their suspected AV block, it is important that an ECG is also obtained while having symptoms. Physicians may also order a continuous ECG (i.e. Holter monitor or implanted cardiac monitor) to monitor the patient for symptoms and conduction abnormalities over a longer period of time, as AV blocks can be intermittent.Because some types of AV block can be associated with underlying structural heart disease, patients may also undergo echocardiogram to look at the heart and assess the function.Laboratory diagnosis for AV blocks include electrolyte, drug level and cardiac enzyme level tests. Based upon clinical suspicion, the physician may do lab tests to assess for reversible causes of AV block, such as hypothyroidism, rheumatologic disorders, and infections (such as Lyme disease). Management Management is dependent upon the severity, or degree, of the blockage, the consistency of symptoms, as well as the cause of the AV block.Patients with first-degree AV block do not have any resulting severe or life-threatening symptoms, such as symptomatic bradycardia or hypotension, and, thus, do not require treatment.Similarly, patients with second-degree Mobitz I AV block rarely develop life-threatening symptoms, and patients who are asymptomatic do not require treatment. However, in some cases, patients with Mobitz I block can develop life-threatening symptoms that require intervention. These patients often respond well to atropine, but may require temporary transcutaneous pacing or transvenous pacing until they are no longer symptomatic.Patients with second-degree Mobitz II and third-degree heart block are much more likely to have symptomatic bradycardia and hemodynamic instability, such as hypotension. Additionally, there is an increased risk of patients with Mobitz II heart block developing third-degree heart block. Therefore, these patients often require temporary pacing with transcutaneous or transvenous pacing wires, and many will ultimately require a permanent implanted pacemaker.If the heart block is found to be caused by a reversible condition, such as Lyme disease, the underlying condition should first be treated. Often, this will lead to resolution of the heart block and the associated symptoms. References External links Second-Degree Atrioventricular Block at eMedicine
Complication	Complication or complications may refer to: Dramatic arts "Complications" (CSI: Miami), an episode of CSI: Miami "Complications" (Terminator: The Sarah Connor Chronicles), an episode of Terminator: The Sarah Connor Chronicles Complications (TV series), a 2015 USA Network television series starring Jason OMara Medicine Complication (medicine), an unfavorable evolution of a disease, health condition or medical treatment Music Albums Complications - Trilogy of Intricacy, a 2005 EP by Norwegian progressive metal band Age of Silence Complications (Dover album), a 2015 album by Spanish rock band Dover Songs "Complication", a 1999 song by Nine Inch Nails from The Fragile "Complications", a 2008 song by deadmau5 from Random Album Title Technology Complication (horology), a clock display other than the time Smartwatch complication Complication (horology)#Use in smartwatches
Ovarian disease	Ovarian diseases refer to diseases or disorders of the ovary.These can be classified as endocrine disorders or as a disorders of the reproductive system. If the egg fails to release from the follicle in the ovary an ovarian cyst may form. Small ovarian cysts are common in healthy women. Some women have more follicles than usual (polycystic ovary syndrome), which inhibits the follicles to grow normally and this will cause cycle irregularities. Various types of ovarian diseases exist. Some of the ovarian diseases or disorders include: endometriosis, ovarian cysts, ovarian epithelial cancer, ovarian germ cell tumors, ovarian low malignant potential tumors, and polycystic ovary syndrome (PCOS). Endometriosis Endometriosis is a condition in which tissues lining the uterus (endometrial stroma and gland) grows abnormally beyond the uterus that may become quite painful. In simpler terms, it means that the tissue lining the uterus develops in different parts outside of it. It can be either at ovary, fallopian tubes, or peritoneal spaces.There is no single cause of endometriosis.Symptoms: Menstrual cramps, heavy menstrual bleeding, bowel or urinary problems, nausea, vomiting, blood with stools, painful intercourse, fatigues, spotting or bleeding between periods.Treatment: Surgery at extreme situations Hormonal treatments using birth controls. Healthier lifestyle. Ovarian cysts It is common for many women to develop a cyst in their lifetime. At times, these can go unnoticed without pain or visible symptoms. A cyst may develop in either of the ovaries that are responsible for producing hormones and carrying eggs in the bodies of women. Ovarian cysts can be of various types like dermoid cysts, endometrioma cysts and the functional cyst being the most common one [1] Symptoms: Abdominal bloating or swelling. Painful bowel movement. Pelvic pain before or after the menstrual cycle. Painful intercourse. Pain in the lower back or thighs. Breast tenderness. Nausea and vomiting. Fever. Rapid breathing. Faintness or dizziness. Sharp pelvic pain.Treatment: Taking of oral contraceptives or birth control pills as prescribed by the doctor. Laparoscopy: Surgery to remove the cyst. Hysterectomy in case the cyst is cancerous. Ovarian epithelial cancer It is one of the common ovarian cancers that affect women worldwide. It develops outside the ovaries and ultimately spreads outside and can affect other organs. Causes: It may happen if there is a family medical history of breast cancer, colon cancer, rectal cancer or uterine cancer, or Lynch syndrome. If someone is under Estrogen Replacement Therapy for a long time. Smoking habits may also lead to the same. [2] Treatment: Surgery to remove the uterus. Chemotherapy. Ovarian germ cell tumors Ovarian germ cell tumors are common among teenagers and young women. It is a growth in the ovaries. [3] Causes: Though the exact causes are not known, it may happen owing to certain birth defects affecting the genitals, nervous system or the urinary tract. There may be genetic conditions affecting the sex chromosomes that result in these kind of tumors as well.Symptoms Belly swelling. Pain or pressure in the belly. Swollen abdomen. Vaginal bleeding after menopause.Treatment: Surgery to remove the tumor, or the Fallopian tubes or one or more ovaries. Hysterectomy. Chemotherapy in case the tumor is cancerous. Radiation therapy to prevent the cancerous cells from developing. Ovarian low malignant potential tumors The tumor forms in the ovaries and gradually spreads to the outside of ovary. This mostly affects younger women and also hinders the reproductive system.Causes: Causes are debatable and these may occur to both pregnant women and women who do not opt for pregnancy Symptoms: Abdominal pain or swelling. Bowel problems or constipation.Treatment: Depending on the size of the tumor, choice of pregnancy, the spreading of the tumor, age and choices, removing the affected ovary is the most common treatment. In rare situations, the tumor is taken out of the ovary. Also, hysterectomy can be an option. Polycystic ovary syndrome This is a hormonal imbalance, where androgens (also called male hormones) are elevated.The increased level of androgens may result in irregular menstrual cycle and diabetes and heart problem in the long run. It also affects the body in various ways like problem getting pregnant, sleep apnea, depression and anxiety, can enhance the risk of endometrial cancer. Symptoms: Irregular periods. Heavy bleeding during periods. Excess hair growth on face and other parts of the body like chest, back, belly. Acne. Weight gain. Darkening of skin. Headaches.Treatment: Oral contraceptives to promote regular periods Healthier lifestyle.Other conditions include: Ovarian cancer Luteoma Hypogonadism Hyperthecosis References == External links ==
Causality	Causality (also referred to as causation, or cause and effect) is influence by which one event, process, state, or object (a cause) contributes to the production of another event, process, state, or object (an effect) where the cause is partly responsible for the effect, and the effect is partly dependent on the cause. In general, a process has many causes, which are also said to be causal factors for it, and all lie in its past. An effect can in turn be a cause of, or causal factor for, many other effects, which all lie in its future. Some writers have held that causality is metaphysically prior to notions of time and space.Causality is an abstraction that indicates how the world progresses. As such a basic concept, it is more apt as an explanation of other concepts of progression than as something to be explained by others more basic. The concept is like those of agency and efficacy. For this reason, a leap of intuition may be needed to grasp it. Accordingly, causality is implicit in the logic and structure of ordinary language.In English studies of Aristotelian philosophy, the word "cause" is used as a specialized technical term, the translation of Aristotles term αἰτία, by which Aristotle meant "explanation" or "answer to a why question". Aristotle categorized the four types of answers as material, formal, efficient, and final "causes". In this case, the "cause" is the explanans for the explanandum, and failure to recognize that different kinds of "cause" are being considered can lead to futile debate. Of Aristotles four explanatory modes, the one nearest to the concerns of the present article is the "efficient" one. David Hume, as part of his opposition to rationalism, argued that pure reason alone cannot prove the reality of efficient causality; instead, he appealed to custom and mental habit, observing that all human knowledge derives solely from experience. The topic of causality remains a staple in contemporary philosophy. Concept Metaphysics The nature of cause and effect is a concern of the subject known as metaphysics. Kant thought that time and space were notions prior to human understanding of the progress or evolution of the world, and he also recognized the priority of causality. But he did not have the understanding that came with knowledge of Minkowski geometry and the special theory of relativity, that the notion of causality can be used as a prior foundation from which to construct notions of time and space. Ontology A general metaphysical question about cause and effect is what kind of entity can be a cause, and what kind of entity can be an effect. One viewpoint on this question is that cause and effect are of one and the same kind of entity, with causality an asymmetric relation between them. That is to say, it would make good sense grammatically to say either "A is the cause and B the effect" or "B is the cause and A the effect", though only one of those two can be actually true. In this view, one opinion, proposed as a metaphysical principle in process philosophy, is that every cause and every effect is respectively some process, event, becoming, or happening. An example is his tripping over the step was the cause, and his breaking his ankle the effect. Another view is that causes and effects are states of affairs, with the exact natures of those entities being less restrictively defined than in process philosophy.Another viewpoint on the question is the more classical one, that a cause and its effect can be of different kinds of entity. For example, in Aristotles efficient causal explanation, an action can be a cause while an enduring object is its effect. For example, the generative actions of his parents can be regarded as the efficient cause, with Socrates being the effect, Socrates being regarded as an enduring object, in philosophical tradition called a substance, as distinct from an action. Epistemology Since causality is a subtle metaphysical notion, considerable intellectual effort, along with exhibition of evidence, is needed to establish knowledge of it in particular empirical circumstances. According to David Hume, the human mind is unable to perceive causal relations directly. On this ground, the scholar distinguished between the regularity view on causality and the counterfactual notion. According to the counterfactual view, X causes Y if and only if, without X, Y would not exist. Hume interpreted the latter as an ontological view, i.e., as a description of the nature of causality but, given the limitations of the human mind, advised using the former (stating, roughly, that X causes Y if and only if the two events are spatiotemporally conjoined, and X precedes Y) as an epistemic definition of causality. Having an epistemic concept of causality is needed to distinguish between causal and noncausal relations. The contemporary philosophical literature on causality can be divided into five big approaches to causality. These include the (mentioned above) regularity, probabilistic, counterfactual, mechanistic, and manipulationist views. The five approaches can be shown to be reductive, i.e., define causality in terms of relations of other types. According to this reading, they define causality in terms of, respectively, empirical regularities (constant conjunctions of events), changes in conditional probabilities, counterfactual conditions, mechanisms underlying causal relations, and invariance under intervention. Geometrical significance Causality has the properties of antecedence and contiguity. These are topological, and are ingredients for space-time geometry. As developed by Alfred Robb, these properties allow the derivation of the notions of time and space. Max Jammer writes "the Einstein postulate... opens the way to a straightforward construction of the causal topology... of Minkowski space." Causal efficacy propagates no faster than light.Thus, the notion of causality is metaphysically prior to the notions of time and space. In practical terms, this is because use of the relation of causality is necessary for the interpretation of empirical experiments. Interpretation of experiments is needed to establish the physical and geometrical notions of time and space. Volition The deterministic world-view holds that the history of the universe can be exhaustively represented as a progression of events following one after as cause and effect. The incompatibilist version of this holds that there is no such thing as "free will". Compatibilism, on the other hand, holds that determinism is compatible with, or even necessary for, free will. Necessary and sufficient causes Causes may sometimes be distinguished into two types: necessary and sufficient. A third type of causation, which requires neither necessity nor sufficiency in and of itself, but which contributes to the effect, is called a "contributory cause". Necessary causes If x is a necessary cause of y, then the presence of y necessarily implies the prior occurrence of x. The presence of x, however, does not imply that y will occur. Sufficient causes If x is a sufficient cause of y, then the presence of x necessarily implies the subsequent occurrence of y. However, another cause z may alternatively cause y. Thus the presence of y does not imply the prior occurrence of x. Contributory causes For some specific effect, in a singular case, a factor that is a contributory cause is one among several co-occurrent causes. It is implicit that all of them are contributory. For the specific effect, in general, there is no implication that a contributory cause is necessary, though it may be so. In general, a factor that is a contributory cause is not sufficient, because it is by definition accompanied by other causes, which would not count as causes if it were sufficient. For the specific effect, a factor that is on some occasions a contributory cause might on some other occasions be sufficient, but on those other occasions it would not be merely contributory.J. L. Mackie argues that usual talk of "cause" in fact refers to INUS conditions (insufficient but non-redundant parts of a condition which is itself unnecessary but sufficient for the occurrence of the effect). An example is a short circuit as a cause for a house burning down. Consider the collection of events: the short circuit, the proximity of flammable material, and the absence of firefighters. Together these are unnecessary but sufficient to the houses burning down (since many other collections of events certainly could have led to the house burning down, for example shooting the house with a flamethrower in the presence of oxygen and so forth). Within this collection, the short circuit is an insufficient (since the short circuit by itself would not have caused the fire) but non-redundant (because the fire would not have happened without it, everything else being equal) part of a condition which is itself unnecessary but sufficient for the occurrence of the effect. So, the short circuit is an INUS condition for the occurrence of the house burning down. Contrasted with conditionals Conditional statements are not statements of causality. An important distinction is that statements of causality require the antecedent to precede or coincide with the consequent in time, whereas conditional statements do not require this temporal order. Confusion commonly arises since many different statements in English may be presented using "If..., then..." form (and, arguably, because this form is far more commonly used to make a statement of causality). The two types of statements are distinct, however. For example, all of the following statements are true when interpreting "If..., then..." as the material conditional: If Barack Obama is president of the United States in 2011, then Germany is in Europe. If George Washington is president of the United States in 2011, then ⟨arbitrary statement⟩.The first is true since both the antecedent and the consequent are true. The second is true in sentential logic and indeterminate in natural language, regardless of the consequent statement that follows, because the antecedent is false. The ordinary indicative conditional has somewhat more structure than the material conditional. For instance, although the first is the closest, neither of the preceding two statements seems true as an ordinary indicative reading. But the sentence: If Shakespeare of Stratford-on-Avon did not write Macbeth, then someone else did.intuitively seems to be true, even though there is no straightforward causal relation in this hypothetical situation between Shakespeares not writing Macbeth and someone elses actually writing it. Another sort of conditional, the counterfactual conditional, has a stronger connection with causality, yet even counterfactual statements are not all examples of causality. Consider the following two statements: If A were a triangle, then A would have three sides. If switch S were thrown, then bulb B would light.In the first case, it would not be correct to say that As being a triangle caused it to have three sides, since the relationship between triangularity and three-sidedness is that of definition. The property of having three sides actually determines As state as a triangle. Nonetheless, even when interpreted counterfactually, the first statement is true. An early version of Aristotles "four cause" theory is described as recognizing "essential cause". In this version of the theory, that the closed polygon has three sides is said to be the "essential cause" of its being a triangle. This use of the word cause is of course now far obsolete. Nevertheless, it is within the scope of ordinary language to say that it is essential to a triangle that it has three sides. A full grasp of the concept of conditionals is important to understanding the literature on causality. In everyday language, loose conditional statements are often enough made, and need to be interpreted carefully. Questionable cause Fallacies of questionable cause, also known as causal fallacies, non-causa pro causa (Latin for "non-cause for cause"), or false cause, are informal fallacies where a cause is incorrectly identified. Theories Counterfactual theories Counterfactual theories define causation in terms of a counterfactual relation. These theories can often be seeing as "floating" their account of causality on top of an account of the logic of counterfactual conditionals. This approach can be traced back to David Humes definition of the causal relation as that "where, if the first object had not been, the second never had existed." More full-fledged analysis of causation in terms of counterfactual conditionals only came in the 20th century after development of the possible world semantics for the evaluation of counterfactual conditionals. In his 1973 paper "Causation," David Lewis proposed the following definition of the notion of causal dependence: An event E causally depends on C if, and only if, (i) if C had occurred, then E would have occurred, and (ii) if C had not occurred, then E would not have occurred.Causation is then defined as a chain of causal dependence. That is, C causes E if and only if there exists a sequence of events C, D1, D2,... Dk, E such that each event in the sequence depends on the previous. This chain may be called a mechanism. Note that the analysis does not purport to explain how we make causal judgements or how we reason about causation, but rather to give a metaphysical account of what it is for there to be a causal relation between some pair of events. If correct, the analysis has the power to explain certain features of causation. Knowing that causation is a matter of counterfactual dependence, we may reflect on the nature of counterfactual dependence to account for the nature of causation. For example, in his paper "Counterfactual Dependence and Times Arrow," Lewis sought to account for the time-directedness of counterfactual dependence in terms of the semantics of the counterfactual conditional. If correct, this theory can serve to explain a fundamental part of our experience, which is that we can only causally affect the future but not the past. Probabilistic causation Interpreting causation as a deterministic relation means that if A causes B, then A must always be followed by B. In this sense, war does not cause deaths, nor does smoking cause cancer or emphysema. As a result, many turn to a notion of probabilistic causation. Informally, A ("The person is a smoker") probabilistically causes B ("The person has now or will have cancer at some time in the future"), if the information that A occurred increases the likelihood of Bs occurrence. Formally, P{B\|A}≥ P{B} where P{B\|A} is the conditional probability that B will occur given the information that A occurred, and P{B} is the probability that B will occur having no knowledge whether A did or did not occur. This intuitive condition is not adequate as a definition for probabilistic causation because of its being too general and thus not meeting our intuitive notion of cause and effect. For example, if A denotes the event "The person is a smoker," B denotes the event "The person now has or will have cancer at some time in the future" and C denotes the event "The person now has or will have emphysema some time in the future," then the following three relationships hold: P{B\|A} ≥ P{B}, P{C\|A} ≥ P{C} and P{B\|C} ≥ P{B}. The last relationship states that knowing that the person has emphysema increases the likelihood that he will have cancer. The reason for this is that having the information that the person has emphysema increases the likelihood that the person is a smoker, thus indirectly increasing the likelihood that the person will have cancer. However, we would not want to conclude that having emphysema causes cancer. Thus, we need additional conditions such as temporal relationship of A to B and a rational explanation as to the mechanism of action. It is hard to quantify this last requirement and thus different authors prefer somewhat different definitions. Causal calculus When experimental interventions are infeasible or illegal, the derivation of a cause-and-effect relationship from observational studies must rest on some qualitative theoretical assumptions, for example, that symptoms do not cause diseases, usually expressed in the form of missing arrows in causal graphs such as Bayesian networks or path diagrams. The theory underlying these derivations relies on the distinction between conditional probabilities, as in P ( c a n c e r \| s m o k i n g ) {\displaystyle P(cancer\|smoking)} , and interventional probabilities, as in P ( c a n c e r \| d o ( s m o k i n g ) ) {\displaystyle P(cancer\|do(smoking))} . The former reads: "the probability of finding cancer in a person known to smoke, having started, unforced by the experimenter, to do so at an unspecified time in the past", while the latter reads: "the probability of finding cancer in a person forced by the experimenter to smoke at a specified time in the past". The former is a statistical notion that can be estimated by observation with negligible intervention by the experimenter, while the latter is a causal notion which is estimated in an experiment with an important controlled randomized intervention. It is specifically characteristic of quantal phenomena that observations defined by incompatible variables always involve important intervention by the experimenter, as described quantitatively by the observer effect. In classical thermodynamics, processes are initiated by interventions called thermodynamic operations. In other branches of science, for example astronomy, the experimenter can often observe with negligible intervention. The theory of "causal calculus" (also known as do-calculus, Judea Pearls Causal Calculus, Calculus of Actions) permits one to infer interventional probabilities from conditional probabilities in causal Bayesian networks with unmeasured variables. One very practical result of this theory is the characterization of confounding variables, namely, a sufficient set of variables that, if adjusted for, would yield the correct causal effect between variables of interest. It can be shown that a sufficient set for estimating the causal effect of X {\displaystyle X} on Y {\displaystyle Y} is any set of non-descendants of X {\displaystyle X} that d {\displaystyle d} -separate X {\displaystyle X} from Y {\displaystyle Y} after removing all arrows emanating from X {\displaystyle X} . This criterion, called "backdoor", provides a mathematical definition of "confounding" and helps researchers identify accessible sets of variables worthy of measurement. Structure learning While derivations in causal calculus rely on the structure of the causal graph, parts of the causal structure can, under certain assumptions, be learned from statistical data. The basic idea goes back to Sewall Wrights 1921 work on path analysis. A "recovery" algorithm was developed by Rebane and Pearl (1987) which rests on Wrights distinction between the three possible types of causal substructures allowed in a directed acyclic graph (DAG): X → Y → Z {\displaystyle X\rightarrow Y\rightarrow Z} X ← Y → Z {\displaystyle X\leftarrow Y\rightarrow Z} X → Y ← Z {\displaystyle X\rightarrow Y\leftarrow Z} Type 1 and type 2 represent the same statistical dependencies (i.e., X {\displaystyle X} and Z {\displaystyle Z} are independent given Y {\displaystyle Y} ) and are, therefore, indistinguishable within purely cross-sectional data. Type 3, however, can be uniquely identified, since X {\displaystyle X} and Z {\displaystyle Z} are marginally independent and all other pairs are dependent. Thus, while the skeletons (the graphs stripped of arrows) of these three triplets are identical, the directionality of the arrows is partially identifiable. The same distinction applies when X {\displaystyle X} and Z {\displaystyle Z} have common ancestors, except that one must first condition on those ancestors. Algorithms have been developed to systematically determine the skeleton of the underlying graph and, then, orient all arrows whose directionality is dictated by the conditional independencies observed.Alternative methods of structure learning search through the many possible causal structures among the variables, and remove ones which are strongly incompatible with the observed correlations. In general this leaves a set of possible causal relations, which should then be tested by analyzing time series data or, preferably, designing appropriately controlled experiments. In contrast with Bayesian Networks, path analysis (and its generalization, structural equation modeling), serve better to estimate a known causal effect or to test a causal model than to generate causal hypotheses. For nonexperimental data, causal direction can often be inferred if information about time is available. This is because (according to many, though not all, theories) causes must precede their effects temporally. This can be determined by statistical time series models, for instance, or with a statistical test based on the idea of Granger causality, or by direct experimental manipulation. The use of temporal data can permit statistical tests of a pre-existing theory of causal direction. For instance, our degree of confidence in the direction and nature of causality is much greater when supported by cross-correlations, ARIMA models, or cross-spectral analysis using vector time series data than by cross-sectional data. Derivation theories Nobel laureate Herbert A. Simon and philosopher Nicholas Rescher claim that the asymmetry of the causal relation is unrelated to the asymmetry of any mode of implication that contraposes. Rather, a causal relation is not a relation between values of variables, but a function of one variable (the cause) on to another (the effect). So, given a system of equations, and a set of variables appearing in these equations, we can introduce an asymmetric relation among individual equations and variables that corresponds perfectly to our commonsense notion of a causal ordering. The system of equations must have certain properties, most importantly, if some values are chosen arbitrarily, the remaining values will be determined uniquely through a path of serial discovery that is perfectly causal. They postulate the inherent serialization of such a system of equations may correctly capture causation in all empirical fields, including physics and economics. Manipulation theories Some theorists have equated causality with manipulability. Under these theories, x causes y only in the case that one can change x in order to change y. This coincides with commonsense notions of causations, since often we ask causal questions in order to change some feature of the world. For instance, we are interested in knowing the causes of crime so that we might find ways of reducing it. These theories have been criticized on two primary grounds. First, theorists complain that these accounts are circular. Attempting to reduce causal claims to manipulation requires that manipulation is more basic than causal interaction. But describing manipulations in non-causal terms has provided a substantial difficulty. The second criticism centers around concerns of anthropocentrism. It seems to many people that causality is some existing relationship in the world that we can harness for our desires. If causality is identified with our manipulation, then this intuition is lost. In this sense, it makes humans overly central to interactions in the world. Some attempts to defend manipulability theories are recent accounts that do not claim to reduce causality to manipulation. These accounts use manipulation as a sign or feature in causation without claiming that manipulation is more fundamental than causation. Process theories Some theorists are interested in distinguishing between causal processes and non-causal processes (Russell 1948; Salmon 1984). These theorists often want to distinguish between a process and a pseudo-process. As an example, a ball moving through the air (a process) is contrasted with the motion of a shadow (a pseudo-process). The former is causal in nature while the latter is not. Salmon (1984) claims that causal processes can be identified by their ability to transmit an alteration over space and time. An alteration of the ball (a mark by a pen, perhaps) is carried with it as the ball goes through the air. On the other hand, an alteration of the shadow (insofar as it is possible) will not be transmitted by the shadow as it moves along. These theorists claim that the important concept for understanding causality is not causal relationships or causal interactions, but rather identifying causal processes. The former notions can then be defined in terms of causal processes. A subgroup of the process theories is the mechanistic view on causality. It states that that causal relations supervene on mechanisms. While the notion of mechanism is understood differently, the definition put forward by the group of philosophers referred to as the New Mechanists dominate the literature. Fields Science For the scientific investigation of efficient causality, the cause and effect are each best conceived of as temporally transient processes. Within the conceptual frame of the scientific method, an investigator sets up several distinct and contrasting temporally transient material processes that have the structure of experiments, and records candidate material responses, normally intending to determine causality in the physical world. For instance, one may want to know whether a high intake of carrots causes humans to develop the bubonic plague. The quantity of carrot intake is a process that is varied from occasion to occasion. The occurrence or non-occurrence of subsequent bubonic plague is recorded. To establish causality, the experiment must fulfill certain criteria, only one example of which is mentioned here. For example, instances of the hypothesized cause must be set up to occur at a time when the hypothesized effect is relatively unlikely in the absence of the hypothesized cause; such unlikelihood is to be established by empirical evidence. A mere observation of a correlation is not nearly adequate to establish causality. In nearly all cases, establishment of causality relies on repetition of experiments and probabilistic reasoning. Hardly ever is causality established more firmly than as more or less probable. It is most convenient for establishment of causality if the contrasting material states of affairs are precisely matched, except for only one variable factor, perhaps measured by a real number. Physics One has to be careful in the use of the word cause in physics. Properly speaking, the hypothesized cause and the hypothesized effect are each temporally transient processes. For example, force is a useful concept for the explanation of acceleration, but force is not by itself a cause. More is needed. For example, a temporally transient process might be characterized by a definite change of force at a definite time. Such a process can be regarded as a cause. Causality is not inherently implied in equations of motion, but postulated as an additional constraint that needs to be satisfied (i.e. a cause always precedes its effect). This constraint has mathematical implications such as the Kramers-Kronig relations. Causality is one of the most fundamental and essential notions of physics. Causal efficacy cannot propagate faster than light. Otherwise, reference coordinate systems could be constructed (using the Lorentz transform of special relativity) in which an observer would see an effect precede its cause (i.e. the postulate of causality would be violated). Causal notions appear in the context of the flow of mass-energy. Any actual process has causal efficacy that can propagate no faster than light. In contrast, an abstraction has no causal efficacy. Its mathematical expression does not propagate in the ordinary sense of the word, though it may refer to virtual or nominal velocities with magnitudes greater than that of light. For example, wave packets are mathematical objects that have group velocity and phase velocity. The energy of a wave packet travels at the group velocity (under normal circumstances); since energy has causal efficacy, the group velocity cannot be faster than the speed of light. The phase of a wave packet travels at the phase velocity; since phase is not causal, the phase velocity of a wave packet can be faster than light.Causal notions are important in general relativity to the extent that the existence of an arrow of
Causality	time demands that the universes semi-Riemannian manifold be orientable, so that "future" and "past" are globally definable quantities. Engineering A causal system is a system with output and internal states that depends only on the current and previous input values. A system that has some dependence on input values from the future (in addition to possible past or current input values) is termed an acausal system, and a system that depends solely on future input values is an anticausal system. Acausal filters, for example, can only exist as postprocessing filters, because these filters can extract future values from a memory buffer or a file. Biology, medicine and epidemiology Austin Bradford Hill built upon the work of Hume and Popper and suggested in his paper "The Environment and Disease: Association or Causation?" that aspects of an association such as strength, consistency, specificity, and temporality be considered in attempting to distinguish causal from noncausal associations in the epidemiological situation. (See Bradford-Hill criteria.) He did not note however, that temporality is the only necessary criterion among those aspects. Directed acyclic graphs (DAGs) are increasingly used in epidemiology to help enlighten causal thinking. Psychology Psychologists take an empirical approach to causality, investigating how people and non-human animals detect or infer causation from sensory information, prior experience and innate knowledge. AttributionAttribution theory is the theory concerning how people explain individual occurrences of causation. Attribution can be external (assigning causality to an outside agent or force—claiming that some outside thing motivated the event) or internal (assigning causality to factors within the person—taking personal responsibility or accountability for ones actions and claiming that the person was directly responsible for the event). Taking causation one step further, the type of attribution a person provides influences their future behavior. The intention behind the cause or the effect can be covered by the subject of action. See also accident; blame; intent; and responsibility. Causal powersWhereas David Hume argued that causes are inferred from non-causal observations, Immanuel Kant claimed that people have innate assumptions about causes. Within psychology, Patricia Cheng attempted to reconcile the Humean and Kantian views. According to her power PC theory, people filter observations of events through an intuition that causes have the power to generate (or prevent) their effects, thereby inferring specific cause-effect relations. Causation and salienceOur view of causation depends on what we consider to be the relevant events. Another way to view the statement, "Lightning causes thunder" is to see both lightning and thunder as two perceptions of the same event, viz., an electric discharge that we perceive first visually and then aurally. Naming and causalityDavid Sobel and Alison Gopnik from the Psychology Department of UC Berkeley designed a device known as the blicket detector which would turn on when an object was placed on it. Their research suggests that "even young children will easily and swiftly learn about a new causal power of an object and spontaneously use that information in classifying and naming the object." Perception of launching eventsSome researchers such as Anjan Chatterjee at the University of Pennsylvania and Jonathan Fugelsang at the University of Waterloo are using neuroscience techniques to investigate the neural and psychological underpinnings of causal launching events in which one object causes another object to move. Both temporal and spatial factors can be manipulated.See Causal Reasoning (Psychology) for more information. Statistics and economics Statistics and economics usually employ pre-existing data or experimental data to infer causality by regression methods. The body of statistical techniques involves substantial use of regression analysis. Typically a linear relationship such as y i = a 0 + a 1 x 1 , i + a 2 x 2 , i + ⋯ + a k x k , i + e i {\displaystyle y_{i}=a_{0}+a_{1}x_{1,i}+a_{2}x_{2,i}+\dots +a_{k}x_{k,i}+e_{i}} is postulated, in which y i {\displaystyle y_{i}} is the ith observation of the dependent variable (hypothesized to be the caused variable), x j , i {\displaystyle x_{j,i}} for j=1,...,k is the ith observation on the jth independent variable (hypothesized to be a causative variable), and e i {\displaystyle e_{i}} is the error term for the ith observation (containing the combined effects of all other causative variables, which must be uncorrelated with the included independent variables). If there is reason to believe that none of the x j {\displaystyle x_{j}} s is caused by y, then estimates of the coefficients a j {\displaystyle a_{j}} are obtained. If the null hypothesis that a j = 0 {\displaystyle a_{j}=0} is rejected, then the alternative hypothesis that a j ≠ 0 {\displaystyle a_{j}\neq 0} and equivalently that x j {\displaystyle x_{j}} causes y cannot be rejected. On the other hand, if the null hypothesis that a j = 0 {\displaystyle a_{j}=0} cannot be rejected, then equivalently the hypothesis of no causal effect of x j {\displaystyle x_{j}} on y cannot be rejected. Here the notion of causality is one of contributory causality as discussed above: If the true value a j ≠ 0 {\displaystyle a_{j}\neq 0} , then a change in x j {\displaystyle x_{j}} will result in a change in y unless some other causative variable(s), either included in the regression or implicit in the error term, change in such a way as to exactly offset its effect; thus a change in x j {\displaystyle x_{j}} is not sufficient to change y. Likewise, a change in x j {\displaystyle x_{j}} is not necessary to change y, because a change in y could be caused by something implicit in the error term (or by some other causative explanatory variable included in the model). The above way of testing for causality requires belief that there is no reverse causation, in which y would cause x j {\displaystyle x_{j}} . This belief can be established in one of several ways. First, the variable x j {\displaystyle x_{j}} may be a non-economic variable: for example, if rainfall amount x j {\displaystyle x_{j}} is hypothesized to affect the futures price y of some agricultural commodity, it is impossible that in fact the futures price affects rainfall amount (provided that cloud seeding is never attempted). Second, the instrumental variables technique may be employed to remove any reverse causation by introducing a role for other variables (instruments) that are known to be unaffected by the dependent variable. Third, the principle that effects cannot precede causes can be invoked, by including on the right side of the regression only variables that precede in time the dependent variable; this principle is invoked, for example, in testing for Granger causality and in its multivariate analog, vector autoregression, both of which control for lagged values of the dependent variable while testing for causal effects of lagged independent variables. Regression analysis controls for other relevant variables by including them as regressors (explanatory variables). This helps to avoid false inferences of causality due to the presence of a third, underlying, variable that influences both the potentially causative variable and the potentially caused variable: its effect on the potentially caused variable is captured by directly including it in the regression, so that effect will not be picked up as an indirect effect through the potentially causative variable of interest. Given the above procedures, coincidental (as opposed to causal) correlation can be probabilistically rejected if data samples are large and if regression results pass cross-validation tests showing that the correlations hold even for data that were not used in the regression. Asserting with certitude that a common-cause is absent and the regression represents the true causal structure is in principle impossible.Apart from constructing statistical models of observational and experimental data, economists use axiomatic (mathematical) models to infer and represent causal mechanisms. Highly abstract theoretical models that isolate and idealize one mechanism dominate microeconomics. In macroeconomics, economists use broad mathematical models that are calibrated on historical data. A subgroup of calibrated models, dynamic stochastic general equilibrium (DSGE) models are employed to represent (in a simplified way) the whole economy and simulate changes in fiscal and monetary policy. Management For quality control in manufacturing in the 1960s, Kaoru Ishikawa developed a cause and effect diagram, known as an Ishikawa diagram or fishbone diagram. The diagram categorizes causes, such as into the six main categories shown here. These categories are then sub-divided. Ishikawas method identifies "causes" in brainstorming sessions conducted among various groups involved in the manufacturing process. These groups can then be labeled as categories in the diagrams. The use of these diagrams has now spread beyond quality control, and they are used in other areas of management and in design and engineering. Ishikawa diagrams have been criticized for failing to make the distinction between necessary conditions and sufficient conditions. It seems that Ishikawa was not even aware of this distinction. Humanities History In the discussion of history, events are sometimes considered as if in some way being agents that can then bring about other historical events. Thus, the combination of poor harvests, the hardships of the peasants, high taxes, lack of representation of the people, and kingly ineptitude are among the causes of the French Revolution. This is a somewhat Platonic and Hegelian view that reifies causes as ontological entities. In Aristotelian terminology, this use approximates to the case of the efficient cause. Some philosophers of history such as Arthur Danto have claimed that "explanations in history and elsewhere" describe "not simply an event—something that happens—but a change". Like many practicing historians, they treat causes as intersecting actions and sets of actions which bring about "larger changes", in Dantos words: to decide "what are the elements which persist through a change" is "rather simple" when treating an individuals "shift in attitude", but "it is considerably more complex and metaphysically challenging when we are interested in such a change as, say, the break-up of feudalism or the emergence of nationalism".Much of the historical debate about causes has focused on the relationship between communicative and other actions, between singular and repeated ones, and between actions, structures of action or group and institutional contexts and wider sets of conditions. John Gaddis has distinguished between exceptional and general causes (following Marc Bloch) and between "routine" and "distinctive links" in causal relationships: "in accounting for what happened at Hiroshima on August 6, 1945, we attach greater importance to the fact that President Truman ordered the dropping of an atomic bomb than to the decision of the Army Air Force to carry out his orders." He has also pointed to the difference between immediate, intermediate and distant causes. For his part, Christopher Lloyd puts forward four "general concepts of causation" used in history: the "metaphysical idealist concept, which asserts that the phenomena of the universe are products of or emanations from an omnipotent being or such final cause"; "the empiricist (or Humean) regularity concept, which is based on the idea of causation being a matter of constant conjunctions of events"; "the functional/teleological/consequential concept", which is "goal-directed, so that goals are causes"; and the "realist, structurist and dispositional approach, which sees relational structures and internal dispositions as the causes of phenomena". Law According to law and jurisprudence, legal cause must be demonstrated to hold a defendant liable for a crime or a tort (i.e. a civil wrong such as negligence or trespass). It must be proven that causality, or a "sufficient causal link" relates the defendants actions to the criminal event or damage in question. Causation is also an essential legal element that must be proven to qualify for remedy measures under international trade law. History Hindu philosophy Vedic period (c. 1750–500 BCE) literature has karmas Eastern origins. Karma is the belief held by Sanatana Dharma and major religions that a persons actions cause certain effects in the current life and/or in future life, positively or negatively. The various philosophical schools (darshanas) provide different accounts of the subject. The doctrine of satkaryavada affirms that the effect inheres in the cause in some way. The effect is thus either a real or apparent modification of the cause. The doctrine of asatkaryavada affirms that the effect does not inhere in the cause, but is a new arising. See Nyaya for some details of the theory of causation in the Nyaya school. In Brahma Samhita, Brahma describes Krishna as the prime cause of all causes.Bhagavad-gītā 18.14 identifies five causes for any action (knowing which it can be perfected): the body, the individual soul, the senses, the efforts and the supersoul. According to Monier-Williams, in the Nyāya causation theory from Sutra I.2.I,2 in the Vaisheshika philosophy, from causal non-existence is effectual non-existence; but, not effectual non-existence from causal non-existence. A cause precedes an effect. With a threads and cloth metaphors, three causes are: Co-inherence cause: resulting from substantial contact, substantial causes, threads are substantial to cloth, corresponding to Aristotles material cause. Non-substantial cause: Methods putting threads into cloth, corresponding to Aristotles formal cause. Instrumental cause: Tools to make the cloth, corresponding to Aristotles efficient cause.Monier-Williams also proposed that Aristotles and the Nyayas causality are considered conditional aggregates necessary to mans productive work. Buddhist philosophy Karma is the causality principle focusing on 1) causes, 2) actions, 3) effects, where it is the minds phenomena that guide the actions that the actor performs. Buddhism trains the actors actions for continued and uncontrived virtuous outcomes aimed at reducing suffering. This follows the Subject–verb–object structure.The general or universal definition of pratityasamutpada (or "dependent origination" or "dependent arising" or "interdependent co-arising") is that everything arises in dependence upon multiple causes and conditions; nothing exists as a singular, independent entity. A traditional example in Buddhist texts is of three sticks standing upright and leaning against each other and supporting each other. If one stick is taken away, the other two will fall to the ground.Causality in the Chittamatrin Buddhist school approach, Asangas (c. 400 CE) mind-only Buddhist school, asserts that objects cause consciousness in the minds image. Because causes precede effects, which must be different entities, then subject and object are different. For this school, there are no objects which are entities external to a perceiving consciousness. The Chittamatrin and the Yogachara Svatantrika schools accept that there are no objects external to the observers causality. This largely follows the Nikayas approach.The Vaibhashika (c. 500 CE) is an early Buddhist school which favors direct object contact and accepts simultaneous cause and effects. This is based in the consciousness example which says, intentions and feelings are mutually accompanying mental factors that support each other like poles in tripod. In contrast, simultaneous cause and effect rejectors say that if the effect already exists, then it cannot effect the same way again. How past, present and future are accepted is a basis for various Buddhist schools causality viewpoints.All the classic Buddhist schools teach karma. "The law of karma is a special instance of the law of cause and effect, according to which all our actions of body, speech, and mind are causes and all our experiences are their effects." Western philosophy Aristotelian Aristotle identified four kinds of answer or explanatory mode to various "Why?" questions. He thought that, for any given topic, all four kinds of explanatory mode were important, each in its own right. As a result of traditional specialized philosophical peculiarities of language, with translations between ancient Greek, Latin, and English, the word cause is nowadays in specialized philosophical writings used to label Aristotles four kinds. In ordinary language, the word cause has a variety of meanings, the most common of which refers to efficient causation, which is the topic of the present article. Material cause, the material whence a thing has come or that which persists while it changes, as for example, ones mother or the bronze of a statue (see also substance theory). Formal cause, whereby a things dynamic form or static shape determines the things properties and function, as a human differs from a statue of a human or as a statue differs from a lump of bronze. Efficient cause, which imparts the first relevant movement, as a human lifts a rock or raises a statue. This is the main topic of the present article. Final cause, the criterion of completion, or the end; it may refer to an action or to an inanimate process. Examples: Socrates takes a walk after dinner for the sake of his health; earth falls to the lowest level because that is its nature.Of Aristotles four kinds or explanatory modes, only one, the efficient cause is a cause as defined in the leading paragraph of this present article. The other three explanatory modes might be rendered material composition, structure and dynamics, and, again, criterion of completion. The word that Aristotle used was αἰτία. For the present purpose, that Greek word would be better translated as "explanation" than as "cause" as those words are most often used in current English. Another translation of Aristotle is that he meant "the four Becauses" as four kinds of answer to "why" questions.Aristotle assumed efficient causality as referring to a basic fact of experience, not explicable by, or reducible to, anything more fundamental or basic. In some works of Aristotle, the four causes are listed as (1) the essential cause, (2) the logical ground, (3) the moving cause, and (4) the final cause. In this listing, a statement of essential cause is a demonstration that an indicated object conforms to a definition of the word that refers to it. A statement of logical ground is an argument as to why an object statement is true. These are further examples of the idea that a "cause" in general in the context of Aristotles usage is an "explanation".The word "efficient" used here can also be translated from Aristotle as "moving" or "initiating".Efficient causation was connected with Aristotelian physics, which recognized the four elements (earth, air, fire, water), and added the fifth element (aether). Water and earth by their intrinsic property gravitas or heaviness intrinsically fall toward, whereas air and fire by their intrinsic property levitas or lightness intrinsically rise away from, Earths center—the motionless center of the universe—in a straight line while accelerating during the substances approach to its natural place. As air remained on Earth, however, and did not escape Earth while eventually achieving infinite speed—an absurdity—Aristotle inferred that the universe is finite in size and contains an invisible substance that held planet Earth and its atmosphere, the sublunary sphere, centered in the universe. And since celestial bodies exhibit perpetual, unaccelerated motion orbiting planet Earth in unchanging relations, Aristotle inferred that the fifth element, aither, that fills space and composes celestial bodies intrinsically moves in perpetual circles, the only constant motion between two points. (An object traveling a straight line from point A to B and back must stop at either point before returning to the other.) Left to itself, a thing exhibits natural motion, but can—according to Aristotelian metaphysics—exhibit enforced motion imparted by an efficient cause. The form of plants endows plants with the processes nutrition and reproduction, the form of animals adds locomotion, and the form of humankind adds reason atop these. A rock normally exhibits natural motion—explained by the rocks material cause of being composed of the element earth—but a living thing can lift the rock, an enforced motion diverting the rock from its natural place and natural motion. As a further kind of explanation, Aristotle identified the final cause, specifying a purpose or criterion of completion in light of which something should be understood. Aristotle himself explained, Cause means (a) in one sense, that as the result of whose presence something comes into being—e.g., the bronze of a statue and the silver of a cup, and the classes which contain these [i.e., the material cause]; (b) in another sense, the form or pattern; that is, the essential formula and the classes which contain it—e.g. the ratio 2:1 and number in general is the cause of the octave—and the parts of the formula [i.e., the formal cause]. (c) The source of the first beginning of change or rest; e.g. the man who plans is a cause, and the father is the cause of the child, and in general that which produces is the cause of that which is produced, and that which changes of that which is changed [i.e., the efficient cause]. (d) The same as "end"; i.e. the final cause; e.g., as the "end" of walking is health. For why does a man walk? "To be healthy", we say, and by saying this we consider that we have supplied the cause [the final cause]. (e) All those means towards the end which arise at the instigation of something else, as, e.g., fat-reducing, purging, drugs, and instruments are causes of health; for they all have the end as their object, although they differ from each other as being some instruments, others actions [i.e., necessary conditions]. Aristotle further discerned two modes of causation: proper (prior) causation and accidental (chance) causation. All causes, proper and accidental, can be spoken as potential or as actual, particular or generic. The same language refers to the effects of causes, so that generic effects are assigned to generic causes, particular effects to particular causes, and actual effects to operating causes. Averting infinite regress, Aristotle inferred the first mover—an unmoved mover. The first movers motion, too, must have been caused, but, being an unmoved mover, must have moved only toward a particular goal or desire. Pyrrhonism While the plausibility of causality was accepted in Pyrrhonism, it was equally accepted that it was plausible that nothing was the cause of anything. Middle Ages In line with Aristotelian cosmology, Thomas Aquinas posed a hierarchy prioritizing Aristotles four causes: "final > efficient > material > formal". Aquinas sought to identify the first efficient cause—now simply first cause—as everyone would agree, said Aquinas, to call it God. Later in the Middle Ages, many scholars conceded that the first cause was God, but explained that many earthly events occur within Gods design or plan, and thereby scholars sought freedom to investigate the numerous secondary causes. After the Middle Ages For Aristotelian philosophy before Aquinas, the word cause had a broad meaning. It meant answer to a why question or explanation, and Aristotelian scholars recognized four kinds of such answers. With the end of the Middle Ages, in many philosophical usages, the meaning of the word cause narrowed. It often lost that broad meaning, and was restricted to just one of the four kinds. For authors such as Niccolò Machiavelli, in the field of political thinking, and Francis Bacon, concerning science more generally, Aristotles moving cause was the focus of their interest. A widely used modern definition of causality in this newly narrowed sense was assumed by David Hume. He undertook an epistemological and metaphysical investigation of the notion of moving cause. He denied that we can ever perceive cause and effect, except by developing a habit or custom of mind where we come to associate two types of object or event, always contiguous and occurring one after the other. In Part III, section XV of his book A Treatise of Human Nature, Hume expanded this to a list of eight ways of judging whether two things might be cause and effect. The first three: "The cause and effect must be contiguous in space and time." "The cause must be prior to the effect." "There must be a constant union betwixt the cause and effect. Tis chiefly this quality, that constitutes the relation." And then additionally there are three connected criteria which come from our experience and which are "the source of most of our philosophical reasonings": And then two more: In 1949, physicist Max Born distinguished determination from causality. For him, determination meant that actual events are so linked by laws of nature that certainly reliable predictions and retrodictions can be made from sufficient present data about them. He describes two kinds of causation: nomic or generic causation and singular causation. Nomic causality means that cause and effect are linked by more or less certain or probabilistic general laws covering many possible or potential instances; this can be recognized as a probabilized version of Humes criterion 3. An occasion of singular causation is a particular occurrence of a definite complex of events that are physically linked by antecedence and contiguity, which may be recognized as criteria 1 and 2. See also References Further reading Spirtes, Peter, Clark Glymour and Richard Scheines Causation, Prediction, and Search, MIT Press, ISBN 0-262-19440-6 University of California journal articles, including Judea Pearls articles between 1984 and 1998 Search Results - Technical Reports. Miguel Espinoza, Théorie du déterminisme causal, LHarmattan, Paris, 2006. ISBN 2-296-01198-5. External links Causality at PhilPapers Causality at the Indiana Philosophy Ontology Project Causation – Internet Encyclopedia of Philosophy Metaphysics of Science – Internet Encyclopedia of Philosophy Causal Processes at the Stanford Encyclopedia of Philosophy The Art and Science of Cause and Effect – A slide show and tutorial lecture by Judea Pearl Donald Davidson: Causal Explanation of Action – The Internet Encyclopedia of Philosophy Causal inference in statistics: An overview – By Judea Pearl (September 2009) An R implementation of causal calculus TimeSleuth - A tool for discovering causality
Ischemic cardiomyopathy	Ischemic cardiomyopathy is a type of cardiomyopathy caused by a narrowing of the coronary arteries which supply blood to the heart. Typically, patients with ischemic cardiomyopathy have a history of acute myocardial infarction, however, it may occur in patients with coronary artery disease, but without a past history of acute myocardial infarction. This cardiomyopathy is one of the leading causes of sudden cardiac death. The adjective ischemic means characteristic of, or accompanied by, ischemia — local anemia due to mechanical obstruction of the blood supply. Signs and symptoms Signs and symptoms of ischemic cardiomyopathy include sudden fatigue, shortness of breath, dizziness, and palpitations. Cause Ischemic cardiomyopathy is the cause of more than 60% of all cases of systolic congestive heart failure in most countries of the world. A chest radiograph that demonstrates coronary artery calcification is a probable indication of ischemic cardiomyopathy. The following are causes of ischemic cardiomyopathy: Diabetes Atherosclerosis Vasospasm Inflammation of arteries Pathophysiology Ischemic cardiomyopathy is caused by too little blood flow and hence oxygen reaching the muscular layer of the heart due to a narrowing of coronary arteries in turn causing cell death. This can cause different levels of tissue injury and affect large and intermediate arteries alike. Diagnosis Ischemic cardiomyopathy can be diagnosed via magnetic resonance imaging (MRI) protocol, imaging both global and regional function. Also the Look-Locker technique is used to identify diffuse fibrosis; it is therefore important to be able to determine the extent of the ischemic scar. Some argue that only left main- or proximal-left anterior descending artery disease is relevant to the diagnostic criteria for ischemic cardiomyopathy. Myocardial imaging usually demonstrates left ventricular dilation, severe ventricular dysfunction, and multiple infarctions. Signs include congestive heart failure, angina edema, weight gain and fainting, among others. Management Restoring adequate blood flow to the heart muscle in people with heart failure and significant coronary artery disease is strongly associated with improved survival, some research showing up to 75% survival rates over 5 years. A stem cell study indicated that using autologous cardiac stem cells as a regenerative approach for the human heart (after a heart attack) has great potential.American Heart Association practice guidelines recommend implantable cardioverter-defibrillator (ICD) use in those with ischemic cardiomyopathy (40 days post-MI) that are (NYHA) New York Heart Association functional class I. A LVEF measurement (simply called LVEF alone among cardiologists) of greater than (>) 30% is often used to differentiate primary from ischemic cardiomyopathy, and as a prognostic indicator.A 2004 study showed the patients in that study who underwent ventricular restoration as well as a coronary artery bypass achieved greater postoperative LVEF than with the latter surgery alone. Severe cases are treated with heart transplantation. Prognosis One of the most important features differentiating ischemic cardiomyopathy from the other forms of cardiomyopathy is the shortened, or worsened all-cause mortality in patients with ischemic cardiomyopathy. According to several studies, coronary artery bypass graft surgery has a survival advantage over medical therapy (for ischemic cardiomyopathy) across varied follow-ups. References Further reading Likoff, Jessup Mariell, Chandler Sheryl L., Kay Harold R. (1987). "Clinical determinants of mortality in chronic congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy". The American Journal of Cardiology. 59 (6): 634–638. doi:10.1016/0002-9149(87)91183-0. PMID 3825904.{{cite journal}}: CS1 maint: multiple names: authors list (link) Carmeliet Peter; et al. (1999). "Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188". Nature Medicine. 5 (5): 495–502. doi:10.1038/8379. PMID 10229225. S2CID 7536458. Menasché Philippe; et al. (2008). "The myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial first randomized Placebo-controlled study of myoblast transplantation". Circulation. 117 (9): 1189–1200. doi:10.1161/circulationaha.107.734103. PMID 18285565. Beltrami Carlo Alberto; et al. (1994). "Structural basis of end-stage failure in ischemic cardiomyopathy in humans". Circulation. 89 (1): 151–163. doi:10.1161/01.cir.89.1.151. PMID 8281642. == External links ==
Tornado	A tornado is a violently rotating column of air that is in contact with both the surface of the Earth and a cumulonimbus cloud or, in rare cases, the base of a cumulus cloud. It is often referred to as a twister, whirlwind or cyclone, although the word cyclone is used in meteorology to name a weather system with a low-pressure area in the center around which, from an observer looking down toward the surface of the Earth, winds blow counterclockwise in the Northern Hemisphere and clockwise in the Southern. Tornadoes come in many shapes and sizes, and they are often visible in the form of a condensation funnel originating from the base of a cumulonimbus cloud, with a cloud of rotating debris and dust beneath it. Most tornadoes have wind speeds less than 180 km/h (110 mph), are about 80 m (250 feet) across, and travel several kilometers (a few miles) before dissipating. The most extreme tornadoes can attain wind speeds of more than 480 km/h (300 mph), are more than 3 km (2 miles) in diameter, and stay on the ground for more than 100 km (60 miles).Various types of tornadoes include the multiple vortex tornado, landspout, and waterspout. Waterspouts are characterized by a spiraling funnel-shaped wind current, connecting to a large cumulus or cumulonimbus cloud. They are generally classified as non-supercellular tornadoes that develop over bodies of water, but there is disagreement over whether to classify them as true tornadoes. These spiraling columns of air frequently develop in tropical areas close to the equator and are less common at high latitudes. Other tornado-like phenomena that exist in nature include the gustnado, dust devil, fire whirl, and steam devil. Tornadoes occur most frequently in North America (particularly in central and southeastern regions of the United States colloquially known as Tornado Alley; the US and Canada have by far the most tornadoes of any countries in the world). Tornados also occur in South Africa, much of Europe (except Spain, most of the Alps, Balkans, and northern Scandinavia), western and eastern Australia, New Zealand, Bangladesh and adjacent eastern India, Japan, Philippines, and southeastern South America (Uruguay and Argentina). Tornadoes can be detected before or as they occur through the use of pulse-Doppler radar by recognizing patterns in velocity and reflectivity data, such as hook echoes or debris balls, as well as through the efforts of storm spotters. Tornado rating scales There are several scales for rating the strength of tornadoes. The Fujita scale rates tornadoes by damage caused and has been replaced in some countries by the updated Enhanced Fujita Scale. An F0 or EF0 tornado, the weakest category, damages trees, but not substantial structures. An F5 or EF5 tornado, the strongest category, rips buildings off their foundations and can deform large skyscrapers. The similar TORRO scale ranges from T0 for extremely weak tornadoes to T11 for the most powerful known tornadoes. Doppler radar data, photogrammetry, and ground swirl patterns (trochoidal marks) may also be analyzed to determine intensity and assign a rating. Etymology The word tornado comes from the Spanish word tornado (past participle of to turn, or to have turned, which comes from the Latin tonare to thunder. Tornadoes opposite phenomena are the widespread, straight-line derechoes (, from Spanish: derecho [deˈɾetʃo], straight). A tornado is also commonly referred to as a "twister" or the old-fashioned colloquial term cyclone. Definitions A tornado is a violently rotating column of air, in contact with the ground, either pendant from a cumuliform cloud or underneath a cumuliform cloud, and often (but not always) visible as a funnel cloud. For a vortex to be classified as a tornado, it must be in contact with both the ground and the cloud base. The term is not precisely defined; for example, there is disagreement as to whether separate touchdowns of the same funnel constitute separate tornadoes. Tornado refers to the vortex of wind, not the condensation cloud. Funnel cloud A tornado is not necessarily visible; however, the intense low pressure caused by the high wind speeds (as described by Bernoullis principle) and rapid rotation (due to cyclostrophic balance) usually cause water vapor in the air to condense into cloud droplets due to adiabatic cooling. This results in the formation of a visible funnel cloud or condensation funnel.There is some disagreement over the definition of a funnel cloud and a condensation funnel. According to the Glossary of Meteorology, a funnel cloud is any rotating cloud pendant from a cumulus or cumulonimbus, and thus most tornadoes are included under this definition. Among many meteorologists, the funnel cloud term is strictly defined as a rotating cloud which is not associated with strong winds at the surface, and condensation funnel is a broad term for any rotating cloud below a cumuliform cloud.Tornadoes often begin as funnel clouds with no associated strong winds at the surface, and not all funnel clouds evolve into tornadoes. Most tornadoes produce strong winds at the surface while the visible funnel is still above the ground, so it is difficult to discern the difference between a funnel cloud and a tornado from a distance. Outbreaks and families Occasionally, a single storm will produce more than one tornado, either simultaneously or in succession. Multiple tornadoes produced by the same storm cell are referred to as a "tornado family". Several tornadoes are sometimes spawned from the same large-scale storm system. If there is no break in activity, this is considered a tornado outbreak (although the term "tornado outbreak" has various definitions). A period of several successive days with tornado outbreaks in the same general area (spawned by multiple weather systems) is a tornado outbreak sequence, occasionally called an extended tornado outbreak. Characteristics Size and shape Most tornadoes take on the appearance of a narrow funnel, a few hundred meters (yards) across, with a small cloud of debris near the ground. Tornadoes may be obscured completely by rain or dust. These tornadoes are especially dangerous, as even experienced meteorologists might not see them.Small, relatively weak landspouts may be visible only as a small swirl of dust on the ground. Although the condensation funnel may not extend all the way to the ground, if associated surface winds are greater than 64 km/h (40 mph), the circulation is considered a tornado. A tornado with a nearly cylindrical profile and relatively low height is sometimes referred to as a "stovepipe" tornado. Large tornadoes which appear at least as wide as their cloud-to-ground height can look like large wedges stuck into the ground, and so are known as "wedge tornadoes" or "wedges". The "stovepipe" classification is also used for this type of tornado if it otherwise fits that profile. A wedge can be so wide that it appears to be a block of dark clouds, wider than the distance from the cloud base to the ground. Even experienced storm observers may not be able to tell the difference between a low-hanging cloud and a wedge tornado from a distance. Many, but not all major tornadoes are wedges. Tornadoes in the dissipating stage can resemble narrow tubes or ropes, and often curl or twist into complex shapes. These tornadoes are said to be "roping out", or becoming a "rope tornado". When they rope out, the length of their funnel increases, which forces the winds within the funnel to weaken due to conservation of angular momentum. Multiple-vortex tornadoes can appear as a family of swirls circling a common center, or they may be completely obscured by condensation, dust, and debris, appearing to be a single funnel.In the United States, tornadoes are around 500 feet (150 m) across on average and travel on the ground for 5 miles (8.0 km). However, there is a wide range of tornado sizes. Weak tornadoes, or strong yet dissipating tornadoes, can be exceedingly narrow, sometimes only a few feet or couple meters across. One tornado was reported to have a damage path only 7 feet (2.1 m) long. On the other end of the spectrum, wedge tornadoes can have a damage path a mile (1.6 km) wide or more. A tornado that affected Hallam, Nebraska on May 22, 2004, was up to 2.5 miles (4.0 km) wide at the ground, and a tornado in El Reno, Oklahoma on May 31, 2013, was approximately 2.6 miles (4.2 km) wide, the widest on record.In terms of path length, the Tri-State Tornado, which affected parts of Missouri, Illinois, and Indiana on March 18, 1925, was on the ground continuously for 219 miles (352 km). Many tornadoes which appear to have path lengths of 100 miles (160 km) or longer are composed of a family of tornadoes which have formed in quick succession; however, there is no substantial evidence that this occurred in the case of the Tri-State Tornado. In fact, modern reanalysis of the path suggests that the tornado may have begun 15 miles (24 km) further west than previously thought. Appearance Tornadoes can have a wide range of colors, depending on the environment in which they form. Those that form in dry environments can be nearly invisible, marked only by swirling debris at the base of the funnel. Condensation funnels that pick up little or no debris can be gray to white. While traveling over a body of water (as a waterspout), tornadoes can turn white or even blue. Slow-moving funnels, which ingest a considerable amount of debris and dirt, are usually darker, taking on the color of debris. Tornadoes in the Great Plains can turn red because of the reddish tint of the soil, and tornadoes in mountainous areas can travel over snow-covered ground, turning white. Lighting conditions are a major factor in the appearance of a tornado. A tornado which is "back-lit" (viewed with the sun behind it) appears very dark. The same tornado, viewed with the sun at the observers back, may appear gray or brilliant white. Tornadoes which occur near the time of sunset can be many different colors, appearing in hues of yellow, orange, and pink.Dust kicked up by the winds of the parent thunderstorm, heavy rain and hail, and the darkness of night are all factors that can reduce the visibility of tornadoes. Tornadoes occurring in these conditions are especially dangerous, since only weather radar observations, or possibly the sound of an approaching tornado, serve as any warning to those in the storms path. Most significant tornadoes form under the storms updraft base, which is rain-free, making them visible. Also, most tornadoes occur in the late afternoon, when the bright sun can penetrate even the thickest clouds.There is mounting evidence, including Doppler on Wheels mobile radar images and eyewitness accounts, that most tornadoes have a clear, calm center with extremely low pressure, akin to the eye of tropical cyclones. Lightning is said to be the source of illumination for those who claim to have seen the interior of a tornado. Rotation Tornadoes normally rotate cyclonically (when viewed from above, this is counterclockwise in the northern hemisphere and clockwise in the southern). While large-scale storms always rotate cyclonically due to the Coriolis effect, thunderstorms and tornadoes are so small that the direct influence of the Coriolis effect is unimportant, as indicated by their large Rossby numbers. Supercells and tornadoes rotate cyclonically in numerical simulations even when the Coriolis effect is neglected. Low-level mesocyclones and tornadoes owe their rotation to complex processes within the supercell and ambient environment.Approximately 1 percent of tornadoes rotate in an anticyclonic direction in the northern hemisphere. Typically, systems as weak as landspouts and gustnadoes can rotate anticyclonically, and usually only those which form on the anticyclonic shear side of the descending rear flank downdraft (RFD) in a cyclonic supercell. On rare occasions, anticyclonic tornadoes form in association with the mesoanticyclone of an anticyclonic supercell, in the same manner as the typical cyclonic tornado, or as a companion tornado either as a satellite tornado or associated with anticyclonic eddies within a supercell. Sound and seismology Tornadoes emit widely on the acoustics spectrum and the sounds are caused by multiple mechanisms. Various sounds of tornadoes have been reported, mostly related to familiar sounds for the witness and generally some variation of a whooshing roar. Popularly reported sounds include a freight train, rushing rapids or waterfall, a nearby jet engine, or combinations of these. Many tornadoes are not audible from much distance; the nature of and the propagation distance of the audible sound depends on atmospheric conditions and topography.The winds of the tornado vortex and of constituent turbulent eddies, as well as airflow interaction with the surface and debris, contribute to the sounds. Funnel clouds also produce sounds. Funnel clouds and small tornadoes are reported as whistling, whining, humming, or the buzzing of innumerable bees or electricity, or more or less harmonic, whereas many tornadoes are reported as a continuous, deep rumbling, or an irregular sound of "noise".Since many tornadoes are audible only when very near, sound is not to be thought of as a reliable warning signal for a tornado. Tornadoes are also not the only source of such sounds in severe thunderstorms; any strong, damaging wind, a severe hail volley, or continuous thunder in a thunderstorm may produce a roaring sound.Tornadoes also produce identifiable inaudible infrasonic signatures.Unlike audible signatures, tornadic signatures have been isolated; due to the long-distance propagation of low-frequency sound, efforts are ongoing to develop tornado prediction and detection devices with additional value in understanding tornado morphology, dynamics, and creation. Tornadoes also produce a detectable seismic signature, and research continues on isolating it and understanding the process. Electromagnetic, lightning, and other effects Tornadoes emit on the electromagnetic spectrum, with sferics and E-field effects detected. There are observed correlations between tornadoes and patterns of lightning. Tornadic storms do not contain more lightning than other storms and some tornadic cells never produce lightning at all. More often than not, overall cloud-to-ground (CG) lightning activity decreases as a tornado touches the surface and returns to the baseline level when the tornado dissipates. In many cases, intense tornadoes and thunderstorms exhibit an increased and anomalous dominance of positive polarity CG discharges. Electromagnetics and lightning have little or nothing to do directly with what drives tornadoes (tornadoes are basically a thermodynamic phenomenon), although there are likely connections with the storm and environment affecting both phenomena.Luminosity has been reported in the past and is probably due to misidentification of external light sources such as lightning, city lights, and power flashes from broken lines, as internal sources are now uncommonly reported and are not known to ever have been recorded. In addition to winds, tornadoes also exhibit changes in atmospheric variables such as temperature, moisture, and pressure. For example, on June 24, 2003, near Manchester, South Dakota, a probe measured a 100-millibar (100 hPa; 3.0 inHg) pressure decrease. The pressure dropped gradually as the vortex approached then dropped extremely rapidly to 850 mbar (850 hPa; 25 inHg) in the core of the violent tornado before rising rapidly as the vortex moved away, resulting in a V-shape pressure trace. Temperature tends to decrease and moisture content to increase in the immediate vicinity of a tornado. Life cycle Supercell relationship Tornadoes often develop from a class of thunderstorms known as supercells. Supercells contain mesocyclones, an area of organized rotation a few kilometers/miles up in the atmosphere, usually 1.6–9.7 km (1–6 miles) across. Most intense tornadoes (EF3 to EF5 on the Enhanced Fujita Scale) develop from supercells. In addition to tornadoes, very heavy rain, frequent lightning, strong wind gusts, and hail are common in such storms.Most tornadoes from supercells follow a recognizable life cycle which begins when increasing rainfall drags with it an area of quickly descending air known as the rear flank downdraft (RFD). This downdraft accelerates as it approaches the ground, and drags the supercells rotating mesocyclone towards the ground with it. Formation As the mesocyclone lowers below the cloud base, it begins to take in cool, moist air from the downdraft region of the storm. The convergence of warm air in the updraft and cool air causes a rotating wall cloud to form. The RFD also focuses the mesocyclones base, causing it to draw air from a smaller and smaller area on the ground. As the updraft intensifies, it creates an area of low pressure at the surface. This pulls the focused mesocyclone down, in the form of a visible condensation funnel. As the funnel descends, the RFD also reaches the ground, fanning outward and creating a gust front that can cause severe damage a considerable distance from the tornado. Usually, the funnel cloud begins causing damage on the ground (becoming a tornado) within a few minutes of the RFD reaching the ground. Maturity Initially, the tornado has a good source of warm, moist air flowing inward to power it, and it grows until it reaches the "mature stage". This can last from a few minutes to more than an hour, and during that time a tornado often causes the most damage, and in rare cases can be more than 1.6 km (1 mile) across. The low pressured atmosphere at the base of the tornado is essential to the endurance of the system. Meanwhile, the RFD, now an area of cool surface winds, begins to wrap around the tornado, cutting off the inflow of warm air which previously fed the tornado. The flow inside the funnel of the tornado is downward, supplying water vapor from the cloud above. This is contrary to the upward flow inside hurricanes, supplying water vapor from the warm ocean below. Therefore, the energy of the tornado is supplied from the cloud above. The complicated mechanism is explained in Dissipation As the RFD completely wraps around and chokes off the tornados air supply, the vortex begins to weaken, becoming thin and rope-like. This is the "dissipating stage", often lasting no more than a few minutes, after which the tornado ends. During this stage, the shape of the tornado becomes highly influenced by the winds of the parent storm, and can be blown into fantastic patterns. Even though the tornado is dissipating, it is still capable of causing damage. The storm is contracting into a rope-like tube and, due to conservation of angular momentum, winds can increase at this point.As the tornado enters the dissipating stage, its associated mesocyclone often weakens as well, as the rear flank downdraft cuts off the inflow powering it. Sometimes, in intense supercells, tornadoes can develop cyclically. As the first mesocyclone and associated tornado dissipate, the storms inflow may be concentrated into a new area closer to the center of the storm and possibly feed a new mesocyclone. If a new mesocyclone develops, the cycle may start again, producing one or more new tornadoes. Occasionally, the old (occluded) mesocyclone and the new mesocyclone produce a tornado at the same time.Although this is a widely accepted theory for how most tornadoes form, live, and die, it does not explain the formation of smaller tornadoes, such as landspouts, long-lived tornadoes, or tornadoes with multiple vortices. These each have different mechanisms which influence their development—however, most tornadoes follow a pattern similar to this one. Types Multiple vortex A multiple-vortex tornado is a type of tornado in which two or more columns of spinning air rotate about their own axes and at the same time revolve around a common center. A multi-vortex structure can occur in almost any circulation, but is very often observed in intense tornadoes. These vortices often create small areas of heavier damage along the main tornado path. This is a phenomenon that is distinct from a satellite tornado, which is a smaller tornado that forms very near a large, strong tornado contained within the same mesocyclone. The satellite tornado may appear to "orbit" the larger tornado (hence the name), giving the appearance of one, large multi-vortex tornado. However, a satellite tornado is a distinct circulation, and is much smaller than the main funnel. Waterspout A waterspout is defined by the National Weather Service as a tornado over water. However, researchers typically distinguish "fair weather" waterspouts from tornadic (i.e. associated with a mesocyclone) waterspouts. Fair weather waterspouts are less severe but far more common, and are similar to dust devils and landspouts. They form at the bases of cumulus congestus clouds over tropical and subtropical waters. They have relatively weak winds, smooth laminar walls, and typically travel very slowly. They occur most commonly in the Florida Keys and in the northern Adriatic Sea. In contrast, tornadic waterspouts are stronger tornadoes over water. They form over water similarly to mesocyclonic tornadoes, or are stronger tornadoes which cross over water. Since they form from severe thunderstorms and can be far more intense, faster, and longer-lived than fair weather waterspouts, they are more dangerous. In official tornado statistics, waterspouts are generally not counted unless they affect land, though some European weather agencies count waterspouts and tornadoes together. Landspout A landspout, or dust-tube tornado, is a tornado not associated with a mesocyclone. The name stems from their characterization as a "fair weather waterspout on land". Waterspouts and landspouts share many defining characteristics, including relative weakness, short lifespan, and a small, smooth condensation funnel that often does not reach the surface. Landspouts also create a distinctively laminar cloud of dust when they make contact with the ground, due to their differing mechanics from true mesoform tornadoes. Though usually weaker than classic tornadoes, they can produce strong winds which could cause serious damage. Similar circulations Gustnado A gustnado, or gust front tornado, is a small, vertical swirl associated with a gust front or downburst. Because they are not connected with a cloud base, there is some debate as to whether or not gustnadoes are tornadoes. They are formed when fast-moving cold, dry outflow air from a thunderstorm is blown through a mass of stationary, warm, moist air near the outflow boundary, resulting in a "rolling" effect (often exemplified through a roll cloud). If low level wind shear is strong enough, the rotation can be turned vertically or diagonally and make contact with the ground. The result is a gustnado. They usually cause small areas of heavier rotational wind damage among areas of straight-line wind damage. Dust devil A dust devil (also known as a whirlwind) resembles a tornado in that it is a vertical swirling column of air. However, they form under clear skies and are no stronger than the weakest tornadoes. They form when a strong convective updraft is formed near the ground on a hot day. If there is enough low-level wind shear, the column of hot, rising air can develop a small cyclonic motion that can be seen near the ground. They are not considered tornadoes because they form during fair weather and are not associated with any clouds. However, they can, on occasion, result in major damage. Fire whirls Small-scale, tornado-like circulations can occur near any intense surface heat source. Those that occur near intense wildfires are called fire whirls. They are not considered tornadoes, except in the rare case where they connect to a pyrocumulus or other cumuliform cloud above. Fire whirls usually are not as strong as tornadoes associated with thunderstorms. They can, however, produce significant damage. Steam devils A steam devil is a rotating updraft between 50-and-200-metre wide (160 and 660 ft) that involves steam or smoke. These formations do not involve high wind speeds, only completing a few rotations per minute. Steam devils are very rare. They most often form from smoke issuing from a power plants smokestack. Hot springs and deserts may also be suitable locations for a tighter, faster-rotating steam devil to form. The phenomenon can occur over water, when cold arctic air passes over relatively warm water. Intensity and damage The Fujita scale and the Enhanced Fujita Scale rate tornadoes by damage caused. The Enhanced Fujita (EF) Scale was an update to the older Fujita scale, by expert elicitation, using engineered wind estimates and better damage descriptions. The EF Scale was designed so that a tornado rated on the Fujita scale would receive the same numerical rating, and was implemented starting in the United States in 2007. An EF0 tornado will probably damage trees but not substantial structures, whereas an EF5 tornado can rip buildings off their foundations leaving them bare and even deform large skyscrapers. The similar TORRO scale ranges from a T0 for extremely weak tornadoes to T11 for the most powerful known tornadoes. Doppler weather radar data, photogrammetry, and ground swirl patterns (cycloidal marks) may also be analyzed to determine intensity and award a rating. Tornadoes vary in intensity regardless of shape, size, and location, though strong tornadoes are typically larger than weak tornadoes. The association with track length and duration also varies, although longer track tornadoes tend to be stronger. In the case of violent tornadoes, only a small portion of the path is of violent intensity, most of the higher intensity from subvortices.In the United States, 80% of tornadoes are EF0 and EF1 (T0 through T3) tornadoes. The rate of occurrence drops off quickly with increasing strength—less than 1% are violent tornadoes (EF4, T8 or stronger). Current records may significantly underestimate the frequency of strong (EF2-EF3) and violent (EF4-EF5) tornadoes, as damage-based intensity estimates are limited to structures and vegetation that a tornado impacts. A tornado may be much stronger than its damage-based rating indicates if its strongest winds occur away from suitable damage indicators, such as in an open field. Outside Tornado Alley, and North America in general, violent tornadoes are extremely rare. This is apparently mostly due to the lesser number of tornadoes overall, as research shows that tornado intensity distributions are fairly similar worldwide. A few significant tornadoes occur annually in Europe, Asia, southern Africa, and southeastern South America. Climatology The United States has the most tornadoes of any country, nearly four times more than estimated in all of Europe, excluding waterspouts. This is mostly due to the unique geography of the continent. North America is a large continent that extends from the tropics north into arctic areas, and has no major east–west mountain range to block air flow between these two areas. In the middle latitudes, where most tornadoes of the world occur, the Rocky Mountains block moisture and buckle the atmospheric flow, forcing drier air at mid-levels of the troposphere due to downsloped winds, and causing the formation of a low pressure area downwind to the east of the mountains. Increased westerly flow off the Rockies force the formation of a dry line when the flow aloft is strong, while the Gulf of Mexico fuels abundant low-level moisture in the southerly flow to its east. This unique topography allows for frequent collisions of warm and cold air, the conditions that breed strong, long-lived storms throughout the year. A large portion of these tornadoes form in an area of the central United States known as Tornado Alley. This area extends into Canada, particularly Ontario and the Prairie Provinces, although southeast Quebec, the interior of British Columbia, and western New Brunswick are also tornado-prone. Tornadoes also occur across northeastern Mexico.The United States averages about 1,200 tornadoes per year, followed by Canada, averaging 62 reported per year. NOAAs has a higher average 100 per year in
Tornado	Canada. The Netherlands has the highest average number of recorded tornadoes per area of any country (more than 20, or 0.00048/km2, 0.0012/sq mi annually), followed by the UK (around 33, 0.00013/km2, 0.00034/sq mi per year), although those are of lower intensity, briefer and cause minor damage. Tornadoes kill an average of 179 people per year in Bangladesh, the most in the world. Reasons for this include the regions high population density, poor construction quality, and lack of tornado safety knowledge. Other areas of the world that have frequent tornadoes include South Africa, the La Plata Basin area, portions of Europe, Australia and New Zealand, and far eastern Asia.Tornadoes are most common in spring and least common in winter, but tornadoes can occur any time of year that favorable conditions occur. Spring and fall experience peaks of activity as those are the seasons when stronger winds, wind shear, and atmospheric instability are present. Tornadoes are focused in the right front quadrant of landfalling tropical cyclones, which tend to occur in the late summer and autumn. Tornadoes can also be spawned as a result of eyewall mesovortices, which persist until landfall.Tornado occurrence is highly dependent on the time of day, because of solar heating. Worldwide, most tornadoes occur in the late afternoon, between 15:00 (3 pm) and 19:00 (7 pm) local time, with a peak near 17:00 (5 pm). Destructive tornadoes can occur at any time of day. The Gainesville Tornado of 1936, one of the deadliest tornadoes in history, occurred at 8:30 am local time.The United Kingdom has the highest incidence of tornadoes per unit area of land in the world. Unsettled conditions and weather fronts transverse the British Isles at all times of the years, and are responsible for spawning the tornadoes, which consequently form at all times of the year. The United Kingdom has at least 34 tornadoes per year and possibly as many as 50. Most tornadoes in the United Kingdom are weak, but they are occasionally destructive. For example, the Birmingham tornado of 2005 and the London tornado of 2006 both registered F2 on the Fujita scale and both caused significant damage and injury. Associations with climate and climate change Associations with various climate and environmental trends exist. For example, an increase in the sea surface temperature of a source region (e.g. Gulf of Mexico and Mediterranean Sea) increases atmospheric moisture content. Increased moisture can fuel an increase in severe weather and tornado activity, particularly in the cool season.Some evidence does suggest that the Southern Oscillation is weakly correlated with changes in tornado activity, which vary by season and region, as well as whether the ENSO phase is that of El Niño or La Niña. Research has found that fewer tornadoes and hailstorms occur in winter and spring in the U.S. central and southern plains during El Niño, and more occur during La Niña, than in years when temperatures in the Pacific are relatively stable. Ocean conditions could be used to forecast extreme spring storm events several months in advance.Climatic shifts may affect tornadoes via teleconnections in shifting the jet stream and the larger weather patterns. The climate-tornado link is confounded by the forces affecting larger patterns and by the local, nuanced nature of tornadoes. Although it is reasonable to suspect that global warming may affect trends in tornado activity, any such effect is not yet identifiable due to the complexity, local nature of the storms, and database quality issues. Any effect would vary by region. Detection Rigorous attempts to warn of tornadoes began in the United States in the mid-20th century. Before the 1950s, the only method of detecting a tornado was by someone seeing it on the ground. Often, news of a tornado would reach a local weather office after the storm. However, with the advent of weather radar, areas near a local office could get advance warning of severe weather. The first public tornado warnings were issued in 1950 and the first tornado watches and convective outlooks came about in 1952. In 1953, it was confirmed that hook echoes were associated with tornadoes. By recognizing these radar signatures, meteorologists could detect thunderstorms probably producing tornadoes from several miles away. Radar Today most developed countries have a network of weather radars, which serves as the primary method of detecting hook signatures that are likely associated with tornadoes. In the United States and a few other countries, Doppler weather radar stations are used. These devices measure the velocity and radial direction (towards or away from the radar) of the winds within a storm, and so can spot evidence of rotation in storms from over 160 km (100 miles) away. When storms are distant from a radar, only areas high within the storm are observed and the important areas below are not sampled. Data resolution also decreases with distance from the radar. Some meteorological situations leading to tornadogenesis are not readily detectable by radar and tornado development may occasionally take place more quickly than radar can complete a scan and send the batch of data. Doppler radar systems can detect mesocyclones within a supercell thunderstorm. This allows meteorologists to predict tornado formations throughout thunderstorms. Storm spotting In the mid-1970s, the U.S. National Weather Service (NWS) increased its efforts to train storm spotters so they could spot key features of storms that indicate severe hail, damaging winds, and tornadoes, as well as storm damage and flash flooding. The program was called Skywarn, and the spotters were local sheriffs deputies, state troopers, firefighters, ambulance drivers, amateur radio operators, civil defense (now emergency management) spotters, storm chasers, and ordinary citizens. When severe weather is anticipated, local weather service offices request these spotters to look out for severe weather and report any tornadoes immediately, so that the office can warn of the hazard.Spotters usually are trained by the NWS on behalf of their respective organizations, and report to them. The organizations activate public warning systems such as sirens and the Emergency Alert System (EAS), and they forward the report to the NWS. There are more than 230,000 trained Skywarn weather spotters across the United States.In Canada, a similar network of volunteer weather watchers, called Canwarn, helps spot severe weather, with more than 1,000 volunteers. In Europe, several nations are organizing spotter networks under the auspices of Skywarn Europe and the Tornado and Storm Research Organisation (TORRO) has maintained a network of spotters in the United Kingdom since 1974.Storm spotters are required because radar systems such as NEXRAD detect signatures that suggest the presence of tornadoes, rather than tornadoes as such. Radar may give a warning before there is any visual evidence of a tornado or an imminent one, but ground truth from an observer can give definitive information. The spotters ability to see what radar cannot is especially important as distance from the radar site increases, because the radar beam becomes progressively higher in altitude further away from the radar, chiefly due to curvature of Earth, and the beam also spreads out. Visual evidence Storm spotters are trained to discern whether or not a storm seen from a distance is a supercell. They typically look to its rear, the main region of updraft and inflow. Under that updraft is a rain-free base, and the next step of tornadogenesis is the formation of a rotating wall cloud. The vast majority of intense tornadoes occur with a wall cloud on the backside of a supercell.Evidence of a supercell is based on the storms shape and structure, and cloud tower features such as a hard and vigorous updraft tower, a persistent, large overshooting top, a hard anvil (especially when backsheared against strong upper level winds), and a corkscrew look or striations. Under the storm and closer to where most tornadoes are found, evidence of a supercell and the likelihood of a tornado includes inflow bands (particularly when curved) such as a "beaver tail", and other clues such as strength of inflow, warmth and moistness of inflow air, how outflow- or inflow-dominant a storm appears, and how far is the front flank precipitation core from the wall cloud. Tornadogenesis is most likely at the interface of the updraft and rear flank downdraft, and requires a balance between the outflow and inflow.Only wall clouds that rotate spawn tornadoes, and they usually precede the tornado between five and thirty minutes. Rotating wall clouds may be a visual manifestation of a low-level mesocyclone. Barring a low-level boundary, tornadogenesis is highly unlikely unless a rear flank downdraft occurs, which is usually visibly evidenced by evaporation of cloud adjacent to a corner of a wall cloud. A tornado often occurs as this happens or shortly afterwards; first, a funnel cloud dips and in nearly all cases by the time it reaches halfway down, a surface swirl has already developed, signifying a tornado is on the ground before condensation connects the surface circulation to the storm. Tornadoes may also develop without wall clouds, under flanking lines and on the leading edge. Spotters watch all areas of a storm, and the cloud base and surface. Extremes The tornado which holds most records in history was the Tri-State Tornado, which roared through parts of Missouri, Illinois, and Indiana on March 18, 1925. It was likely an F5, though tornadoes were not ranked on any scale in that era. It holds records for longest path length (219 miles; 352 km), longest duration (about 3.5 hours), and fastest forward speed for a significant tornado (73 mph; 117 km/h) anywhere on Earth. In addition, it is the deadliest single tornado in United States history (695 dead). The tornado was also the costliest tornado in history at the time (unadjusted for inflation), but in the years since has been surpassed by several others if population changes over time are not considered. When costs are normalized for wealth and inflation, it ranks third today.The deadliest tornado in world history was the Daultipur-Salturia Tornado in Bangladesh on April 26, 1989, which killed approximately 1,300 people.Bangladesh has had at least 19 tornadoes in its history that killed more than 100 people, almost half of the total in the rest of the world.One of the most extensive tornado outbreaks on record was the 1974 Super Outbreak, which affected a large area of the central United States and extreme southern Ontario on April 3 and 4, 1974. The outbreak featured 148 tornadoes in 18 hours, many of which were violent; six were of F5 intensity, and twenty-four peaked at F4 strength. Sixteen tornadoes were on the ground at the same time during its peak. More than 300 people, possibly as many as 330, were killed.While direct measurement of the most violent tornado wind speeds is nearly impossible, since conventional anemometers would be destroyed by the intense winds and flying debris, some tornadoes have been scanned by mobile Doppler radar units, which can provide a good estimate of the tornados winds. The highest wind speed ever measured in a tornado, which is also the highest wind speed ever recorded on the planet, is 301 ± 20 mph (484 ± 32 km/h) in the F5 Bridge Creek-Moore, Oklahoma, tornado which killed 36 people. The reading was taken about 100 feet (30 m) above the ground.Storms that produce tornadoes can feature intense updrafts, sometimes exceeding 150 mph (240 km/h). Debris from a tornado can be lofted into the parent storm and carried a very long distance. A tornado which affected Great Bend, Kansas, in November 1915, was an extreme case, where a "rain of debris" occurred 80 miles (130 km) from the town, a sack of flour was found 110 miles (180 km) away, and a cancelled check from the Great Bend bank was found in a field outside of Palmyra, Nebraska, 305 miles (491 km) to the northeast. Waterspouts and tornadoes have been advanced as an explanation for instances of raining fish and other animals. Safety Though tornadoes can strike in an instant, there are precautions and preventative measures that can be taken to increase the chances of survival. Authorities such as the Storm Prediction Center in the United States advise having a pre-determined plan should a tornado warning be issued. When a warning is issued, going to a basement or an interior first-floor room of a sturdy building greatly increases chances of survival. In tornado-prone areas, many buildings have underground storm cellars, which have saved thousands of lives.Some countries have meteorological agencies which distribute tornado forecasts and increase levels of alert of a possible tornado (such as tornado watches and warnings in the United States and Canada). Weather radios provide an alarm when a severe weather advisory is issued for the local area, mainly available only in the United States. Unless the tornado is far away and highly visible, meteorologists advise that drivers park their vehicles far to the side of the road (so as not to block emergency traffic), and find a sturdy shelter. If no sturdy shelter is nearby, getting low in a ditch is the next best option. Highway overpasses are one of the worst places to take shelter during tornadoes, as the constricted space can be subject to increased wind speed and funneling of debris underneath the overpass. Myths and misconceptions Folklore often identifies a green sky with tornadoes, and though the phenomenon may be associated with severe weather, there is no evidence linking it specifically with tornadoes. It is often thought that opening windows will lessen the damage caused by the tornado. While there is a large drop in atmospheric pressure inside a strong tornado, the pressure difference is unlikely to cause significant damage. Opening windows may instead increase the severity of the tornados damage. A violent tornado can destroy a house whether its windows are open or closed. Another commonly held misconception is that highway overpasses provide adequate shelter from tornadoes. This belief is partly inspired by widely circulated video captured during the 1991 tornado outbreak near Andover, Kansas, where a news crew and several other people took shelter under an overpass on the Kansas Turnpike and safely rode out a tornado as it passed by. However, a highway overpass is a dangerous place during a tornado, and the subjects of the video remained safe due to an unlikely combination of events: the storm in question was a weak tornado, the tornado did not directly strike the overpass, and the overpass itself was of a unique design. Due to the Venturi effect, tornadic winds are accelerated in the confined space of an overpass. Indeed, in the 1999 Oklahoma tornado outbreak of May 3, 1999, three highway overpasses were directly struck by tornadoes, and at each of the three locations there was a fatality, along with many life-threatening injuries. By comparison, during the same tornado outbreak, more than 2,000 homes were completely destroyed and another 7,000 damaged, and yet only a few dozen people died in their homes.An old belief is that the southwest corner of a basement provides the most protection during a tornado. The safest place is the side or corner of an underground room opposite the tornados direction of approach (usually the northeast corner), or the central-most room on the lowest floor. Taking shelter in a basement, under a staircase, or under a sturdy piece of furniture such as a workbench further increases the chances of survival.There are areas which people believe to be protected from tornadoes, whether by being in a city, near a major river, hill, or mountain, or even protected by supernatural forces. Tornadoes have been known to cross major rivers, climb mountains, affect valleys, and have damaged several city centers. As a general rule, no area is safe from tornadoes, though some areas are more susceptible than others. Ongoing research Meteorology is a relatively young science and the study of tornadoes is newer still. Although researched for about 140 years and intensively for around 60 years, there are still aspects of tornadoes which remain a mystery. Meteorologists have a fairly good understanding of the development of thunderstorms and mesocyclones, and the meteorological conditions conducive to their formation. However, the step from supercell, or other respective formative processes, to tornadogenesis and the prediction of tornadic vs. non-tornadic mesocyclones is not yet well known and is the focus of much research.Also under study are the low-level mesocyclone and the stretching of low-level vorticity which tightens into a tornado, in particular, what are the processes and what is the relationship of the environment and the convective storm. Intense tornadoes have been observed forming simultaneously with a mesocyclone aloft (rather than succeeding mesocyclogenesis) and some intense tornadoes have occurred without a mid-level mesocyclone.In particular, the role of downdrafts, particularly the rear-flank downdraft, and the role of baroclinic boundaries, are intense areas of study.Reliably predicting tornado intensity and longevity remains a problem, as do details affecting characteristics of a tornado during its life cycle and tornadolysis. Other rich areas of research are tornadoes associated with mesovortices within linear thunderstorm structures and within tropical cyclones.Meteorologists still do not know the exact mechanisms by which most tornadoes form, and occasional tornadoes still strike without a tornado warning being issued. Analysis of observations including both stationary and mobile (surface and aerial) in-situ and remote sensing (passive and active) instruments generates new ideas and refines existing notions. Numerical modeling also provides new insights as observations and new discoveries are integrated into our physical understanding and then tested in computer simulations which validate new notions as well as produce entirely new theoretical findings, many of which are otherwise unattainable. Importantly, development of new observation technologies and installation of finer spatial and temporal resolution observation networks have aided increased understanding and better predictions.Research programs, including field projects such as the VORTEX projects (Verification of the Origins of Rotation in Tornadoes Experiment), deployment of TOTO (the TOtable Tornado Observatory), Doppler on Wheels (DOW), and dozens of other programs, hope to solve many questions that still plague meteorologists. Universities, government agencies such as the National Severe Storms Laboratory, private-sector meteorologists, and the National Center for Atmospheric Research are some of the organizations very active in research; with various sources of funding, both private and public, a chief entity being the National Science Foundation. The pace of research is partly constrained by the number of observations that can be taken; gaps in information about the wind, pressure, and moisture content throughout the local atmosphere; and the computing power available for simulation.Solar storms similar to tornadoes have been recorded, but it is unknown how closely related they are to their terrestrial counterparts. Gallery See also References Further reading Bluestein, Howard B. (1999). Tornado Alley: Monster Storms of the Great Plains. New York: Oxford University Press. ISBN 0-19-510552-4. Bradford, Marlene (2001). Scanning the Skies: A History of Tornado Forecasting. Norman, OK: University of Oklahoma Press. ISBN 0-8061-3302-3. Grazulis, Thomas P. (January 1997). Significant Tornadoes Update, 1992–1995. St. Johnsbury, VT: Environmental Films. ISBN 1-879362-04-X. Pybus, Nani (Spring 2016). "Cyclone Jones: Dr. Herbert L. Jones and the Origins of Tornado Research in Oklahoma". Chronicles of Oklahoma. 94: 4–31. Retrieved May 5, 2022. Heavily illustrated. External links NOAA Storm Events Database 1950–present European Severe Weather Database Tornado Detection and Warnings Electronic Journal of Severe Storms Meteorology NOAA Tornado Preparedness Guide Tornado History Project – Maps and statistics from 1950 to present Physics Today What we know and dont know about Tornadoes September 2014 U.S. Billion-dollar Weather and Climate Disasters
Barth syndrome	Barth syndrome (BTHS) is a rare but serious X-linked genetic disorder, caused by changes in phospholipid structure and metabolism. It may affect multiple body systems (though mainly characterized by pronounced pediatric-onset cardiomyopathy), and is potentially fatal. The syndrome is diagnosed almost exclusively in males. Presentation Though not always present, the cardinal characteristics of this multi-system disorder include: cardiomyopathy (dilated or hypertrophic, possibly with left ventricular noncompaction and/or endocardial fibroelastosis), neutropenia (chronic, cyclic, or intermittent), underdeveloped skeletal musculature and muscle weakness, growth delay, exercise intolerance, cardiolipin abnormalities, and 3-methylglutaconic aciduria. It can be associated with stillbirth.Barth Syndrome is manifested in a variety of ways at birth. A majority of patients are hypotonic at birth; show signs of cardiomyopathy within the first few months of life; and experience a deceleration in growth in the first year, despite adequate nutrition. As patients progress into childhood, their height and weight lag significantly behind average. While most patients express normal intelligence, a significant proportion of patients also express mild or moderate learning disabilities. Physical activity is also hindered due to diminished muscular development and muscular hypotonia. Many of these disorders are resolved after puberty. Growth accelerates during puberty, and many patients reach a normal adult height.Cardiomyopathy is one of the more severe manifestations of Barth Syndrome. The myocardium is dilated, reducing the systolic pump of the ventricles. For this reason, most patients have left myocardial thickening (hypertrophy). While cardiomyopathy can be life-threatening, it is commonly resolved or substantially improved in Barth Syndrome patients after puberty.Neutropenia, a granulocyte disorder that results in a low production of neutrophils, the bodys primary defenders against bacterial infections, is another severe manifestation of Barth Syndrome. In general, lower levels of neutrophils render a patient more vulnerable to bacterial infections; in Barth Syndrome patients, however, there are reports of relatively fewer bacterial infections as compared to non-Barth patients with neutropenia. Cause The tafazzin gene (TAZ, also called G4.5 or NG_009634) is highly expressed in cardiac and skeletal muscle; its gene product, Taz1p, functions as an acyltransferase in complex lipid metabolism. Any type of mutation of TAZ (missense, nonsense, deletion, frameshift, and/or splicing) is closely associated with Barth syndrome.In 2008, Dr. Kulik found that every patient with Barth Syndrome that he tested had abnormalities in their cardiolipin, a lipid found inside the mitochondria of cells. Cardiolipin is intimately connected with the electron transport chain proteins and the membrane structure of the mitochondrion, the energy-producing organelle of the cell. iPLA2-VIA has been suggested as a target for treatment.The human tafazzin gene is over 10,000 base pairs in length, the full-length mRNA, NM_000116, being 1919 nucleotides long, encoding 11 exons with a predicted protein length of 292 amino acids and a molecular weight of 33.5 kDa. It is located at Xq28; the long arm of the X chromosome. This explains the X-linked nature of Barth Syndrome. There are some case reports of women who are asymptomatic carriers of the TAZ mutation. Any of their children might inherit the modified gene with a 50% probability, with the males developing Barth Syndrome and the females going on to be carriers themselves. Thus, it is vitally important to take familial histories of Barth Syndrome patients in order to determine genetic risk. Ideally, any male who is matrilineally related to an individual with Barth Syndrome should be tested for TAZ mutation(s). Because the phenotype can vary widely, even among affected siblings, symptomatology (or lack thereof) by itself is insufficient for diagnosis. Diagnosis Early diagnosis of the syndrome is complicated, but of critical importance. Clinical presentation in Barth Syndrome is highly variable, with the only common denominator being early-onset and pronounced cardiomyopathy. Diagnosis is established based upon several tests, among which can be blood tests (neutropenia, white blood cell count), urinalysis (increased urinary organic acid levels), echocardiography (cardiac ultrasound, to assess (and detect abnormalities in) the hearts structure, function and condition), and, with reasonable suspicion of Barth Syndrome, DNA sequencing (to verify TAZ gene status). Differential diagnosis Based on symptoms at time of presentation, the differential diagnosis may include other hereditary and/or nutritional causes of (dilated) cardiomyopathy and (cyclic or idiopathic) neutropenia. Treatment Currently, there is no treatment for Barth syndrome, although some of the symptoms can be successfully managed. Clinical trials for possible treatments are ongoing, and preliminary research into AAV9-mediated TAZ gene replacement by the University of Florida has been promising. However, more research and (pre-)clinical testing is needed before the gene therapy is eligible for approval by the FDA as a treatment modality. Epidemiology Being X-linked, Barth syndrome has been predominantly diagnosed in males (as of July 2009: 120+ males), although by 2012 a female case had been reported.The syndrome is believed to be severely under-reported due to the complexity of (early) diagnosis. Reports on its incidence and prevalence in the international literature vary; around 1 in every 454,000 individuals are thought to suffer from Barth Syndrome. Incidence has been estimated at anywhere between 1:140,000 (South West England, South Wales) and 1:300,000 - 1:400,000 live births (United States). Geographical distribution is homogenous, with patients (and their family members) on every continent (with known cases in, for example, the US, Canada, Europe, Japan, South Africa, Kuwait, and Australia). History The syndrome was named for Dr. Peter Barth (b. 1932), a Dutch pediatric neurologist, for his research into and the discovery of the syndrome in 1983. He described a pedigree chart, showing that this is an inherited trait and not a communicated (i.e. infectious) disease. See also 3-Methylglutaconic aciduria noncompaction cardiomyopathy: mutations to the affected genes in Barth syndrome are also present here. References External links Barth Syndrome at NINDS
Dermatomyositis	Dermatomyositis (DM) is a long-term inflammatory disorder which affects skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over time. These may occur suddenly or develop over months. Other symptoms may include weight loss, fever, lung inflammation, or light sensitivity. Complications may include calcium deposits in muscles or skin.The cause is unknown. Theories include that it is an autoimmune disease or a result of a viral infection. Dermatomyositis may develop as a paraneoplastic syndrome associated with several forms of malignancy. It is a type of inflammatory myopathy. Diagnosis is typically based on some combination of symptoms, blood tests, electromyography, and muscle biopsies.While no cure for the condition is known, treatments generally improve symptoms. Treatments may include medication, physical therapy, exercise, heat therapy, orthotics and assistive devices, and rest. Medications in the corticosteroids family are typically used with other agents such as methotrexate or azathioprine recommended if steroids are not working well. Intravenous immunoglobulin may also improve outcomes. Most people improve with treatment and in some, the condition resolves completely.About one per 100,000 people per year are newly affected. The condition usually occurs in those in their 40s and 50s with women being affected more often than men. People of any age, however, may be affected. The condition was first described in the 1800s. Signs and symptoms The main symptoms include several kinds of skin rash along with muscle weakness in both upper arms or thighs. Skin One form the rashes take is called "heliotrope" (a purplish color) or lilac, but may also be red. It can occur around the eyes along with swelling, but also occurs on the upper chest or back what is called the "shawl" (around the neck) or "V-sign" above the breasts and may also occur on the face, upper arms, thighs, or hands. Another form the rash takes is called Gottrons sign which are red or violet, sometimes scaly, slightly raised papules that erupt on any of the finger joints (the metacarpophalangeal joints or the interphalangeal joints). Gottrons papules may also be found over other bony prominences including the elbows, knees, or feet. All these rashes are made worse by exposure to sunlight, and are often very itchy, painful, and may bleed.If a person exhibits only skin findings characteristic of DM, without weakness or abnormal muscle enzymes, then he or she may be experiencing amyopathic dermatomyositis (ADM), formerly known as "dermatomyositis sine myositis". Muscles People with DM experience progressively worsening muscle weakness in the proximal muscles (for example, the shoulders and thighs). Tasks that use these muscles: standing from sitting, lifting, and climbing stairs, can become increasingly difficult for people with dermatomyositis. Other Around 30% of people have swollen, painful joints, but this is generally mild.In some people, the condition affects the lungs, and they may have a cough or difficulty breathing. If the disease affects the heart, arrhythmias may occur. If it affects the blood vessels in the stomach or intestines, which is more common in juvenile DM, the people might vomit blood, have black tarry bowel movements, or may develop a hole somewhere in their GI tract.There are further complications possible with Dermatomyositis. These complications include difficulty swallowing due to the muscles in the esophagus being affected which can result in malnutrition and can cause the breathing of food or liquids, into the lungs. Examples of dermatomyositis Causes The cause is unknown, but it may result from an initial viral infection or cancer, either of which could raise an autoimmune response.Between 7 and 30% of dermatomyositis cases arise from cancer, probably as an autoimmune response. The most commonly associated cancers are ovarian cancer, breast cancer, and lung cancer. Between 18 and 25 per cent of people with amyopathic DM also have cancer. Malignancy in association with dermatomyositis is more prevalent after age 60. Some cases are inherited, and HLA subtypes HLA-DR3, HLA-DR52, and HLA-DR6 seem to create a disposition to autoimmune dermatomyositis. Diagnosis The diagnosis of dermatomyositis is based on five criteria, which are also used to differentially diagnose with respect to polymyositis: Muscle weakness in both thighs or both upper arms Using a blood test, finding higher levels of enzymes found in skeletal muscle, including creatinine kinase, aldolase, and glutamate oxaloacetate, pyruvate transaminases and lactate dehydrogenase Using testing of electric signalling in muscles, finding all three of: erratic, repetitive, high-frequency signals; short, low-energy signals between skeletal muscles and motor neurons that have multiple phases; and sharp activity when a needle is inserted into the muscle Examining a muscle biopsy under a microscope and finding mononuclear white blood cells between the muscle cells, and finding abnormal muscle cell degeneration and regeneration, dying muscle cells, and muscle cells being consumed by other cells (phagocytosis) Rashes typical of dermatomyositis, which include heliotrope rash, Gottron sign, and Gottron papulesThe fifth criterion is what differentiates dermatomyositis from polymyositis; the diagnosis is considered definite for dermatomyositis if three of items 1 through 4 are present in addition to 5, probable with any two in addition to 5, and possible if just one is present in addition to 5.Dermatomyositis is associated with autoantibodies, especially antinuclear antibodies (ANA). Around 80% of people with DM test positive for ANA and around 30% of people have myositis-specific autoantibodies which include antibodies to aminoacyl-tRNA synthetases (anti-synthetase antibodies), including antibodies against histidine—tRNA ligase (also called Jo-1); antibodies to signal recognition particle (SRP); and anti-Mi-2 antibodies.Magnetic resonance imaging may be useful to guide muscle biopsy and to investigate involvement of internal organs; X-ray may be used to investigate joint involvement and calcifications.A given case of dermatomyositis may be classified as amyopathic dermatomyositis if only skin is affected and no muscle weakness for longer than 6 months is seen according to one 2016 review, or two years according to another. Classification Dermatomyositis is a form of systemic connective tissue disorder, a class of diseases that often involves autoimmune dysfunction.It has also been classified as an idiopathic inflammatory myopathy, along with polymyositis, necrotizing autoimmune myositis, cancer-associated myositis, and sporadic inclusion body myositis.A form of this disorder that occurs prior to adulthood is known as juvenile dermatomyositis. Treatment No cure for dermatomyositis is known, but the symptoms can be treated. Options include medication, physical therapy, exercise, heat therapy (including microwave and ultrasound), orthotics and assistive devices, and rest. The standard treatment for dermatomyositis is a corticosteroid drug, given either in pill form or intravenously. Immunosuppressant drugs, such as azathioprine and methotrexate, may reduce inflammation in people who do not respond well to prednisone. Periodic treatment using intravenous immunoglobulin can also improve recovery. Other immunosuppressive agents used to treat the inflammation associated with dermatomyositis include cyclosporine A, cyclophosphamide, and tacrolimus.Physical therapy is usually recommended to prevent muscle atrophy and to regain muscle strength and range of motion. Many individuals with dermatomyositis may need a topical ointment, such as topical corticosteroids, for their skin disorder. They should wear high-protection sunscreen and protective clothing. Surgery may be required to remove calcium deposits that cause nerve pain and recurrent infections.Antimalarial medications, especially hydroxychloroquine and chloroquine, are used to treat the rashes, as is done for similar conditions.Rituximab is used when people do not respond to other treatments.As of 2016, treatments for amyopathic dermatomyositis in adults did not have a strong evidence base; published treatments included antimalarial medications, steroids, taken or orally or applied to the skin, calcineurin inhibitors applied to the skin, dapsone, intravenous immunoglobulin, methotrexate, azathioprine, and mycophenolate mofetil. None appears to be very effective; among them, intravenous immunoglobulin has had the best outcomes. Prognosis Before the advent of modern treatments such as prednisone, intravenous immunoglobulin, plasmapheresis, chemotherapies, and other drugs, the prognosis was poor.The cutaneous manifestations of dermatomyositis may or may not improve with therapy in parallel with the improvement of the myositis. In some people, the weakness and rash resolve together. In others, the two are not linked, with one or the other being more challenging to control. Often, cutaneous disease persists after adequate control of the muscle disease.The risk of death from the condition is much higher if the heart or lungs are affected. Epidemiology Incidence of DM peaks at ages 40–50, but the disease can affect people of all ages. It tends to affect more women than men. The prevalence of DM ranges from one to 22 per 100,000 people. History The diagnostic criteria were proposed in 1975 and became widely adopted. Amyopathic DM, also called DM sine myositis, was named in 2002. People who died with dermatomyositis Opera singer Maria Callas (1923–1977) allegedly had dermatomyositis from 1975 until her death. Actor Laurence Olivier (1907–1989) had dermatomyositis from 1974 until his death. American football running back Ricky Bell (1955–1984), the runner-up for the Heisman Trophy in 1976, and the number-one pick in the NFL draft in 1977, died at the age of 29 from heart failure caused by this disease. Rob Buckman (1948–2011) a doctor, comedian, author, and the president of the Humanist Association of Canada. Research As of 2016, research was ongoing into causes for DM, as well as biomarkers; clinical trials were ongoing for use of the following drugs in DM: ajulemic acid (Phase II), adrenocorticotropic hormone gel (Phase IV, open label), IMO-8400, an antagonist of Toll-like receptor 7,8 and 9 (Ph II), abatacept (Phase IV, open label), and sodium thiosulfate (Phase II). References This article incorporates public domain material from NINDS Dermatomyositis Information Page. United States Department of Health and Human Services. Retrieved 12 December 2016. == External links ==
Oligohydramnios	Oligohydramnios is a medical condition in pregnancy characterized by a deficiency of amniotic fluid, the fluid that surrounds the fetus in the abdomen, in the amniotic sac. It is typically diagnosed by ultrasound when the amniotic fluid index (AFI) measures less than 5 cm or when the single deepest pocket (SDP) of amniotic fluid measures less than 2 cm. Amniotic fluid is necessary to allow for normal fetal movement, lung development, and cushioning from uterine compression. Low amniotic fluid can be attributed to a maternal, fetal, placental or idiopathic cause and can result in poor fetal outcomes including death. The prognosis of the fetus is dependent on the etiology, gestational age at diagnosis, and the severity of the oligohydramnios. The opposite of oligohydramnios is polyhydramnios, or an excess of amniotic fluid. Etiology The amount of amniotic fluid available is based on how much fluid is produced and how much is removed from the amniotic sac. In the first trimester, the main sources of amniotic fluid are fetal lung secretions, transportation of maternal plasma across the fetal membranes, and the surface of the placenta. By the second trimester, the fetal kidneys start to produce urine which becomes the main source of the amniotic fluid for the remainder of the pregnancy.The development of oligohydramnios may be idiopathic or have a maternal, fetal, or placental cause. Maternal Conditions such as preeclampsia, chronic hypertension, collagen vascular disease, nephropathy, and thrombophilia cause uteroplacental insufficiency. These conditions decrease the blood flow to vital organs such as the placenta which supplies blood, oxygen, and nutrients to the developing fetus. Decreased blood flow to the fetus causes impaired urine production which leads to reduced amniotic fluid and oligohydramnios. Medications such as angiotensin converting enzyme inhibitors (lisinopril), prostaglandin synthetase inhibitors (NSAIDs, anti-inflammatory steroids), and trastuzumab decrease blood flow to the kidneys of the fetus. When the fetal kidneys are not able to produce adequate amounts of urine, this leads to reduced amniotic fluid or oligohydramnios. Maternal dehydration, especially in the hotter summer months Infections such as the TORCH infections (toxoplasma gondii, rubella, cytomegalovirus, herpes simplex virus) and parvovirus B19 Fetal Chromosomal abnormalities such as Down syndrome which are associated with gastrointestinal abnormalities Congenital abnormalities such as renal agenesis and cystic renal disease are associated with impaired urine production, and posterior urethral valves or urethral atresia which are associated with obstruction of the lower urinary tract Intrauterine demise Post-term pregnancy Rupture of membranes Intrauterine growth restriction (IUGR) associated with placental insufficiency Amnion nodosum; failure of secretion by the cells of the amnion covering the placenta Placental Placental abruption Twin-twin transfusion Placental thrombosis or infarction Diagnosis Clinical Manifestation The volume of amniotic fluid typically increases until 36 weeks and starts decreasing after 40 weeks in post-term gestations. For this reason, discrepancies between fundal height measurements and gestational age can be a clinical indication of amniotic fluid abnormality and should be evaluated by ultrasound. Other common clinical presentations include fetal malpresentation, undue prominence of fetal parts, premature rupture of membranes, and reduced amount of amniotic fluid. Diagnosis Diagnosis of oligohydramnios is made by conducting a transabdominal ultrasound of the abdomen. There are two methods that can be used to make the diagnosis. The first is by using an amniotic fluid index (AFI). In this method, the sonographer measures the amniotic fluid in each of the four quadrants of the abdomen (right upper quadrant, left upper quadrant, right lower quadrant, left lower quadrant) and adds the values together. For reference, a normal AFI is 5–25 cm. An AFI <5 cm is considered oligohydramnios and an AFI >25 cm is considered polyhydramnios. Randomized control trials have shown that use of AFI can cause an increased number of false positive diagnosis of oligohydramnios and recommend using the measurement of a single deepest pocket (SDP) of amniotic fluid to diagnose oligohydramnios instead.To calculate a single deepest pocket, the sonographer scans each of the four quadrants of the abdomen looking for the deepest pocket of amniotic fluid that does not include any fetal body parts or an umbilical cord. It is measured from the 12 oclock position to the 6 oclock position. For reference, a normal SDP is 2–8 cm. A SDP <2 cm is considered oligohydramnios and a SDP >8 cm is considered polyhydramnios. The use of a SDP for diagnosis of oligohydramnios is associated with less false positives and thus less unnecessary interventions without an increase in adverse perinatal outcomes.In a multiple gestation pregnancy, measuring a single deepest pocket is the most accurate determination of adequate amniotic fluid levels. Management After initial diagnosis of oligohydramnios has been made, the next step is to perform a thorough history and physical exam, followed by diagnostic testing if indicated. Retaking a maternal and family history and performing a physical exam can point to maternal conditions or medications that might be causing the oligohydramnios. Premature prelabor rupture of membranes or prelabor rupture of membranes is ruled out with a nitrizine test, evidence of ferning, or evidence pooling of liquid in the cervix. Sonographic evaluation of the fetus is done to identify fetal anomalies, aneuploidy, fetal growth restriction, or placental abnormalities. The National Institute of Health recommends detailed documentation of certain fetal organs that are most likely to be involved such as the kidneys, bladder, and the umbilical cord. If the lack of amniotic fluid prevents accurate visualization on ultraosund, MRI imaging can be considered. Genetic testing can be useful if fetal anomalies are documented on imaging. An elevated maternal serum alpha fetal protein (MSAFP) can indicate leaking amniotic fluid due to damage to fetal membranes or the placenta. This is associated with a poor prognosis. A maternal blood test or amniotic fluid test can be performed if suspicion of a TORCH infection is high. Increasing amniotic fluid There is no way to permanently increase the volume of amniotic fluid, but it can be temporarily increased to allow for a complete anatomy scan of the fetus on ultrasound.One way to achieve this is through an amnioinfusion, which is the insertion of 200mL of saline into the amniotic sac. One study showed an improvement in fetal structure visibility by 26% (51% to 77% before and after the infusion respectively). There is also some low quality data that may indicate a potential benefit of amnioinfusion is to facilitate external cephalic version. Amnioinfusion can be used during labor to prevent umbilical cord compression. There is uncertainty about the procedures safety and efficacy, and it is recommended that it should only be performed in centers specializing in invasive fetal medicine and in the context of a multidisciplinary team.One to two liters of oral hydration can temporarily increase amniotic fluid in dehydrated patients with isolated oligohydramnios.Other investigational therapies may also be useful such as desmopressin, tissue sealants, or sildenafil citrate. These methods are less commonly used and are experimental.In case of congenital lower urinary tract obstruction, fetal surgery seems to improve survival, according to a randomized yet small study. Prenatal care Patients who are preterm are managed in the outpatient setting with weekly or biweekly testing to monitor for accurate fetal growth and decrease chances of unexpected fetal death. This includes a weekly non-stress test (NST) and single deepest pocket (SDP) assessment which is also referred to as the modified BPP. Sonographic fetal growth exams may also be indicated. Timing of delivery Idiopathic, uncomplicated, and persistent oligohydramnios can be delivered at 36 0/7 weeks – 37 6/7 weeks of gestation or at diagnosis if diagnosis is later. Complications Complications may include cord compression, musculoskeletal abnormalities such as facial distortion and clubfoot, pulmonary hypoplasia and intrauterine growth restriction. Amnion nodosum is frequently also present (nodules on the fetal surface of the amnion).The use of oligohydramnios as a predictor of gestational complications is controversial.Potter syndrome is a condition caused by oligohydramnios. Affected fetuses develop pulmonary hypoplasia, limb deformities, and characteristic facies. Bilateral agenesis of the fetal kidneys is the most common cause due to the lack of fetal urine. See also Fetal intervention Potters sequence References External links 00435 at CHORUS
Pneumococcal infection	A pneumococcal infection is an infection caused by the bacterium Streptococcus pneumoniae, which is also called the pneumococcus. S. pneumoniae is a common member of the bacterial flora colonizing the nose and throat of 5–10% of healthy adults and 20–40% of healthy children. However, it is also a cause of significant disease, being a leading cause of pneumonia, bacterial meningitis, and sepsis. The World Health Organization estimates that in 2005 pneumococcal infections were responsible for the death of 1.6 million children worldwide. Infections Pneumococcal pneumonia represents 15%–50% of all episodes of community-acquired pneumonia, 30–50% of all cases of acute otitis media, and a significant proportion of bloodstream infections and bacterial meningitis.As estimated by WHO in 2005 it killed about 1.6 million children every year worldwide with 0.7–1 million of them being under the age of five. The majority of these deaths were in developing countries. Pathogenesis S. pneumoniae is normally found in the nose and throat of 5–10% of healthy adults and 20–40% of healthy children. It can be found in higher amounts in certain environments, especially those where people are spending a great deal of time in close proximity to each other (day-care centers, military barracks). It attaches to nasopharyngeal cells through interaction of bacterial surface adhesins. This normal colonization can become infectious if the organisms are carried into areas such as the Eustachian tube or nasal sinuses where it can cause otitis media and sinusitis, respectively. Pneumonia occurs if the organisms are inhaled into the lungs and not cleared (again, viral infection, or smoking-induced ciliary paralysis might be contributing factors). The organisms polysaccharide capsule makes it resistant to phagocytosis and if there is no pre-existing anticapsular antibody alveolar macrophages cannot adequately kill the pneumococci. The organism spreads to the blood stream (where it can cause bacteremia) and is carried to the meninges, joint spaces, bones, and peritoneal cavity, and may result in meningitis, brain abscess, septic arthritis, or osteomyelitis.S. pneumoniae has several virulence factors, including the polysaccharide capsule mentioned earlier, that help it evade a hosts immune system. It has pneumococcal surface proteins that inhibit complement-mediated opsonization, and it secretes IgA1 protease that will destroy secretory IgA produced by the body and mediates its attachment to respiratory mucosa.The risk of pneumococcal infection is much increased in persons with impaired IgG synthesis, impaired phagocytosis, or defective clearance of pneumococci. In particular, the absence of a functional spleen, through congenital asplenia, surgical removal of the spleen, or sickle-cell disease predisposes one to a more severe course of infection (overwhelming post-splenectomy infection) and prevention measures are indicatedPeople with a compromised immune system, such as those living with HIV, are also at higher risk of pneumococcal disease. In HIV patients with access to treatment, the risk of invasive pneumoccal disease is 0.2–1% per year and has a fatality rate of 8%.There is an association between pneumococcal pneumonia and influenza. Damage to the lining of the airways (respiratory epithelium) and upper respiratory system caused by influenza may facilitate pneumococcal entry and infection. Other risk factors include smoking, injection drug use, Hepatitis C, and COPD. Virulence factors S. pneumoniae expresses different virulence factors on its cell surface and inside the organism. These virulence factors contribute to some of the clinical manifestations during infection with S. pneumoniae. Polysaccharide capsule—prevents phagocytosis by host immune cells by inhibiting C3b opsonization of the bacterial cells Pneumolysin (Ply)—a 53-kDa pore-forming protein that can cause lysis of host cells and activate complement Autolysin (LytA)—activation of this protein lyses the bacteria releasing its internal contents (i.e., pneumolysin) Hydrogen peroxide—causes damage to host cells (can cause apoptosis in neuronal cells during meningitis) and has bactericidal effects against competing bacteria (Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus) Pili—hair-like structures that extend from the surface of many strains of S. pneumoniae. They contribute to colonization of upper respiratory tract and increase the formation of large amounts of TNF by the immune system during sepsis, raising the possibility of septic shock Choline binding protein A/Pneumococcal surface protein A (CbpA/PspA)—an adhesin that can interact with carbohydrates on the cell surface of pulmonary epithelial cells and can inhibit complement-mediated opsonization of pneumococci Competence for genetic transformation likely plays an important role in nasal colonization fitness and virulence (lung infectivity) Diagnosis Depending on the nature of infection an appropriate sample is collected for laboratory identification. Pneumococci are typically gram-positive cocci seen in pairs or chains. When cultured on blood agar plates with added optochin antibiotic disk they show alpha-hemolytic colonies and a clear zone of inhibition around the disk indicating sensitivity to the antibiotic. Pneumococci are also bile soluble. Just like other streptococci they are catalase-negative. A Quellung test can identify specific capsular polysaccharides.Pneumococcal antigen (cell wall C polysaccharide) may be detected in various body fluids. Older detection kits, based on latex agglutination, added little value above Gram staining and were occasionally false-positive. Better results are achieved with rapid immunochromatography, which has a sensitivity (identifies the cause) of 70–80% and >90% specificity (when positive identifies the actual cause) in pneumococcal infections. The test was initially validated on urine samples but has been applied successfully to other body fluids. Chest X-rays can also be conducted to confirm inflammation though are not specific to the causative agent. Prevention Due to the importance of disease caused by S. pneumoniae several vaccines have been developed to protect against invasive infection. The World Health Organization recommend routine childhood pneumococcal vaccination; it is incorporated into the childhood immunization schedule in a number of countries including the United Kingdom, United States, and South Africa. Treatment Throughout history treatment relied primarily on β-lactam antibiotics. In the 1960s nearly all strains of S. pneumoniae were susceptible to penicillin, but more recently there has been an increasing prevalence of penicillin resistance especially in areas of high antibiotic use. A varying proportion of strains may also be resistant to cephalosporins, macrolides (such as erythromycin), tetracycline, clindamycin and the fluoroquinolones. Penicillin-resistant strains are more likely to be resistant to other antibiotics. Most isolates remain susceptible to vancomycin, though its use in a β-lactam-susceptible isolate is less desirable because of tissue distribution of the medication and concerns of development of vancomycin resistance.More advanced beta-lactam antibiotics (cephalosporins) are commonly used in combination with other antibiotics to treat meningitis and community-acquired pneumonia. In adults recently developed fluoroquinolones such as levofloxacin and moxifloxacin are often used to provide empiric coverage for patients with pneumonia, but in parts of the world where these medications are used to treat tuberculosis, resistance has been described.Susceptibility testing should be routine with empiric antibiotic treatment guided by resistance patterns in the community in which the organism was acquired. There is currently debate as to how relevant the results of susceptibility testing are to clinical outcome. There is slight clinical evidence that penicillins may act synergistically with macrolides to improve outcomes.Resistant Pneumococci strains are called penicillin-resistant Pneumococci (PRP), penicillin-resistant Streptococcus pneumoniae (PRSP), Streptococcus pneumoniae penicillin resistant (SPPR), or drug-resistant Strepotococcus pneumomoniae (DRSP). History In the 19th century it was demonstrated that immunization of rabbits with killed pneumococci protected them against subsequent challenge with viable pneumococci. Serum from immunized rabbits or from humans who had recovered from pneumococcal pneumonia also conferred protection. In the 20th century, the efficacy of immunization was demonstrated in South African miners.It was discovered that the pneumococcuss capsule made it resistant to phagocytosis, and in the 1920s it was shown that an antibody specific for capsular polysaccharide aided the killing of S. pneumoniae. In 1936, a pneumococcal capsular polysaccharide vaccine was used to abort an epidemic of pneumococcal pneumonia. In the 1940s, experiments on capsular transformation by pneumococci first identified DNA as the material that carries genetic information.In 1900 it was recognized that different serovars of pneumococci exist and that immunization with a given serovar did not protect against infection with other serovars. Since then over ninety serovars have been discovered each with a unique polysaccharide capsule that can be identified by the quellung reaction. Because some of these serovars cause disease more commonly than others it is possible to provide reasonable protection by immunizing with less than 90 serovars; current vaccines contain up to 23 serovars (i.e., it is "23-valent").The serovars are numbered according to two systems: the American system, which numbers them in the order in which they were discovered, and the Danish system, which groups them according to antigenic similarities. References External links November 2nd: World Pneumonia Day Website Pneumococcal Vaccine Accelerated Development and Introduction Plan
Patau syndrome	Patau syndrome is a syndrome caused by a chromosomal abnormality, in which some or all of the cells of the body contain extra genetic material from chromosome 13. The extra genetic material disrupts normal development, causing multiple and complex organ defects. This can occur either because each cell contains a full extra copy of chromosome 13 (a disorder known as trisomy 13 or trisomy D or T13), or because each cell contains an extra partial copy of the chromosome, or because there are two different lines of cells—one healthy with the correct number of chromosomes 13 and one that contains an extra copy of the chromosome—mosaic Patau syndrome. Full trisomy 13 is caused by nondisjunction of chromosomes during meiosis (the mosaic form is caused by nondisjunction during mitosis). Like all nondisjunction conditions (such as Down syndrome and Edwards syndrome), the risk of this syndrome in the offspring increases with maternal age at pregnancy, with about 31 years being the average. Patau syndrome affects somewhere between 1 in 10,000 and 1 in 21,700 live births. Signs and symptoms Of those fetuses that do survive to gestation and birth, common abnormalities may include: Nervous system Intellectual disability and motor disorder Microcephaly Holoprosencephaly (failure of the forebrain to divide properly) and associated facial deformities such as cyclopia Structural eye defects, including microphthalmia, Peters anomaly, cataract, iris or fundus (coloboma), retinal dysplasia or retinal detachment, sensory nystagmus, cortical visual loss, and optic nerve hypoplasia Meningomyelocele (a spinal defect) Musculoskeletal and cutaneous Polydactyly (extra digits) Proboscis Congenital trigger digits Low-set ears Prominent heel Deformed feet known as rocker-bottom feet Omphalocele (abdominal defect) Abnormal palm pattern Overlapping of fingers over thumb Cutis aplasia (missing portion of the skin/hair) Cleft palate Urogenital Abnormal genitalia Kidney defects Other Heart defects (ventricular septal defect) (Patent Ductus Arteriosus) Dextrocardia Single umbilical artery Causes Patau syndrome is the result of trisomy 13, meaning each cell in the body has three copies of chromosome 13 instead of the usual two. A small percentage of cases occur when only some of the bodys cells have an extra copy; such cases are called mosaic trisomy 13.Patau syndrome can also occur when part of chromosome 13 becomes attached to another chromosome (translocated) before or at conception in a Robertsonian translocation. Affected people have two copies of chromosome 13, plus extra material from chromosome 13 attached to another chromosome. With a translocation, the person has a partial trisomy for chromosome 13 and often the physical signs of the syndrome differ from the typical Patau syndrome.Most cases of Patau syndrome are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called non-disjunction can result in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of the chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra chromosome 13 in each of the bodys cells. Mosaic Patau syndrome is also not inherited. It occurs as a random error during cell division early in fetal development.Patau syndrome due to a translocation can be inherited. An unaffected person can carry a rearrangement of genetic material between chromosome 13 and another chromosome. This rearrangement is called a balanced translocation because there is no extra material from chromosome 13. Although they do not have signs of Patau syndrome, people who carry this type of balanced translocation are at an increased risk of having children with the condition. Recurrence risk Unless one of the parents is a carrier of a translocation, the chances of a couple having another trisomy 13 affected child is less than 1%, below that of Down syndrome. Diagnosis Diagnosis is usually based on clinical findings, although fetal chromosome testing will show trisomy 13. While many of the physical findings are similar to Edwards syndrome, there are a few unique traits, such as polydactyly. However, unlike Edwards syndrome and Down syndrome, the quad screen does not provide a reliable means of screening for this disorder. This is due to the variability of the results seen in fetuses with Patau. Treatment Medical management of children with Trisomy 13 is planned on a case-by-case basis and depends on the individual circumstances of the patient. Treatment of Patau syndrome focuses on the particular physical problems with which each child is born. Many infants have difficulty surviving the first few days or weeks due to severe neurological problems or complex heart defects. Surgery may be necessary to repair heart defects or cleft lip and cleft palate. Physical, occupational, and speech therapy will help individuals with Patau syndrome reach their full developmental potential. Surviving children are described as happy and parents report that they enrich their lives. Prognosis Approximately 90% of infants with Patau syndrome die within the first year of life. Those children who do survive past 1 year of life are typically severely disabled with intellectual disability, seizures, and psychomotor issues. Children with the mosaic variation are usually affected to a lesser extent. In a retrospective Canadian study of 174 children with trisomy 13, median survival time was 12.5 days. One and ten year survival was 19.8% and 12.9% respectively, including those who underwent aggressive surgical intervention. History Trisomy 13 was first observed by Thomas Bartholin in 1657, but the chromosomal nature of the disease was ascertained by Dr. Klaus Patau and Dr. Eeva Therman in 1960. The disease is named in Pataus honor.In England and Wales during 2008–09, there were 172 diagnoses of Patau syndrome (trisomy 13), with 91% of diagnoses made prenatally. There were 111 elective abortions, 14 stillbirth/miscarriage/fetal deaths, 30 outcomes unknown, and 17 live births. Approximately 4% of Patau syndrome with unknown outcomes are likely to result in a live birth, therefore the total number of live births is estimated to be 18. References External links Trisomy 13 at WebMD
Klippel–Feil syndrome	Klippel–Feil syndrome (KFS), also known as cervical vertebral fusion syndrome, is a rare congenital condition characterized by the abnormal fusion of any two of the seven bones in the neck (cervical vertebrae).: 578 It results in a limited ability to move the neck and shortness of the neck, resulting in the appearance of a low hairline.The syndrome is difficult to diagnose, as it occurs in a group of patients affected with many different abnormalities who can only be unified by the presence of fused or segmental cervical vertebrae. KFS is not always genetic and not always known about on the date of birth. The disease was initially reported in 1884 by Maurice Klippel and André Feil from France. In 1919, in his Doctor of Philosophy thesis, André Feil suggested another classification of the syndrome, encompassing not only deformation of the cervical spine, but also deformation of the lumbar and thoracic spine. Signs and symptoms KFS is associated with many other abnormalities of the body, hence thorough evaluation of all patients with fused cervical vertebrae at birth is required. Furthermore, it is unclear whether KFS is a unique disease, or if it is one part of a spectrum of congenital spinal deformities.KFS is usually diagnosed after birth. The most common signs of the disorder are restricted mobility of the neck and upper spine and a shortened neck with the appearance of a low hairline at the back of the head.Associated abnormalities may include: Scoliosis (sideways curvature of the spine) Spina bifida Problems with the kidneys and the ribs Cleft palate Dental problems (delayed dentition, cavities, missing teeth) Respiratory problems Heart defects Short stature Duane syndrome Srbs anomaly Sprengels deformityThe disorder also may be associated with abnormalities of the head and face, skeleton, sex organs, muscles, brain and spinal cord, arms, legs and fingers. Genetics Mutations of the GDF6, GDF3 and MEOX1 gene are associated with KFS. The cause of the condition is unknown in individuals with KFS who do not have mutations of these two genes. GDF6 and GDF3 provide the body with instructions for making proteins involved in regulating the growth and maturation of bone and cartilage. GDF6 specifically is involved in the formation of vertebral bones, among others, and establishing boundaries between bones in skeletal development. GDF3 is involved with bone and cartilage growth. Mutations of GDF6, GDF3 and MEOX1 cause a reduced number of functional proteins that are coded by these genes, but it is unclear exactly how a shortage in these proteins leads to incomplete separation of the vertebrae in people with KFS. However, when the GDF6 gene was removed in mice, the result was the fusion of bones.These mutations can be inherited in two ways: Autosomal dominant inheritance, where one copy of the altered gene in each cell is sufficient to cause the disorder, is especially associated with C2-C3 fusion. Autosomal recessive inheritance, where both copies of a gene contain mutations, is especially associated with C5-C6 fusion. Another autosomal dominant form (mapped on locus 8q22.2), known as KFS with laryngeal malformation, has been identified. It is also known as segmentation syndrome 1. Diagnosis The heterogeneity of KFS has made it difficult to outline the diagnosis as well as the prognosis for this disease. Classification In 1912, Maurice Klippel and Andre Feil independently provided the first descriptions of KFS. They described patients who had a short, webbed neck; decreased range of motion (ROM) in the cervical spine; and a low hairline. Feil subsequently classified the syndrome into 3 categories: Type I—Fusion of C2 and C3 with occipitalization of the atlas. In 1953, further complications were later reported by McRae; flexion and extension is concentrated within the C1 and C2 vertebrae. As with aging, the odontoid process can become hypermobile, narrowing the space where the spinal cord and brain stem travel (spinal stenosis). Type II—Long fusion below C2 with an abnormal occipital-cervical junction. Similar to the C2-C3 fusion of McRae and could be viewed as a more elaborate variation. Flexion, extension, and rotation are all concentrated in the area of an abnormal odontoid process or poorly developed ring of C1 which cannot withstand the effects of aging. Type III—A single open interspace between two fused segments. Cervical spine motion is concentrated at single open articulation. This hypermobility may lead to instability or degenerative osteoarthritis. This pattern can be recognized as the cervical spine is often seen to be at an angle or hinge at this open segment.A classification scheme for KFS was proposed in 1919 by Andre Feil, which accounted for cervical, thoracic, and lumbar spine malformations.However, in 2006, Dino Samartzis and colleagues proposed three classification-types that specifically addressed the cervical spine anomalies and their associated cervical spine-related symptoms, with additional elaboration on various time-dependent factors regarding this syndrome. Treatment Treatment for KFS is symptomatic and may include surgery to relieve cervical or craniocervical instability and constriction of the spinal cord, and to correct scoliosis.If symptomatic treatment fails, spinal surgery may provide relief. Adjacent segment disease and scoliosis are two examples of common symptoms associated with Klippel–Feil syndrome, and they may be treated surgically. The three categories treated for types of spinal cord deficiencies are massive fusion of the cervical spine (Type I), the fusion of 1 or 2 vertebrae (Type II), and the presence of thoracic and lumbar spine anomalies in association with type I or type II Klippel–Feil syndrome (Type III).Adjacent segment disease can be addressed by performing cervical disc arthroplasty using a device such as the Bryan cervical disc prosthesis. The option of the surgery is to maintain range of motion and attenuate the rate of adjacent segment disease advancement without fusion. Another type of arthroplasty that is becoming an alternate choice to spinal fusion is Total Disc Replacement. Total disc replacement objective is to reduce pain or eradicate it. Spinal fusion is commonly used to correct spinal deformities such as scoliosis. Arthrodesis is the last resort in pain relieving procedures, usually when arthroplasties fail. Prognosis The prognosis for most individuals with KFS is good if the disorder is treated early and appropriately. Activities that can injure the neck should be avoided, as it may contribute to further damage. Other diseases associated with the syndrome can be fatal if not treated, or if found too late to be treatable.In less than 30% of cases, individuals with KFS will present with heart defects. If these heart defects are present, they often lead to a shortened life expectancy, the average being 35–45 years of age among males and 40–50 among females. This condition is similar to the heart failure seen in gigantism. Epidemiology The prevalence of KFS is unknown due to the lack of studies to determine its prevalence. It is estimated to occur 1 in 40,000 to 42,000 newborns worldwide. In addition, females seem to be affected slightly more often than males. Notable cases Ancient A case of a child in Switzerland was discovered in a necropolis dated between 4500 and 4000 BC. In 2009, archaeologists excavating at a Neolithic site of the Đa Bút culture of northern Vietnam discovered the remains of a young man around age 25, "Burial 9", living between 2000 BC and 1500 BC with Klippel–Feil syndrome, who had apparently been supported by his subsistence-level community for at least a decade before his death. The 18th Dynasty Egyptian pharaoh Tutankhamun is believed by some to have had Klippel–Feil syndrome, though others dispute this claim. Contemporary English cricketer Gladstone Small "Big" Ed Brown from the TLC series, 90 Day Fiancé. Kansas City Chiefs wide receiver Justyn Ross. References This article incorporates information in the public domain prepared by the National Institute of Neurological Disorders and Stroke. External links Klippel–Feil syndrome at Curlie
Motor vehicle	A motor vehicle, also known as motorized vehicle or automotive vehicle, is a self-propelled land vehicle, commonly wheeled, that does not operate on rails (such as trains or trams) and is used for the transportation of people or cargo. The vehicle propulsion is provided by an engine or motor, usually an internal combustion engine or an electric motor, or some combination of the two, such as hybrid electric vehicles and plug-in hybrids. For legal purpose, motor vehicles are often identified within a number of vehicle classes including cars, buses, motorcycles, off-road vehicles, light trucks and regular trucks. These classifications vary according to the legal codes of each country. ISO 3833:1977 is the standard for road vehicle types, terms and definitions. Generally, to avoid requiring people with disabilities from having to possess an operators license to use one, or requiring tags and insurance, powered wheelchairs will be specifically excluded by law from being considered motor vehicles. As of 2011, there were more than one billion motor vehicles in use in the world, excluding off-road vehicles and heavy construction equipment. The US publisher Wards estimates that as of 2019, there were 1.4 billion motor vehicles in use in the world.Global vehicle ownership per capita in 2010 was 148 vehicles in operation (VIO) per 1000 people. China has the largest motor vehicle fleet in the world, with 322 million motor vehicles registered at the end of September 2018. The United States has the highest vehicle ownership per capita in the world, with 832 vehicles in operation per 1000 people in 2016. Also, China became the worlds largest new car market in 2009. In 2011, a total of 80 million cars and commercial vehicles were built, led by China which built a total of 18.4 million motor vehicles. Definitions and terminology In 1968 the Vienna Convention on Road Traffic gave one of the first international definitions of a motor vehicle: (o) “Power-driven vehicle” means any self-propelled road vehicle, other than a moped in the territories of Contracting Parties which do not treat mopeds as motorcycles, and other than a rail-borne vehicle; (p) “Motor vehicle” means any power-driven vehicle which is normally used for carrying persons or goods by road or for drawing, on the road, vehicles used for the carriage of persons or goods. This term embraces trolley-buses, that is to say, vehicles connected to an electric conductor and not rail-borne. It does not cover vehicles, such as agricultural tractors, which are only incidentally used for carrying persons or goods by road or for drawing, on the road, vehicles used for the carriage of persons or goods Other sources might provide other definitions, for instance in the year 1977, ISO 3833:1977 provide other definitions. Ownership trends The US publisher Wards estimates that as of 2010, there were 1.015 billion motor vehicles in use in the world. This figure represents the number of cars, trucks (light, medium and heavy duty), and buses, but does not include off-road vehicles or heavy construction equipment. The world vehicle population passed the 500 million-unit mark in 1986, from 250 million motor vehicles in 1970. Between 1950 and 1970, the vehicle population doubled roughly every 10 years. Navigant Consulting forecasts that the global stock of light-duty motor vehicles will reach 2 billion units in 2035.Global vehicle ownership in 2010 was 148 vehicles in operation per 1000 people, a ratio of 1:6.75 vehicles to people, slightly down from 150 vehicles per 1000 people in 2009, a rate of 1:6.63 vehicles to people. The global rate of motorization increased in 2013 to 174 vehicles per 1000 people. In developing countries vehicle ownership rates rarely exceed 200 cars per 1,000 population.The following table summarizes the evolution of motor vehicle registrations in the world from 1960 to 2019: Alternative fuels and vehicle technology adoption Since the early 2000s, the number of alternative fuel vehicles has been increasing driven by the interest of several governments to promote their widespread adoption through public subsidies and other non-financial incentives. Governments have adopted these policies due to a combination of factors, such as environmental concerns, high oil prices, and less dependence on imported oil.Among the fuels other than traditional petroleum fuels (gasoline or diesel fuel), and alternative technologies for powering the engine of a motor vehicle, the most popular options promoted by different governments are: natural gas vehicles, LPG powered vehicles, flex-fuel vehicles, use of biofuels, hybrid electric vehicles, plug-in hybrids, electric cars, and hydrogen fuel cell cars.Since the late 2000s, China, European countries, the United States, Canada, Japan and other developed countries have been providing strong financial incentives to promote the adoption of plug-in electric vehicle. As of 2020, the stock of light-duty plug-in vehicles in use totaled over 10 million units. As of 2019, in addition, the medium and heavy commercial segments add another 700,000 units to the global stock of plug-in electric vehicles. In 2020 the global market share of plug-in passenger car sales was 4.2%, up from 2.5% in 2019. Nevertheless, despite government support and the rapid growth experienced, the plug-in electric car segment represented just about 1 out of every 250 vehicles (0.4%) on the worlds roads by the end of 2018. China The Peoples Republic of China had 322 million motor vehicles in use at the end of September 2018, of which, 235 million were passenger cars in 2018, making China the country with largest motor vehicle fleet in the world. In 2016, the motor vehicle fleet consisted of 165.6 million cars and 28.4 million trucks and buses. About 13.6 million vehicles were sold in 2009, and motor vehicle registrations in 2010 increased to more than 16.8 million units, representing nearly half the worlds fleet increase in 2010. Ownership per capita rose from 26.6 vehicles per 1000 people in 2006 to 141.2 in 2016.The stock of highway-legal plug-in electric or new energy vehicles in China totaled 2.21 million units by the end of September 2018, of which, 81% are all-electric vehicles. These figures include heavy-duty commercial vehicles such buses and sanitation trucks, which represent about 11% of the total stock. China is also the worlds largest electric bus market, reaching about 385,000 units by the end of 2017.The number of cars and motorcycles in China increased 20 times between 2000 and 2010. This explosive growth has allowed China to become the worlds largest new car market, overtaking the US in 2009. Nevertheless, ownership per capita is 58 vehicles per 1000 people, or a ratio of 1:17.2 vehicles to people, still well below the rate of motorization of developed countries. United States The United States has the second largest fleet of motor vehicles in the world after China. As of 2016, had a motor vehicles stock of 259.14 million, of which, 246 million were light duty vehicles, consisting of 112.96 million passenger cars and 133 million light trucks (includes SUVs). A total of 11.5 million heavy trucks were registered at the end 2016 Vehicle ownership per capita in the U.S. is also the highest in the world, the U.S. Department of Energy (USDoE) reports a motorization rate of 831.9 vehicles in operation per 1000 people in 2016, or a ratio of 1:1.2 vehicles to people.According to USDoE, the rate of motorization peaked in 2007 at 844.5 vehicles per 1000 people. In terms of licensed drivers, as of 2009 the country had 1.0 vehicle for every licensed driver, and 1.87 vehicles per household. Passenger car registrations in the United States declined -11.5% in 2017 and -12.8% in 2018.As of 2016, the stock of alternative fuel vehicles in the United States included over 20 million flex-fuel cars and light trucks, the worlds second largest flexible-fuel fleet in the world after Brazil. However, actual use of ethanol fuel is significantly limited due to the lack of E85 refueling infrastructure.Regarding the electrified segment, the fleet of hybrid electric vehicles in the United States is the second largest in the world after Japan, with more than four million units sold through April 2016. Since the introduction of the Tesla Roadster electric car in 2008, cumulative sales of highway legal plug-in electric vehicles in the U.S. passed one million units in September 2018. The U.S. stock of plug-in vehicles is the second largest after China (2.21 million by September 2018).As of 2017, the countrys fleet also includes more than 160,000 natural gas vehicles, mainly transit buses and delivery fleets. Despite its relative small size, natural gas use accounted for about 52% of all alternative fuels consumed by alternative transportation fuel vehicles in the U.S. in 2009.In the US a motor vehicle is specifically defined as a contrivance used for commercial purposes. As defined in US Code 18 U.S.C. § 31 : US Code - Section 31: Definitions (6) Motor vehicle. - The term "motor vehicle" means every description of carriage or other contrivance propelled or drawn by mechanical power and used for commercial purposes on the highways in the transportation of passengers, passengers and property, or property or cargo. Europe The 27 European Union (EU-27) member countries had a fleet of over 256 million in 2008, and passenger cars accounted for 87% of the unions fleet. The five largest markets, Germany (17.7%), Italy (15.4%), France (13.3%), the UK (12.5%), and Spain (9.5%), accounted for 68% of the regions total registered fleet in 2008. The EU-27 member countries had in 2009 an estimated ownership rate of 473 passenger cars per 1000 people.According to Wards, Italy had the second highest (after the U.S.) vehicle ownership per capita in 2010, with 690 vehicles per 1000 people. Germany had a rate of motorization of 534 vehicles per 1000 people and the UK of 525 vehicles per 1000 people, both in 2008. France had a rate of 575 vehicles per 1000 people and Spain 608 vehicles per 1000 people in 2007. Portugal, between 1991 and 2002 grew up 220% on its motorization rate, having had in 2002, 560 cars per 1000 people.Italy also leads in alternative fuel vehicles, with a fleet of 779,090 natural gas vehicles as of June 2012, the largest NGV fleet in Europe. Sweden, with 225,000 flexible-fuel vehicles, has the largest flexifuel fleet in Europe by mid-2011.More than one million plug-in electric passenger cars and vans have been registered in Europe by June 2018, the worlds second largest regional plug-in stock after China.Norway is the leading plug-in market in Europe with almost 500,000 units registered as of December 2020. In October 2018, Norway became the worlds first country where 10% of all passenger cars on the road are plug-in electrics. Also, the Norwegian plug-in car segment market share has been the highest in the world for several years, achieving 39.2% in 2017, 49.1% in 2018, and 74.7% in 2020. Japan Japan had 73.9 million vehicles by 2010, and had the worlds second largest motor vehicle fleet until 2009. As of 2016, the registered motor vehicle fleet totaled 75.81 million vehicles consisting of 61,40 million cars and 14,41 million trucks and buses. Japan has the largest hybrid electric vehicle fleet in the world. As of March 2018, there were 7.51 million hybrids registered in the country, excluding kei cars, and representing 19.0% of all passenger cars on the road. Brazil The Brazilian vehicle fleet reached 64.8 million vehicles in 2010, up from 29.5 million units in 2000, representing a 119% growth in ten years, and reaching a motorization rate of 340 vehicles per 1000 people. In 2010 Brazil experienced the second largest fleet increase in the world after China, with 2.5 million vehicle registrations.As of 2018, Brazil has the largest alternative fuel vehicle fleet in the world with about 40 million alternative fuel motor vehicles in the road. The clean vehicle stock includes 30.5 million flexible-fuel cars and light utility vehicles and over 6 million flex-fuel motorcycles by March 2018; between 2.4 and 3.0 million neat ethanol vehicles still in use, out of 5.7 million ethanol only light-vehicles produced since 1979; and, as of December 2012, a total of 1.69 million natural gas vehicles.In addition, all the Brazilian gasoline-powered fleet is designed to operate with high ethanol blends, up to 25% ethanol fuel (E25). The market share of flex fuel vehicles reached 88.6% of all light-duty vehicles registered in 2017. India Indias vehicle fleet had the second-largest growth rate after China in 2010, with 8.9%. The fleet went from 19.1 million in 2009 to 20.8 million units in 2010. Indias vehicle fleet has increased to 210 million in March 2015. India has a fleet of 1.1 million natural gas vehicles as of December 2011 . Australia As of January 2011, the Australian motor vehicle fleet had 16.4 million registered vehicles, with an ownership rate of 730 motor vehicles per 1000 people, up from 696 vehicles per 1000 residents in 2006. The motor vehicle fleet grew 14.5% since 2006, for an annual rate of 2.7% during this five-year period. Comparison by regions The following table compares vehicle ownership rates by region with the US, the country with the highest motorization rate in the world, and how it has evolved from 1999 to 2016. Production by country In 2017, a total of 97.3 million cars and commercial vehicles were built worldwide, led by China, with about 29 million motor vehicles manufactured, followed by the United States with 11.2 million, and Japan with 9.7 million. The following table shows the top 15 manufacturing countries for 2017 and their corresponding annual production between 2004 and 2017. See also References == External links ==
Listeriosis	Listeriosis is a bacterial infection most commonly caused by Listeria monocytogenes, although L. ivanovii and L. grayi have been reported in certain cases. Listeriosis can cause severe illness, including severe sepsis, meningitis, or encephalitis, sometimes resulting in lifelong harm and even death. Those at risk of severe illness are the elderly, fetuses, newborns and those who are immunocompromised. In pregnant women it may cause stillbirth or spontaneous abortion, and preterm birth is common. Listeriosis may cause mild, self-limiting gastroenteritis and fever in anyone.Listeria is ubiquitous and is primarily transmitted via the oral route after ingestion of contaminated food products, after which the bacteria penetrates the intestinal tract to cause systemic infections. The diagnosis of listeriosis requires the isolation of the causative bacteria from the blood and/or the cerebrospinal fluid. Treatment includes prolonged administration of antibiotics, primarily ampicillin and gentamicin, to which the organism is usually susceptible. Signs and symptoms The disease primarily affects older adults, persons with weakened immune systems, pregnant women, and newborns. Rarely, people without these risk factors can also be affected. A person with listeriosis usually has fever and muscle aches, often preceded by diarrhea or other gastrointestinal symptoms. Almost everyone who is diagnosed with listeriosis has invasive infection (meaning that the bacteria spread from their intestines to their bloodstream or other body sites). Disease may occur as much as two months after eating contaminated food.The symptoms vary with the infected person: High-risk people other than pregnant women: Symptoms can include fever, muscle aches, headache, stiff neck, confusion, loss of balance, and convulsions. Pregnant women: Pregnant women typically experience only a mild, flu-like illness. However, infections during pregnancy can lead to miscarriage, stillbirth, premature delivery, or life-threatening infection of the newborn. Previously healthy people: People who were previously healthy but were exposed to a very large dose of Listeria can develop a non-invasive illness (meaning that the bacteria have not spread into their blood stream or other body sites). Symptoms can include diarrhea and fever.If an animal has eaten food contaminated with Listeria and does not have any symptoms, most experts believe that no tests or treatment are needed, even for people at high risk for listeriosis. Cause Listeria monocytogenes is ubiquitous in the environment. The main route of acquisition of Listeria is through the ingestion of contaminated food products. Listeria has been isolated from raw meat, dairy products, vegetables, fruit and seafood. Soft cheeses, unpasteurized milk and unpasteurised pâté are potential dangers; however, some outbreaks involving post-pasteurized milk have been reported.Rarely listeriosis may present as cutaneous listeriosis. This infection occurs after direct exposure to L. monocytogenes by intact skin and is largely confined to veterinarians who are handling diseased animals, most often after a listerial abortion.It can be more common in patients with hemochromatosis. Diagnosis In CNS infection cases, L. monocytogenes can often be cultured from the blood or from the CSF (Cerebrospinal fluid). Prevention The main means of prevention is through the promotion of safe handling, cooking and consumption of food. This includes washing raw vegetables and cooking raw food thoroughly, as well as reheating leftover or ready-to-eat foods like hot dogs until steaming hot.Another aspect of prevention is advising high-risk groups such as pregnant women and immunocompromised patients to avoid unpasteurized pâtés and foods such as soft cheeses like feta, Brie, Camembert cheese, and bleu. Cream cheeses, yogurt, and cottage cheese are considered safe. In the United Kingdom, advice along these lines from the Chief Medical Officer posted in maternity clinics led to a sharp decline in cases of listeriosis in pregnancy in the late 1980s. Treatment Bacteremia should be treated for 2 weeks, meningitis for 3 weeks, and brain abscess for at least 6 weeks. Ampicillin generally is considered antibiotic of choice; gentamicin is added frequently for its synergistic effects. Overall mortality rate is 20–30%; of all pregnancy-related cases, 22% resulted in fetal loss or neonatal death, but mothers usually survive. Epidemiology Incidence in 2004–2005 was 2.5–3 cases per million population a year in the United States, where pregnant women accounted for 30% of all cases. Of all nonperinatal infections, 70% occur in immunocompromised patients. Incidence in the U.S. has been falling since the 1990s, in contrast to Europe where changes in eating habits have led to an increase during the same time. In the EU, it has stabilized at around 5 cases per annum per million population, although the rate in each country contributing data to EFSA/ECDC varies greatly.There are four distinct clinical syndromes: Infection in pregnancy: Listeria can proliferate asymptomatically in the vagina and uterus. If the mother becomes symptomatic, it is usually in the third trimester. Symptoms include fever, myalgias, arthralgias and headache. Miscarriage, stillbirth and preterm labor are complications of this infection. Symptoms last 7–10 days. Neonatal infection (granulomatosis infantiseptica): There are two forms. One, an early-onset sepsis, with Listeria acquired in utero, results in premature birth. Listeria can be isolated in the placenta, blood, meconium, nose, ears, and throat. Another, late-onset meningitis is acquired through vaginal transmission, although it also has been reported with caesarean deliveries. Central nervous system (CNS) infection: Listeria has a predilection for the brain parenchyma, especially the brain stem, and the meninges. It can cause cranial nerve palsies, encephalitis, meningitis, meningoencephalitis and abscesses. Mental status changes are common. Seizures occur in at least 25% of patients. Gastroenteritis: L. monocytogenes can produce food-borne diarrheal disease, which typically is noninvasive. The median incubation period is 21 days, with diarrhea lasting anywhere from 1–3 days. Affected people present with fever, muscle aches, gastrointestinal nausea or diarrhea, headache, stiff neck, confusion, loss of balance, or convulsions.Listeria has also been reported to colonize the hearts of some patients. The overall incidence of cardiac infections caused by Listeria is relatively low, with 7–10% of case reports indicating some form of heart involvement. There is some evidence that small subpopulations of clinical isolates are more capable of colonizing the heart throughout the course of infection, but cardiac manifestations are usually sporadic and may rely on a combination of bacterial factors and host predispositions, as they do with other strains of cardiotropic bacteria. Recent outbreaks According to the Centers for Disease Control and Prevention (CDC) there are about 1,600 cases of listeriosis annually in the United States. Compared to 1996–1998, the incidence of listeriosis had declined by about 38% by 2003. However, illnesses and deaths continue to occur. On average from 1998 to 2008, 2.4 outbreaks per year were reported to the CDC.Some notable ones are listed below. 2002 United States outbreak A large outbreak occurred in 2002, when 54 illnesses, 8 deaths, and 3 fetal deaths in 9 states were found to be associated with consumption of contaminated turkey deli meat. 2008 Canadian listeriosis outbreak An outbreak of listeriosis in Canada linked to a Maple Leaf Foods plant in Toronto, Ontario killed 22 people. 2011 United States listeriosis outbreak On September 14, 2011, the U.S. Food and Drug Administration warned consumers not to eat cantaloupes shipped by Jensen Farms from Granada, Colorado due to a potential link to a multi-state outbreak of listeriosis. At that time Jensen Farms voluntarily recalled cantaloupes shipped from July 29 through September 10, and distributed to at least 17 states with possible further distribution.On September 26, the Centers for Disease Control and Prevention reported that a total of 72 persons had been infected with the four outbreak-associated strains of Listeria monocytogenes which had been reported to the CDC from 18 states. All illnesses started on or after July 31, 2011.On September 30, 2011, a random sample of romaine lettuce taken by the U.S. Food and Drug Administration tested positive for listeria on lettuce shipped on September 12 and 13 by an Oregon distributor to at least two other states—Washington and Idaho.By October 18, the CDC reported that 12 states were linked to listeria in cantaloupe and that 123 people had been sickened. A final count on December 8 put the death toll at 30: Colorado (8), Indiana (1), Kansas (3), Louisiana (2), Maryland (1), Missouri (3), Nebraska (1), New Mexico (5), New York (2), Oklahoma (1), Texas (2), and Wyoming (1). Among persons who died, ages ranged from 48 to 96 years, with a median age of 82.5 years. In addition, one woman pregnant at the time of illness had a miscarriage. 2015 United States listeriosis outbreak On March 13, 2015, the CDC announced that state and local health officials, CDC, and Food and Drug Administration were collaborating to investigate an outbreak of listeriosis in Kansas. The joint investigation found that certain Blue Bell Creameries ice cream products, including bars, scoops and cookies, were the likely source for some or all of these illnesses. Upon further investigation the CDC said Blue Bell ice cream had evidence of Listeria bacteria in its Oklahoma manufacturing plant as far back as March 2013. The outbreak led to 3 deaths in Kansas.Blue Bell was the nations third most popular ice cream brand. The items came from the companys production facility in Broken Arrow, Oklahoma . The CDC stated that all five of the sickened individuals, including the three older people who died, were receiving treatment at the same Kansas hospital before developing the listeriosis, suggesting their infections with the Listeria bacteria were nosocomial (acquired, while eating the products, in the hospital). Their pre-existing weakened conditions might help to explain the higher mortality rate in these cases (60%, versus the more normal 20–30%).On April 20, 2015, Blue Bell issued a voluntary recall of all its products, citing further internal testing that found Listeria monocytogenes in an additional half gallon of ice cream from the Brenham facility. 2015–18 European listeriosis outbreak On 5 July 2018 the Manchester Evening News reported that at least four major supermarket retailers had issued major product recalls as a result of a large supplier confirming possible contamination of frozen vegetables sourced from Hungary. The supplier, Greenyard Frozen UK, reported to the UKs Food Standards Agency that the factory in which the food was processed had been shut down by the Hungarian Food Chain Safety Office, after which the European Food Safety Authority and the European Centre for Disease Prevention and Control issued updates stating that at least five EU member states (UK, Austria, Denmark, Finland and Sweden) were affected. Between June 2015 and July 2018, 9 people had reportedly died as a result of listeriosis, of a total of 47 confirmed cases.In an update on the EFSA website, it was stated that the contamination had supposedly been present since at least 2015, and as a result the Hungarian Food Chain Safety Office had prohibited the marketing of all affected frozen vegetables and frozen vegetable packs produced by the plant in Baja between August 2016 and June 2018. This followed a previous study that found the majority of L. monocytogenes isolates had been found in a 2017 sample of various frozen vegetables, with a minority found in a 2016 sample and a small number found in a 2018 sample. The study suggested that the strain identified (L. monocytogenes serogroup IVb, multi-locus sequence type 6 (ST6)) was likely persisting through standard cleaning operations and disinfection procedures, and that since common production lines were in operation, cross-contamination was an additional concern. 2017–18 South African listeriosis outbreak In early December 2017 an outbreak of listeriosis was reported by the South African Department of Health. As of 4 March 2018, with 967 people infected and 180 deaths, this was the largest listeriosis outbreak in history. The source was traced to processed meat products produced at a Tiger Brands Enterprise plant in Polokwane. 2018 Australia listeriosis outbreaks On 2 March 2018 the New South Wales Food Authority confirmed that investigations into a listeriosis outbreak in rockmelons (cantaloupes) began in January. The cantaloupes had infected people from Victoria, Queensland, New South Wales and Tasmania, after being grown on a farm in the Riverina region of NSW.As of 2 March 2018, 13 of 15 cases had been confirmed as originating from listeria infected cantaloupes, and of the 15 people infected, 3 had died. Later victims included a fourth person on 7 March and a Victorian man in his 80s on 16 March. A miscarriage was also linked to listeriosis. Seventeen cases had been confirmed as of 7 March.In July 2018, a number of countries, including Australia, issued recalls of frozen vegetables due to Listeria. 2019 Spain listeriosis outbreak In August 2019, an outbreak was declared in several provinces in Andalusia, southern Spain, as a result of consumption of a contaminated batch of processed-meat products. As of 19 August 2019, 80 people had been diagnosed and 56 were hospitalized (43 of them in the province of Seville), As of 20 August, 114 people were diagnosed, and 18 pregnant woman in hospital, and the first confirmed death (a 90-year-old woman); although the total figure of hospitalised reduced to 53. In addition, eight miscarriages have been related to the outbreak. Spanish Minister of Health María Luisa Carcedo declared that the outbreak had expanded out of the Andalusian Autonomous Community, with one confirmed case in Extremadura and five suspected cases in Extremadura and Madrid. The Minister specified that, although new cases could appear as a consequence of the long incubation period, the contaminated product had been withdrawn. As of 21 August 2019, 132 people were diagnosed and 23 pregnant woman in hospital. On 22 August an international alert was declared. 2022 United States listeriosis outbreak On November 9, 2022 the CDC announced that Listeria in deli meats and cheeses had been linked to at least 16 cases of listeriosis, including 13 hospitalizations and 1 death. Cases were known from Maryland, New York, Illinois, Massachusetts, New Jersey and California. See also List of United States foodborne illness outbreaks 2008 Canadian listeriosis outbreak 2014 Macedonia listeriosis outbreak Listeriosis in animals References External links Media related to Listeriosis at Wikimedia Commons CDC Listeriosis site
Webbed toes	Webbed toes is the informal and common name for syndactyly affecting the feet—the fusion of two or more digits of the feet. This is normal in many birds, such as ducks; amphibians, such as frogs; and some mammals, such as kangaroos. In humans it is rare, occurring once in about 2,000 to 2,500 live births: most commonly the second and third toes are webbed (joined by skin and flexible tissue), which can reach partly or almost fully up the toe. Cause The exact cause of the condition is unknown. In some cases, close family members may share this condition. In other cases, no other related persons have this condition. The scientific name for the condition is syndactyly, although this term covers both webbed fingers and webbed toes. Syndactyly occurs when apoptosis or programmed cell death during gestation is absent or incomplete. Webbed toes occur most commonly in the following circumstances: Syndactyly or familial syndactyly Down syndromeIt is also associated with a number of rare conditions, notably: Aarskog–Scott syndrome Acrocallosal syndrome Apert syndrome Bardet–Biedl syndrome Carpenter syndrome Cornelia de Lange syndrome Edwards syndrome Jackson–Weiss syndrome Fetal hydantoin syndrome Miller syndrome Pfeiffer syndrome Smith–Lemli–Opitz syndrome Timothy syndrome Ectodermal dysplasia Klippel–Feil syndrome Diagnosis This condition is normally discovered at birth. If other symptoms are present, a specific syndrome may be indicated. Diagnosis of a specific syndrome is based on family history, medical history, and a physical exam. Webbed toes are also known as "twin toes," "duck toes," "turkey toes", "tree toes" and "tiger toes." Severity can vary. Most cases involve the second and third toes but any number of toes can be involved. In some cases the toes are joined part way while in some the webbing can extend right up to the nails. In some cases the entire toes, including the nails and bones, can be fused. Treatment Webbed toes can be separated through surgery. Surgical separation of webbed toes is an example of body modification. As with any form of surgery, there are risks of complications. In contrast, when left untreated it is very uncommon for webbed toes to cause complications beyond cosmetic considerations. For this reason, many medical professionals do not recommend surgical separation for typical cases. The end results depend on the extent of the webbing and underlying bone structure. There is usually some degree of scarring, and skin grafts may be required. In rare instances, nerve damage may lead to loss of feeling in the toes and a tingling sensation. There are also reports of partial web grow-back. The skin grafts needed to fill in the space between the toes can lead to additional scars in the places where the skin is removed. Notable cases Dan Aykroyd – Canada, actor Tricia Helfer – Canada, actress Jacqui Hurley – Ireland, sports broadcaster Ashton Kutcher – United States, actor Thomas Robert Malthus - England, political economist and demographer Joseph Stalin – Soviet Union, General Secretary of the Communist Party of the Soviet Union Danielle Panabaker – United States, actress See also Webbed foot Bird feet and legs - webbing and lobation References == External links ==
Gynophobia	Gynophobia or gynephobia is a morbid fear of women, a type of specific social phobia. In the past, the Latin term horror feminae was used.Gynophobia should not be confused with misogyny, the hatred, contempt for and prejudice against women, although some may use the terms interchangeably, in reference to the social, rather than pathological aspect of negative attitudes towards women. The antonym of misogyny is philogyny, the love, respect for and admiration of women.Gynophobia is analogous with androphobia, the extreme and/or irrational fear of men. A subset of gynophobia is caligynephobia, or the fear of beautiful women. Etymology The term gynophobia comes from the Greek γυνή - gunē, meaning "woman" and φόβος - phobos, "fear".Hyponyms of the term "gynophobia" include feminophobia. Ancient mythology Woman as mysterious vessel and fearsome goddess In ancient mythology, the idea of woman as a, "mysterious, magical body-vessel", or "intimidating Great Goddess" is common. In these myths, woman (sometimes also depicted as a Great World Tree, pomegranate, poppyhead, or mountain) bears all living things, and empties them out of herself into the living world. In the "vessel" analogy, the inside of the vessel is unknown, and all body orifices are special zones, each regarded as idols by artistic representation. The historical permanence of woman as body-vessel, is sometimes artistically depicted to elicit fear. For example, Albert Dubout depicted the Great Goddess as eliciting fear from a short man simply by displaying her large breasts and noting that her breasts survived World War II.In India, the goddess "Kali the Terrible" is the mother of the world and a fearsome, gruesome, and bloodthirsty destroyer of human life. She partially expresses her destruction through a wide array of female avatars (or "agents"). Kalis avatars and agents are regarded by believers as responsible for serious maladies such as typhoid fever, whooping cough, epilepsy, delirium, and convulsions. For example, Kalis agent goddess Vasurimala is mythologized as responsible for smallpox and cholera. Believers in the rural Indian town of Cranganore, make symbolic monetary offerings to Kali, to fulfill promises made in fear of being stricken with smallpox or cholera.Woman as "Great Goddess" was often depicted as a goddess of death in ancient Greek mythology as well. For example, in ancient Greek mythology, at least 7 female goddesses are depicted as both nursing mothers and as queens of the dead. Case studies In his book Sadism and Masochism: The Psychology of Hatred and Cruelty, Wilhelm Stekel discusses horror feminae of a male masochist. Proposed possible causes Envy of mothers genitals In The Dread of Woman (1932), Karen Horney proposed that gynophobia may be partially due to a boys fear that his genital is inadequate in relation to the mother. She also remarked that she was surprised at the lack of explicit recognition of gynophobia, after she allegedly found ample historical, clinical, mythological, and anthropological evidence of gynophobia. Differences in gendered-morality, and female hostility toward societal ideals The author of The Fear of Women, Wolfgang Lederer, makes the argument in his book that gynophobia is partially the result of men and women allegedly having different attitudes toward societally-based morality. He argues that women were mostly absent and also sometimes explicitly excluded from the meaningful aspects of the creation of society. He further argues that this contributes to what he sees as historically-universal female hostility toward societal goals such as justice, goals which exist outside practical and immediate interpersonal affairs. Wolfgang argues that this is not just his idea, but projected into religion through all historical communities that have both a father-deity and a mother-deity, where, he argues, the mother-deity is always morally indifferent. Because Wolfgang thinks that men generally have societal ideals, while women generally do not, Wolfgang argues that real women intrude obstinately and necessarily on an imagined ideal of women that men have of them. He states that this births a male fear that women will forever, or sooner or later, be his disappointment. Basic resource access barriers and population expansion limitations Extreme examples of universal, cultural gypnohobia have been found in the highlands of New Guinea, where widespread anti-masturbation propaganda coincides with notions of, "perilous female sexuality". The anthropologist Carol Ember argues that such fears were likely caused by limited availability of basic resources that would be required to increase the population. See also List of phobias == References ==
Orchitis	Orchitis is inflammation of the testes. It can also involve swelling, pains and frequent infection, particularly of the epididymis, as in epididymitis. The term is from the Ancient Greek ὄρχις meaning "testicle"; same root as orchid. Signs and symptoms Symptoms of orchitis are similar to those of testicular torsion. These can include: hematospermia (blood in the semen) hematuria (blood in the urine) severe pain visible swelling of a testicle or testicles and often the inguinal lymph nodes on the affected side. Causes Orchitis can be related to epididymitis infection that has spread to the testicles (then called "epididymo-orchitis"), sometimes caused by the sexually transmitted diseases chlamydia and gonorrhea. It has also been reported in cases of males infected with brucellosis. Orchitis can also be seen during active mumps, particularly in adolescent boys.Ischemic orchitis may result from damage to the blood vessels of the spermatic cord during inguinal herniorrhaphy, and may in the worst event lead to testicular atrophy. Diagnosis Blood – ESR high Urine – Cultural & Sensitivity test Ultrasound scanning Treatment In most cases where orchitis is caused by epididymitis, treatment is an oral antibiotic such as cefalexin or ciprofloxacin until infection clears up. In both causes non-steroidal anti-inflammatory drugs such as naproxen or ibuprofen are recommended to relieve pain. Sometimes stronger pain medications in the opiate category are called for and are frequently prescribed by experienced emergency department physicians. Other animals Orchitis is not rare in bulls and rams. It has also been described in roosters. References Further reading Lefort C, Thoumas D, Badachi Y, et al. (July 2001). "Orchites ischémiques: À propos de 5 cas diagnostiqués en écho-Doppler couleur" [Ischemic orchiditis: review of 5 cases diagnosed by color Doppler ultrasonography]. Journal de Radiologie (in French). 82 (7): 839–42. PMID 11507447. INIST:1080037. Chung JJ, Kim MJ, Lee T, Yoo HS, Lee JT (September 1997). "Sonographic findings in tuberculous epididymitis and epididymo-orchitis". Journal of Clinical Ultrasound. 25 (7): 390–4. doi:10.1002/(SICI)1097-0096(199709)25:7<390::AID-JCU7>3.0.CO;2-5. PMID 9282805. S2CID 23653479. Fong Y, Wantz GE (May 1992). "Prevention of ischemic orchitis during inguinal hernioplasty". Surgery, Gynecology & Obstetrics. 174 (5): 399–402. PMID 1570618. Beard CM, Benson RC, Kelalis PP, Elveback LR, Kurland LT (January 1977). "The incidence and outcome of mumps orchitis in Rochester, Minnesota, 1935 to 1974". Mayo Clinic Proceedings. 52 (1): 3–7. PMID 609284. Bigazzi PE, Kosuda LL, Hsu KC, Andres GA (February 1976). "Immune complex orchitis in vasectomized rabbits". The Journal of Experimental Medicine. 143 (2): 382–404. doi:10.1084/jem.143.2.382. PMC 2190126. PMID 129498. Lynch VP, Eakins D, Morrison E (August 1968). "Granulomatous orchitis". British Journal of Urology. 40 (4): 451–8. doi:10.1111/j.1464-410X.1968.tb11832.x. PMID 5678169. Dreyfuss W (April 1954). "Acute granulomatous orchiditis". The Journal of Urology. 71 (4): 483–7. doi:10.1016/S0022-5347(17)67813-3. PMID 13152871. Lambert B (1951). "The frequency of mumps and of mumps orchitis and the consequences for sexuality and fertility". Acta Genetica et Statistica Medica. 2 (Suppl. 1): 1–166. PMID 15444009. Grünberg H (1926). "Three unusual cases of chronic orchitis clinically resembling tumors of the testis". Frankfurt Z Pathol. 33: 217–27. == External links ==
Bornholm disease	Bornholm disease, also known as epidemic pleurodynia, is a condition characterized by myositis of the abdomen or chest caused by the Coxsackie B virus or other viruses. The myositis manifests as an intermittent stabbing pain in the musculature that is seen primarily in children and young adults.It is named after the Danish island of Bornholm in the Baltic Sea where an outbreak was one of the first to be described. Signs and symptoms The expected symptoms of Bornholm disease include fever, pleuritic chest pain, or epigastric abdominal pain that is frequently spasmodic. Bornholm associated chest pain is distinguished by attacks of severe pain in the lower chest, often on the right side. In a prior study, the episodes were shown to last five to ten minutes and then subside for thirty minutes. The pain is exacerbated by movement and makes walking and breathing more difficult. Patients have found relief from the pain by lying still for a brief period of time. The slightest movement of the rib cage causes a sharp increase in pain, which makes it difficult to breathe, although it generally passes off before any actual harm occurs. The attacks are unpredictable and strike "out of the blue" with a feeling like an iron grip around the rib cage. The colloquial names for the disease, such as the devils grip, (see "other names" below) reflect this symptom. Bornholm disease is a clinical diagnosis that uses the spasmodic pain, fever, and relapses to distinguish the illness from other potential causes of pain such as appendicitis or myocardial infarction. Tachycardia and arrhythmias have been found with Bornholm disease by using an electrocardiogram (ECG). Murmurs, rubs, and pericardial effusions have been detected on physical examination. Maculopapular rashes can also be present with Bornholm disease Etiology Inoculation of throat washings taken from people with this disease into the brains of newborn mice revealed that enteroviruses in the Coxsackie B virus group were likely to be the cause of pleurodynia, and those findings were supported by subsequent studies of IgM antibody responses measured in serum from people with pleurodynia. Other viruses in the enterovirus family, including echovirus and Coxsackie A virus, are less frequently associated with pleurodynia. Echovirus types 1,6,8,9, and 19 and Coxsackie A virus types 4,6,9, and 10 are associated with Bornholm disease. The most common strains causing Bornholm disease are Coxsackie B3 and A9. Viral proliferation in the muscles of the chest wall, diaphragm, and abdomen are thought to contribute to the typical presentation that characterizes the illness. Epidemiology The most common cause of Bornholm disease, Coxsackie B virus, is shed in large amounts in the feces of infected persons and is spread primarily through the fecal-oral route. Respiratory secretions and oral-oral methods have also shown to be modes of transmission. In previous cases the disease has been spread by sharing drink containers, and has been contracted by laboratory personnel working with the virus. The pharynx is typically the initial site for entering the body, however the virus will proliferate in lymphatic tissues and use the blood stream to reach the muscles and produce symptoms. Preventative measures to decrease transmission of the virus causing Bornholm disease emphasize hand hygiene. In previous studies of Bornholm disease the majority of the patients affected were children. Physical exam findings In a studied case of Bornholm disease the chest pain was unable to be reproduced on palpation and failed to improve with changes in position. The pain was made worse during deep inhalation. A pleural rub was present, however lung auscultation was clear and rashes were absent. Laboratory findings and imaging In a prior case of Bornholm disease the laboratory results showed the white blood cell count, hemoglobin, hematocrit, creatinine, liver function test (LFT), troponin, and creatine kinase (CK) were all within normal limits. The chest x-ray showed bilateral pleural effusions which resolved after infection. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were found to be elevated. The electrocardiogram (EKG) did not show any abnormalities related to ischemia. Treatment and prognosis Treatment is symptomatic and includes the administration of non-steroidal anti-inflammatory agents or the application of heat to the affected muscles. Intercostal 2% xylocaine injections with normal saline have been used to relieve symptoms in certain cases. Relapses during the weeks following the initial episode are a characteristic feature of this disease. Bornholm disease typically lasts between one day and one week with an average illness duration of four days. In 20% of cases studied, the illness lasted between one and two weeks. The illness in children was found to be shorter than the illness in adults. Patients typically make a complete recovery with supportive care. Although recovering from Bornholm disease is expected, some rare complications include myocarditis, respiratory failure, hepatic necrosis with coagulopathy, and disseminated intravascular coagulopathy (DIC). Aseptic meningitis, pericarditis and pleurisy are also known potential complications of Bornholm disease. Another uncommon complication is orchitis that manifests as unilateral testicular pain and swelling in the days or weeks following the expected symptoms of Bornholm disease. Differential diagnoses Acute appendicitis, cholecystitis, pancreatitis, pulmonary embolism, acute coronary syndrome, costochondritis, amongst others History In 1872, Anders Daae and Christian Horrebow Homann reported an epidemic of pleurodynia occurring in the community of Bamble, Norway, giving rise to the name "Bamble disease". Subsequent reports, published only in Norwegian, referred to the disease by this name. Niels Ryberg Finsen also described the disease in Iceland in 1874. In 1933, Ejnar Sylvest gave a doctoral thesis describing a Danish outbreak of this disease on Bornholm Island entitled "Bornholm disease-myalgia epidemica", and this name has persisted. In 1949 the Coxsackie B virus was isolated and established as an etiology of Bornholm disease. Other names Bornholm disease is also known as Bamble disease, the devils grip, devils grippe, epidemic myalgia, epidemic pleurodynia. References External links Bornholm Disease on patient.co.uk
Sleep deprivation	Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either chronic or acute and may vary widely in severity. Acute sleep deprivation is when an individual sleeps less than usual or does not sleep at all for a short period of time – usually lasting one to two days. Chronic sleep deprivation means when an individual routinely sleeps less than an optimal amount for ideal functioning. Chronic sleep deficiency is often confused with the term insomnia. Although both chronic sleep deficiency and insomnia share decreased quantity and/or quality of sleep as well as impaired function, their difference lies in the ability to fall asleep. Sleep deprived individuals are able to fall asleep rapidly when allowed but those with insomnia have difficulty falling asleep.The average adult needs seven or more hours of sleep per night to maintain health. The amount of sleep needed can depend on sleep quality, age, pregnancy, and level of sleep deprivation. Insufficient sleep has been linked to weight gain, high blood pressure, diabetes, depression, heart disease, and strokes. Sleep deprivation can also lead to high anxiety, irritability, erratic behavior, poor cognitive functioning and performance, and psychotic episodes.A chronic sleep-restricted state adversely affects the brain and cognitive function. However, in a subset of cases, sleep deprivation can paradoxically lead to increased energy and alertness and enhanced mood; although its long-term consequences have never been evaluated, sleep deprivation has even been used as a treatment for depression.Few studies have compared the effects of acute total sleep deprivation and chronic partial sleep restriction. A complete absence of sleep over a long period is not frequent in humans (unless they have fatal insomnia or specific issues caused by surgery); it appears that brief microsleeps cannot be avoided. Long-term total sleep deprivation has caused death in lab animals. Causes Insomnia Insomnia, one of the six types of dyssomnia, affects 21–37% of the adult population. Many of its symptoms are easily recognizable, including excessive daytime sleepiness; frustration or worry about sleep; problems with attention, concentration, or memory; extreme mood changes or irritability; lack of energy or motivation; poor performance at school or work; and tension headaches or stomach aches. Insomnia can be grouped into primary and secondary, or comorbid, insomnia.Primary insomnia is a sleep disorder not attributable to a medical, psychiatric, or environmental cause. There are three main types of primary insomnia. These include: psychophysiological, idiopathic insomnia, and sleep state misperception (paradoxical insomnia). Psychophysiological insomnia is anxiety-induced. Idiopathic insomnia generally begins in childhood and lasts the rest of a persons life. Its suggested that idiopathic insomnia is a neurochemical problem in a part of the brain that controls the sleep-wake cycle, resulting in either under-active sleep signals or over-active wake signals. Sleep state misperception is diagnosed when people get enough sleep but inaccurately perceive that their sleep is insufficient.Secondary insomnia, or comorbid insomnia, occurs concurrently with other medical, neurological, psychological and psychiatric conditions. Causation is not necessarily implied.Sleep is known to be cumulative. This means that the fatigue and sleep one lost as a result, for example, staying awake all night, would be carried over to the following day. Not getting enough sleep a couple days cumulatively builds up a deficiency and thats when all the symptoms of sleep deprivation come in. A well rested and healthy individual will generally spend less time in the REM stage of sleep. Studies have shown an inverse relationship between time spent in the REM stage of sleep and subsequent wakefulness during waking hours. Sleep apnea Sleep apnea is a serious disorder that has symptoms of both insomnia and sleep deprivation, among other symptoms like excessive daytime sleepiness, abrupt awakenings, difficulty concentrating, etc. Obstructive sleep apnea is often caused by collapse of the upper airway during sleep, which reduces airflow to the lungs. Those with sleep apnea may experience symptoms such as awakening gasping or choking, restless sleep, morning headaches, morning confusion or irritability and restlessness. This disorder affects between 1 and 10 percent of Americans. It has many serious health outcomes if untreated. Positive airway pressure therapy using a CPAP (Continuous positive airway pressure), APAP or BPAP devices is considered to be the first line treatment option for sleep apnea. Mandibular displacement devices in some cases can reposition the jaw and tongue to prevent the airway from collapsing. For some patients supplemental oxygen therapy may be indicated. Nasal problems such as a deviated septum will shut down the airway and increase swelling in the mucus lining and nasal turbinates. Corrective surgery (septoplasty) in some cases may be an appropriate choice of treatment. Central sleep apnea is caused by a failure of the central nervous system to signal the body to breathe during sleep. Treatments similar to obstructive sleep apnea may be used as well as other treatments such as Adaptive Servo Ventilation and certain medications. Some medications such as opioids may contribute to or cause central sleep apnea. Voluntary Sleep deprivation can sometimes be self-imposed due to a lack of desire to sleep or the habitual use of stimulant drugs. Sleep deprivation is also self-imposed to achieve personal fame in the context of record-breaking stunts. Mental illness The specific causal relationships between sleep loss and effects on psychiatric disorders have been most extensively studied in patients with mood disorders. Shifts into mania in bipolar patients are often preceded by periods of insomnia, and sleep deprivation has been shown to induce a manic state in about 30% of patients. Sleep deprivation may represent a final common pathway in the genesis of mania, and manic patients usually have a continuous reduced need for sleep.Chronic sleep problems affect 50% to 80% of patients in a typical psychiatric practice, compared with 10% to 18% of adults in the general U.S. population. Sleep problems are particularly common in patients with anxiety, depression, bipolar disorder, and attention deficit hyperactivity disorder (ADHD).The symptoms of sleep deprivation and those of schizophrenia are paralleled, including those of positive and cognitive symptoms. School The National Sleep Foundation cites a 1996 paper showing that college/university-aged students got an average of less than 6 hours of sleep each night. A 2018 study highlights the need for a good nights sleep for students finding that college students who averaged eight hours of sleep for the five nights of finals week scored higher on their final exams than those who didnt.In the study, 70.6% of students reported obtaining less than 8 hours of sleep, and up to 27% of students may be at risk for at least one sleep disorder. Sleep deprivation is common in first year college students as they adjust to the stress and social activities of college life. Estevan, et al, studied the relationships between sleep and test performance. They found that students tend to sleep less than usual the night before an exam, and that exam performance was positively correlated with sleep duration. A study performed by the Department of Psychology at the National Chung Cheng University in Taiwan concluded that freshmen received the least amount of sleep during the week.Studies of later start times in schools have consistently reported benefits to adolescent sleep, health and learning using a wide variety of methodological approaches. In contrast, there are no studies showing that early start times have any positive impact on sleep, health or learning. Data from international studies demonstrate that "synchronised" start times for adolescents are far later than the start times in the overwhelming majority of educational institutions. In 1997, University of Minnesota research compared students who started school at 7:15 am with those who started at 8:40 am. They found that students who started at 8:40 got higher grades and more sleep on weekday nights than those who started earlier. One in four U.S. high school students admits to falling asleep in class at least once a week.It is known that during human adolescence, circadian rhythms and therefore sleep patterns typically undergo marked changes. Electroencephalogram (EEG) studies indicate a 50% reduction of deep (stage 4) sleep and a 75% reduction in the peak amplitude of delta waves during NREM sleep in adolescence. School schedules are often incompatible with a corresponding delay in sleep offset, leading to a less than optimal amount of sleep for the majority of adolescents. Caffeine Consumption of caffeine in large quantities can have negative effects on ones sleep cycle. While there are short-term performance benefits to caffeine consumption, overuse can lead to insomnia symptoms or worsen pre-existing insomnia. Consuming caffeine to stay awake at night may lead to sleeplessness, anxiety, frequent nighttime awakenings, and overall poorer sleep quality. Hospital stay A study performed nationwide in the Netherlands found that general ward patients staying at the hospital experienced shorter total sleep (83 min. less), more night-time awakenings, and earlier awakenings compared to sleeping at home. Over 70% experienced being woken up by external causes, such as hospital staff (35.8%). Sleep disturbing factors included noise of other patients, medical devices, pain, and toilet visits. Sleep deprivation is even more severe in ICU patients, where the naturally occurring nocturnal peak of melatonin secretion was found to be absent, possibly causing the disruption in the normal sleep-wake cycle. However, as the personal characteristics and the clinical picture of hospital patients are so diverse, the possible solutions to improve sleep and circadian rhythmicity should be tailored to the individual and within the possibilities of the hospital ward. Multiple interventions could be considered to aid patient characteristics, improve hospital routines, or the hospital environment. Internet A study published in the Journal of Economic Behavior and Organisation found out that broadband internet connection was associated with sleep deprivation. The study concluded that the people with a broadband connection tend to sleep 25 minutes less than those without the broadband connection, hence they are less likely to get the scientifically recommended 7–9 hours of sleep. Another study conducted on 435 non-medical staff at King Saud University Medical City reported that 9 out of 10 of the respondents used their smartphones at bedtime, with social media being the most used service (80.5%). The study found participants who spent more than 60 minutes using their smartphones at bedtime were 7.4 times more likely to have poor sleep quality than participants who spent less than 15 minutes. Effects and consequences Brain One study suggested, based on neuroimaging, that 35 hours of total sleep deprivation in healthy controls negatively affected the brains ability to put an emotional event into the proper perspective and make a controlled, suitable response to the event.The negative effects of sleep deprivation on alertness and cognitive performance suggest decreases in brain activity and function. These changes primarily occur in two regions: the thalamus, a structure involved in alertness and attention; and the prefrontal cortex, a region sub-serving alertness, attention, and higher-order cognitive processes. This was the finding of an American study in 2000. Seventeen men in their 20s were tested. Sleep deprivation was progressive with measurements of glucose (absolute regional CMRglu), cognitive performance, alertness, mood, and subjective experiences collected after 0, 24, 48, and 72 hours of sleep deprivation. Additional measures of alertness, cognitive performance, and mood were collected at fixed intervals. PET scans were used and attention was paid to the circadian rhythm of cognitive performance. Interestingly, the effects of sleep deprivation appear to be constant across "night owls" and "early birds", or different sleep chronotypes, as revealed by fMRI and graph theory.A noted 2002 University of California animal study indicated that non-rapid eye movement sleep (NREM) is necessary for turning off neurotransmitters and allowing their receptors to "rest" and regain sensitivity which allows monoamines (norepinephrine, serotonin and histamine) to be effective at naturally produced levels. This leads to improved regulation of mood and increased learning ability. The study also found that rapid eye movement sleep (REM) deprivation may alleviate clinical depression because it mimics selective serotonin reuptake inhibitors (SSRIs). This is because the natural decrease in monoamines during REM is not allowed to occur, which causes the concentration of neurotransmitters in the brain, that are depleted in clinically depressed persons, to increase. Sleep outside of the REM phase may allow enzymes to repair brain cell damage caused by free radicals. High metabolic activity while awake damages the enzymes themselves preventing efficient repair. This study observed the first evidence of brain damage in rats as a direct result of sleep deprivation. Attention and working memory Among the possible physical consequences of sleep deprivation, deficits in attention and working memory are perhaps the most important; such lapses in mundane routines can lead to unfortunate results, from forgetting ingredients while cooking to missing a sentence while taking notes. Performing tasks that require attention appears to be correlated with number of hours of sleep received each night, declining as a function of hours of sleep deprivation. Working memory is tested by methods such as choice-reaction time tasks.The attentional lapses also extend into more critical domains in which the consequences can be life-or-death; car crashes and industrial disasters can result from inattentiveness attributable to sleep deprivation. To empirically measure the magnitude of attention deficits, researchers typically employ the psychomotor vigilance task (PVT) which requires the subject to press a button in response to a light at random intervals. Failure to press the button in response to the stimulus (light) is recorded as an error, attributable to the microsleeps that occur as a product of sleep deprivation.Crucially, individuals subjective evaluations of their fatigue often do not predict actual performance on the PVT. While totally sleep-deprived individuals are usually aware of the degree of their impairment, lapses from chronic (lesser) sleep deprivation can build up over time so that they are equal in number and severity to the lapses occurring from total (acute) sleep deprivation. Chronically sleep-deprived people, however, continue to rate themselves considerably less impaired than totally sleep-deprived participants. Since people usually evaluate their capability on tasks like driving subjectively, their evaluations may lead them to the false conclusion that they can perform tasks that require constant attention when their abilities are in fact impaired. Mood Sleep deprivation can have a negative impact on mood. Staying up all night or taking an unexpected night shift can make one feel irritable. Once one catches up on sleep, ones mood will often return to baseline or normal. Even partial sleep deprivation can have a significant impact on mood. In one study, subjects reported increased sleepiness, fatigue, confusion, tension, and total mood disturbance, which all recovered to their baseline after one to two full nights of sleep.Depression and sleep are in a bidirectional relationship. Poor sleep can lead to development of depression and depression can cause insomnia, hypersomnia, or obstructive sleep apnea. About 75% of adult patients with depression can present insomnia. Sleep deprivation, whether total or not, can induce significant anxiety and longer sleep deprivations tend to result in increased level of anxiety.Sleep deprivation has also shown some positive effects on mood, and can be used to treat depression. Chronotype can affect how sleep deprivation influences mood. Those with morningness (advanced sleep period or "lark") preference become more depressed after sleep deprivation while those with eveningness (delayed sleep period or "owl") preference show an improvement in mood.Mood and mental states can affect sleep as well. Increased agitation and arousal from anxiety or stress can keep one more aroused, awake, and alert. Driving ability The dangers of sleep deprivation are apparent on the road; the American Academy of Sleep Medicine (AASM) reports that one in every five serious motor vehicle injuries is related to driver fatigue, with 80,000 drivers falling asleep behind the wheel every day and 250,000 accidents every year related to sleep, though the National Highway Traffic Safety Administration suggests the figure for traffic accidents may be closer to 100,000. The AASM recommends pulling off the road and taking a 15- or 20-minute nap to alleviate drowsiness.According to a 2000 study published in the British Medical Journal, researchers in Australia and New Zealand reported that sleep deprivation can have some of the same hazardous effects as being drunk. People who drove after being awake for 17–19 hours performed worse than those with a blood alcohol level of 0.05 percent, which is the legal limit for drunk driving in most western European countries and Australia. Another study suggested that performance begins to degrade after 16 hours awake, and 21 hours awake was equivalent to a blood alcohol content of 0.08 percent, which is the blood alcohol limit for drunk driving in Canada, the U.S., and the U.K.Fatigue of drivers of goods trucks and passenger vehicles have come to the attention of authorities in many countries, where specific laws have been introduced with the aim of reducing the risk of traffic accidents due to driver fatigue. Rules concerning minimum break lengths, maximum shift lengths and minimum time between shifts are common in the driving regulations used in different countries and regions, such as the drivers working hours regulations in the European Union and hours of service regulations in the United States. The Exxon Valdez Oil Spill was the second largest oil spill in the United States. This accident occurred when an Exxon oil tanker struck a reef at the Prince William Sound in Alaska. Approximately 10.8 million gallons of oil spilled into the sea. The accident caused great environmental damage including the death of hundreds of thousands of birds and sea creatures. Fatigue and sleep deprivation were the major contributors to the accident. The captain of the ship was asleep after a night of heavy drinking; he was severely fatigued and had been awake for 18 hours. The entire crew was suffering from fatigue and inadequate sleep. Sleep transition Sleep propensity (SP) can be defined as the readiness to transit from wakefulness to sleep, or the ability to stay asleep if already sleeping. Sleep deprivation increases this propensity, which can be measured by polysomnography (PSG), as a reduction in sleep latency (the time needed to fall asleep). An indicator of sleep propensity can also be seen in the shortening of transition from light stages of non-REM sleep to deeper slow-waves oscillations can also be measured as indicator of sleep propensity.On average, the latency in healthy adults decreases by a few minutes after a night without sleep, and the latency from sleep onset to slow-wave sleep is halved. Sleep latency is generally measured with the multiple sleep latency test (MSLT). In contrast, the maintenance of wakefulness test (MWT) also uses sleep latency, but this time as a measure of the capacity of the participants to stay awake (when asked to) instead of falling asleep. Sleep-wake cycle People aged 18 to 64 need seven to nine hours of sleep per night. Research studying sleep deprivation shows its impact on mood, cognitive and motor functioning, due to dysregulation of the sleep-wake cycle and augmented sleep propensity. Multiple studies that identified the role of the hypothalamus and multiple neural systems controlling circadian rhythms and homeostasis have been helpful in understanding sleep deprivation better. To describe the temporal course of the sleep-wake cycle, the two-process model of sleep regulation can be mentioned.This model proposes a homeostatic process (Process S) and a circadian process (Process C) that interact to define the time and intensity of sleep. Process S represents the drive for sleep, increasing during wakefulness and decreasing during sleep, until a defined threshold level, while Process C is the oscillator responsible for these levels. When being sleep deprived, homeostatic pressure accumulates to the point that waking functions will be degraded even at the highest circadian drive for wakefulness. Microsleeps Microsleeps are periods of brief sleep that most frequently occur when a person has a significant level of sleep deprivation. Microsleeps usually last for a few seconds, usually no longer than 15 seconds, and happen most frequently when a person is trying to stay awake when they are feeling sleepy. The person usually falls into microsleep while doing a monotonous task like driving, reading a book, or staring at a computer. Microsleeps are similar to blackouts and a person experiencing them is not consciously aware that they are occurring. An even lighter type of sleep has been seen in rats that have been kept awake for long periods of time. In a process known as local sleep, specific localized brain regions went into periods of short (~80 ms) but frequent (~40/min) NREM-like states. Despite the on and off periods where neurons shut off, the rats appeared to be awake, although they performed poorly at tests. Cardiovascular morbidity Decreased sleep duration is associated with many adverse cardiovascular consequences. The American Heart Association has stated that sleep restriction is a risk factor for adverse cardiometabolic profiles and outcomes. The organization recommends healthy sleep habits for ideal cardiac health along with other well known factors like blood pressure, cholesterol, diet, glucose, weight, smoking, and physical activity. The Centers for Disease Control and Prevention has noted that adults who sleep less than 7 hours per day are more likely to have chronic health conditions including heart attack, coronary heart disease, and stroke compared to those with adequate amount of sleep.In a study that followed over 160,000 healthy, non-obese adults, the subjects who self-reported sleep duration less than 6 hours a day were at an increased risk for developing multiple cardiometabolic risk factors. They presented with increased central obesity, elevated fasting glucose, hypertension, low high-density lipoprotein, hypertriglyceridemia, and metabolic syndrome. The presence or lack of insomnia symptoms did not modify the effects of sleep duration in this study.The United Kingdom Biobank studied nearly 500,000 adults who had no cardiovascular disease, and the subjects who slept less than 6 hours a day were associated with a 20 percent increase in the risk of developing myocardial infarction (MI) over 7 years of follow-up period. Interestingly, long sleep duration of more than 9 hours a night was also a risk factor. Immunosuppression Among the myriad of health consequences that sleep deprivation can cause, disruption of the immune system is one of them. While it is not clearly understood, researchers believe that sleep is essential to providing sufficient energy for the immune system to work and allow inflammation to take place during sleep. Also, just as sleep can reinforce memory in a persons brain, it can help consolidate the memory of the immune system or adaptive immunity.An adequate amount of sleep improves effects of vaccines that utilize adaptive immunity. When vaccines expose the body to a weakened or deactivated antigen, the body initiates an immune response. The immune system learns to recognize that antigen and attacks it when exposed again in the future. Studies have found that people who dont sleep the night after getting a vaccine were less likely to develop a proper immune response to the vaccine and sometimes even required a second dose. People who are sleep deprived in general also do not provide their bodies with sufficient time for an adequate immunological memory to form, and thus, can fail to benefit from vaccination.People who sleep less than 6 hours a night are more prone to infection and are more likely to catch a cold or flu. A lack of sleep can also prolong the recovery time in patients in intensive care unit (ICU). Weight gain A lack of sleep can cause an imbalance in several hormones that are critical in weight gain. Sleep deprivation increases the level of ghrelin (hunger hormone) and decreases the level of leptin (fullness hormone), resulting in an increased feeling of hunger and desire for high-calorie foods. Sleep loss is also associated with decreased growth hormone and elevated cortisol levels, which are connected to obesity. People who do not get sufficient sleep can also feel sleepy and fatigued during the day and get less exercise. Obesity can cause poor sleep quality as well. Individuals who are overweight or obese can experience obstructive sleep apnea, gastroesophageal reflux disease (GERD), depression, asthma, and osteoarthritis which all can disrupt a good nights sleep.In rats, prolonged, complete sleep deprivation increased both food intake and energy expenditure with a net effect of weight loss and ultimately death. This study hypothesizes that the moderate chronic sleep debt associated with habitual short sleep is associated with increased appetite and energy expenditure with the equation tipped towards food intake rather than expenditure in societies where high-calorie food is freely available. Type 2 diabetes It has been suggested that people experiencing short-term sleep restrictions process glucose more slowly than individuals receiving a full 8 hours of sleep, increasing the likelihood of developing type 2 diabetes. Poor sleep quality is linked to high blood sugar levels in diabetic and prediabetic patients but the causal relationship is not clearly understood. Researchers suspect that sleep deprivation affects insulin, cortisol, and oxidative stress, which subsequently influence blood sugar levels. Sleep deprivation can increase the level of ghrelin and decrease the level of leptin. People who get insufficient amount of sleep are more likely to crave food in order to compensate for the lack of energy. This habit can raise blood sugar and put them at risk of obesity and diabetes.In 2005, a study of over 1400 participants showed that participants who habitually slept few hours were more likely to have associations with type 2 diabetes. However, because this study was merely correlational, the direction of cause and effect between little sleep and diabetes is uncertain. The authors point to an earlier study which showed that experimental rather than habitual restriction of sleep resulted in impaired glucose tolerance (IGT). Other effects The National Sleep Foundation identifies several warning signs that a driver is dangerously fatigued. These include rolling down the window, turning up the radio, trouble keeping eyes open, head-nodding, drifting out of their lane, and daydreaming. At particular risk are lone drivers between midnight and 6:00 am.Sleep deprivation can negatively impact overall performance, and has led to major fatal accidents. Due largely to the February 2009 crash of Colgan Air Flight 3407, which killed 50 people and was partially attributed to pilot fatigue, the FAA reviewed its procedures to ensure that pilots are sufficiently rested. Air traffic controllers were under scrutiny when in 2010 there were 10 incidents of controllers falling asleep while on shift. The common practice of turn-around shifts caused sleep deprivation and was a contributing factor to all air traffic control incidents. The FAA reviewed its practices of shift changes and the findings saw that controllers were not well rested. A 2004 study also found medical residents with less than four hours of sleep a night made more than twice as many errors as the 11% of surveyed residents who slept for more than seven hours a night.Twenty-four hours of continuous sleep deprivation results in the choice of less difficult math tasks without decreases in subjective reports of effort applied to the task. Naturally caused sleep loss affects the choice of everyday tasks such that low effort tasks are mostly commonly selected. Adolescents who experience less sleep show a decreased willingness to engage in sports activities that require effort through fine motor coordination and attention to detail.Great sleep deprivation mimics psychosis: distorted perceptions can lead to inappropriate emotional and behavioral responses.Astronauts have reported performance errors and decreased cognitive ability during periods of extended working hours and wakefulness as well as due to sleep loss caused by circadian rhythm disruption and environmental factors.One study has found that a single night of sleep deprivation may cause tachycardia, a condition in which the heartrate exceeds 100 beats per minute (in the following day).Generally, sleep deprivation may facilitate or intensify: aching muscles confusion, memory lapses or loss depression development of false memory hypnagogic and hypnopompic hallucinations during falling asleep and waking, which are entirely normal hand tremor headaches malaise stye periorbital puffiness, commonly known as "bags under eyes" or eye bags increased blood pressure increased stress hormone levels increased risk of Type 2 diabetes lowering of immunity, increased susceptibility to illness increased risk of fibromyalgia irritability nystagmus (rapid involuntary rhythmic eye movement) obesity seizures temper tantrums in children violent behavior yawning mania Sleep inertia symptoms similar to: attention-deficit hyperactivity disorder (ADHD) psychosis Assessment Patients with sleep deprivation may present with complaints of symptoms and signs of insufficient sleep such as fatigue, sleepiness, drowsy driving, and cognitive difficulties. Sleep insufficiency can easily go unrecognized and undiagnosed unless patients are specifically asked about it by their clinicians.Several questions are critical in evaluating sleep duration and quality, as well as the cause of sleep deprivation. Sleep patterns (typical bed time or rise time on weekdays and weekends), shift work, and frequency of naps can reveal the direct cause of poor sleep, and quality of sleep should be discussed to rule out any diseases such as obstructive sleep apnea and restless leg syndrome.Sleep diaries are useful in providing detailed information about sleep patterns. They are inexpensive, readily available, and easy to
Sleep deprivation	use. The diaries can be as simple as a 24-hour log to note the time of being asleep or can be detailed to include other relevant information. Sleep questionnaires such as the Sleep Timing Questionnaire (STQ) can be used instead of sleep diaries if there is any concern for patient adherence.Actigraphy is a useful, objective wrist-worn tool if the validity of self-reported sleep diaries or questionnaires is questionable. Actigraphy works by recording movements and using computerized algorithms to estimate total sleep time, sleep onset latency, the amount of wake after sleep onset, and sleep efficiency. Some devices have light sensors to detect light exposure. Management Although there are numerous causes of sleep deprivation, there are some fundamental measures that promote quality sleep as suggested by organizations such as Centers for Disease Control and Prevention, the National Institute of Health, the National Institute of Aging, and the American Academy of Family Physicians. The key is to implement healthier sleep habits, also known as sleep hygiene. Sleep hygiene recommendations include setting a fixed sleep schedule, taking naps with caution, maintaining a sleep environment that promotes sleep (cool temperature, limited exposure to light and noise, comfortable mattress and pillows), exercising daily, avoiding alcohol, cigarettes, caffeine, and heavy meals in the evening, winding down and avoiding electronic use or physical activities close to bedtime, and getting out of bed if unable to fall asleep.For long term involuntary sleep deprivation, cognitive behavioral therapy for Insomnia (CBT-i) is commonly recommended as a first-line treatment, after exclusion of physical diagnosis (f.e. sleep apnea). CBT-i contains five different components: cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation. These components together have shown to be effective in adults, with clinical meaningful effect sizes. As this approach has minimal adverse effects, and long-term benefits, it is often preferred to (chronic) drug therapy.There are several strategies that help increase alertness and counteract the effects of sleep deprivation. Caffeine is often used over short periods to boost wakefulness when acute sleep deprivation is experienced; however, caffeine is less effective if taken routinely. Other strategies recommended by the American Academy of Sleep Medicine include prophylactic sleep before deprivation, naps, other stimulants, and combinations thereof. However, the only sure and safe way to combat sleep deprivation is to increase nightly sleep time. Uses To facilitate abusive control Sleep deprivation can be used to disorientate abuse victims to help set them up for abusive control. Interrogation Sleep deprivation can be used as a means of interrogation, which has resulted in court trials over whether or not the technique is a form of torture.Under one interrogation technique, a subject might be kept awake for several days and when finally allowed to fall asleep, suddenly awakened and questioned. Menachem Begin, the Prime Minister of Israel from 1977 to 1983, described his experience of sleep deprivation as a prisoner of the NKVD in the Soviet Union as follows: In the head of the interrogated prisoner, a haze begins to form. His spirit is wearied to death, his legs are unsteady, and he has one sole desire: to sleep... Anyone who has experienced this desire knows that not even hunger and thirst are comparable with it. Sleep deprivation was one of the five techniques used by the British government in the 1970s. The European Court of Human Rights ruled that the five techniques "did not occasion suffering of the particular intensity and cruelty implied by the word torture... [but] amounted to a practice of inhuman and degrading treatment", in breach of the European Convention on Human Rights.The United States Justice Department released four memos in August 2002 describing interrogation techniques used by the Central Intelligence Agency. They first described 10 techniques used in the interrogation of Abu Zubaydah, described as a terrorist logistics specialist, including sleep deprivation. Memos signed by Steven G. Bradbury in May 2005 claimed that forced sleep deprivation for up to 180 hours (7+1⁄2 days) by shackling a diapered prisoner to the ceiling did not constitute torture, nor did the combination of multiple interrogation methods (including sleep deprivation) constitute torture under United States law. These memoranda were repudiated and withdrawn during the first months of the Obama administration.The question of extreme use of sleep deprivation as torture has advocates on both sides of the issue. In 2006, Australian Federal Attorney-General Philip Ruddock argued that sleep deprivation does not constitute torture. Nicole Bieske, a spokeswoman for Amnesty International Australia, has stated the opinion of her organization thus: "At the very least, sleep deprivation is cruel, inhumane and degrading. If used for prolonged periods of time it is torture." Treating depression Studies show that sleep restriction has some potential in treating depression. Those with depression tend to have earlier occurrences of REM sleep with an increased number of rapid eye movements; therefore, monitoring patients EEG and awakening them during occurrences of REM sleep appear to have a therapeutic effect, alleviating depressive symptoms. This kind of treatment is known as wake therapy. Although as many as 60% of patients show an immediate recovery when sleep-deprived, most patients relapse the following night. The effect has been shown to be linked to an increase in the brain-derived neurotrophic factor (BDNF). A comprehensive evaluation of the human metabolome in sleep deprivation in 2014 found that 27 metabolites are increased after 24 waking hours and suggested serotonin, tryptophan, and taurine may contribute to the antidepressive effect.The incidence of relapse can be decreased by combining sleep deprivation with medication or a combination of light therapy and phase advance (going to bed substantially earlier than ones normal time). Many tricyclic antidepressants suppress REM sleep, providing an additional evidence for a link between mood and sleep. Similarly, tranylcypromine has been shown to completely suppress REM sleep at adequate doses. Treating insomnia Sleep deprivation can be implemented for a short period of time in the treatment of insomnia. Some common sleep disorders have been shown to respond to cognitive behavioral therapy for insomnia. Cognitive behavioral therapy for insomnia is a multicomponent process that is composed of stimulus control therapy, sleep restriction therapy (SRT), and sleep hygiene therapy. One of the components is a controlled regime of "sleep restriction" in order to restore the homeostatic drive to sleep and encourage normal "sleep efficiency". Stimulus control therapy is intended to limit behaviors intended to condition the body to sleep while in bed. The main goal of stimulus control and sleep restriction therapy is to create an association between bed and sleep. Although sleep restriction therapy shows efficacy when applied as an element of cognitive-behavioral therapy, its efficacy is yet to be proven when used alone. Sleep Hygiene therapy is intended to help patients develop and maintain good sleeping habits. Sleep hygiene therapy is not helpful however, when used as a monotherapy without the pairing of Stimulus control therapy and Sleep restriction therapy.In addition to the cognitive behavioral treatment of insomnia there are also generally four approaches to treating insomnia medically. These are through the use of barbiturates, benzodiazepines, and benzodiazepine receptor agonists. Barbiturates are not considered to be a primary source of treatment due to the fact that they have a low therapeutic index, while melatonin agonists are shown to have a higher therapeutic index. Military training Sleep deprivation has been used by the military in training programs to prepare personnel combat experiences when proper sleep schedules arent realistic. Sleep deprivation is used to create a different time schedule pattern that is beyond a typical 24 hour day. Sleep deprivation is pivotal in training games such as "Keep in Memory" exercises where personnel practice memorizing everything they can while under intense stress physically and mentally and being able to describe in as much detail as they can remember of what they remember seeing days later. Sleep deprivation is used in training to create soldiers who are used to only going off of a few hours or minutes of sleep randomly when available. Changes in American sleep habits National Geographic Magazine has reported that the demands of work, social activities, and the availability of 24-hour home entertainment and Internet access have caused people to sleep less now than in premodern times. USA Today reported in 2007 that most adults in the USA get about an hour less than the average sleep time 40 years ago.Other researchers have questioned these claims. A 2004 editorial in the journal Sleep stated that according to the available data, the average number of hours of sleep in a 24-hour period has not changed significantly in recent decades among adults. Furthermore, the editorial suggests that there is a range of normal sleep time required by healthy adults, and many indicators used to suggest chronic sleepiness among the population as a whole do not stand up to scientific scrutiny.A comparison of data collected from the Bureau of Labor Statistics American Time Use Survey from 1965 to 1985 and 1998–2001 has been used to show that the median amount of sleep, napping, and resting done by the average adult American has changed by less than 0.7%, from a median of 482 minutes per day from 1965 through 1985, to 479 minutes per day from 1998 through 2001. Longest periods without sleep Randy Gardner holds the scientifically documented record for the longest period of time a human being has intentionally gone without sleep not using stimulants of any kind. Gardner stayed awake for 264 hours (11 days), breaking the previous record of 260 hours held by Tom Rounds of Honolulu. Lieutenant Commander John J. Ross of the U.S. Navy Medical Neuropsychiatric Research Unit later published an account of this event, which became well known among sleep-deprivation researchers.The Guinness World Record stands at 449 hours (18 days, 17 hours), held by Maureen Weston, of Peterborough, Cambridgeshire in April 1977, in a rocking-chair marathon.Claims of total sleep deprivation lasting years have been made several times, but none are scientifically verified. Claims of partial sleep deprivation are better documented. For example, Rhett Lamb of St. Petersburg, Florida was initially reported to not sleep at all, but actually had a rare condition permitting him to sleep only one to two hours per day in the first three years of his life. He had a rare abnormality called an Arnold–Chiari malformation where brain tissue protrudes into the spinal canal and the skull puts pressure on the protruding part of the brain. The boy was operated on at All Childrens Hospital in St. Petersburg in May 2008. Two days after surgery he slept through the night.French sleep expert Michel Jouvet and his team reported the case of a patient who was quasi-sleep-deprived for four months, as confirmed by repeated polygraphic recordings showing less than 30 minutes (of stage-1 sleep) per night, a condition they named "agrypnia". The 27-year-old man had Morvans fibrillary chorea, a rare disease that leads to involuntary movements, and in this particular case, extreme insomnia. The researchers found that treatment with 5-HTP restored almost normal sleep stages. However some months after this recovery the patient died during a relapse which was unresponsive to 5-HTP. The cause of death was pulmonary edema. Despite the extreme insomnia, psychological investigation showed no sign of cognitive deficits, except for some hallucinations.Fatal insomnia is a neurodegenerative disease eventually resulting in a complete inability to go past stage 1 of NREM sleep. In addition to insomnia, patients may experience panic attacks, paranoia, phobias, hallucinations, rapid weight loss, and dementia. Death usually occurs between 7 and 36 months from onset. See also == References ==
Cowpox	Cowpox is an infectious disease caused by the cowpox virus (CPXV). It presents with large blisters in the skin, a fever and swollen glands, historically typically following contact with an infected cow, though in the last several decades more often (though overall rarely) from infected cats. The hands and face are most frequently affected and the spots are generally very painful.The virus, part of the genus Orthopoxvirus, is closely related to the vaccinia virus. The virus is zoonotic, meaning that it is transferable between species, such as from cat to human. The transferral of the disease was first observed in dairymaids who touched the udders of infected cows and consequently developed the signature pustules on their hands. Cowpox is more commonly found in animals other than bovines, such as rodents. Cowpox is similar to, but much milder than, the highly contagious and often deadly smallpox disease. Its close resemblance to the mild form of smallpox and the observation that dairy farmers were immune to smallpox inspired the modern smallpox vaccine, created and administered by English physician Edward Jenner.The first description of cowpox was given by Jenner in 1798. "Vaccination" is derived from the Latin adjective vaccinus, meaning "of or from the cow". Once vaccinated, a patient develops antibodies that make them immune to cowpox, but they also develop immunity to the smallpox virus, or Variola virus. The cowpox vaccinations and later incarnations proved so successful that in 1980, the World Health Organization announced that smallpox was the first disease to be eradicated by vaccination efforts worldwide. Other orthopox viruses remain prevalent in certain communities and continue to infect humans, such as the cowpox virus in Europe, vaccinia in Brazil, and monkeypox virus in Central and West Africa. Medical use Naturally occurring cases of cowpox were not common, but it was discovered that the vaccine could be "carried" in humans and reproduced and disseminated human-to-human. Jenners original vaccination used lymph from the cowpox pustule on a milkmaid, and subsequent "arm-to-arm" vaccinations applied the same principle. As this transfer of human fluids came with its own set of complications, a safer manner of producing the vaccine was first introduced in Italy. The new method used cows to manufacture the vaccine using a process called "retrovaccination", in which a heifer was inoculated with humanized cowpox virus, and it was passed from calf to calf to produce massive quantities efficiently and safely. This then led to the next incarnation, "true animal vaccine", which used the same process but began with naturally-occurring cowpox virus, and not the humanized form.This method of production proved to be lucrative and was taken advantage of by many entrepreneurs needing only calves and seed lymph from an infected cow to manufacture crude versions of the vaccine. W. F. Elgin of the National Vaccine Establishment presented his slightly refined technique to the Conference of State and Provincial Boards of Health of North America. A tuberculosis-free calf, stomach shaved, would be bound to an operating table, where incisions would be made on its lower body. Glycerinated lymph from a previously inoculated calf was spread along the cuts. After a few days, the cuts would have scabbed or crusted over. The crust was softened with sterilized water and mixed with glycerin, which disinfected it, then stored hermetically sealed in capillary tubes for later use.At some point, the virus in use was no longer cowpox, but vaccinia. Scientists have not determined exactly when the change or mutation occurred, but the effects of vaccinia and cowpox virus as vaccine are nearly the same.The virus is found in Europe, and mainly in the UK. Human cases today are very rare and most often contracted from domestic cats. The virus is not commonly found in cattle; the reservoir hosts for the virus are woodland rodents, particularly voles. From these rodents, domestic cats contract and transmit the virus to humans. Symptoms in cats include lesions on the face, neck, forelimbs, and paws, and less commonly upper respiratory tract infections. Symptoms of infection with cowpox virus in humans are localized, pustular lesions generally found on the hands and limited to the site of introduction. The incubation period is 9 to 10 days. The virus is prevalent in late summer and autumn. Origin Discovery In the years from 1770 to 1790, at least six people who had contact with a cow had independently tested the possibility of using the cowpox vaccine as an immunization for smallpox in humans. Among them were the English farmer Benjamin Jesty, in Dorset in 1774 and the German teacher Peter Plett in 1791. Jesty inoculated his wife and two young sons with cowpox, in a successful effort to immunize them to smallpox, an epidemic of which had arisen in their town. His patients who had contracted and recovered from the similar but milder cowpox (mainly milkmaids), seemed to be immune not only to further cases of cowpox, but also to smallpox. By scratching the fluid from cowpox lesions into the skin of healthy individuals, he was able to immunize those people against smallpox.Reportedly, farmers and people working regularly with cattle and horses were often spared during smallpox outbreaks. Investigations by the British Army in 1790 showed that horse-mounted troops were less infected by smallpox than infantry, due to probable exposure to the similar horsepox virus (Variola equina). By the early 19th century, more than 100,000 people in Great Britain had been vaccinated. The arm-to-arm method of transfer of the cowpox vaccine was also used to distribute Jenners vaccine throughout the Spanish Empire. Spanish king Charles IVs daughter had been stricken with smallpox in 1798, and after she recovered, he arranged for the rest of his family to be vaccinated.In 1803, the king, convinced of the benefits of the vaccine, ordered his personal physician Francis Xavier de Balmis, to deliver it to the Spanish dominions in North and South America. To maintain the vaccine in an available state during the voyage, the physician recruited 22 young boys who had never had cowpox or smallpox before, aged three to nine years, from the orphanages of Spain. During the trip across the Atlantic, de Balmis vaccinated the orphans in a living chain. Two children were vaccinated immediately before departure, and when cowpox pustules had appeared on their arms, material from these lesions was used to vaccinate two more children.In 1796, English medical practitioner Edward Jenner tested the theory that cowpox could protect someone from being infected by smallpox. There had long been speculation regarding the origins of Jenners variolae vaccinae, until DNA sequencing data showed close similarities between horsepox and cowpox viruses. Jenner noted that farriers sometimes milked cows and that material from the equine disease could produce a vesicular disease in cows from which variolae vaccinae was derived. Contemporary accounts provide support for Jenners speculation that the vaccine probably originated as an equine disease called "grease". Although cowpox originates on the udder of cows, Jenner took his sample from a milkmaid, Sarah Nelmes.Jenner extracted the pus of one of the lesions formed by cowpox on Nelmes to James Phipps, an eight-year-old boy who had never had smallpox. He eventually developed a scab and fever that was manageable. Approximately six weeks later, Jenner then introduced an active sample of the smallpox virus into Phipps to test the theory. After being observed for an extended amount of time, it was recorded that Phipps did not receive a reaction from it. Although Jenner was not the first person to conceive the notion of cowpox protecting against the smallpox virus, his experiment proved the theory. It was later discovered that the cowpox vaccination only worked temporarily against the invasion of smallpox and the procedure would need to be repeated several times through ones lifetime to remain smallpox free.In later years, Jenner popularized the experiment, calling it a vaccination from the Latin for cow, vacca. The amount of vaccinations among people of that era increased drastically. It was widely considered to be a relatively safer procedure compared to the mainstream inoculation. Although Jenner was propelled into the spotlight from the vaccination popularity, he mainly focused on science behind why the cowpox allowed persons to not be infected by smallpox. The honour of the discovery of the vaccination is often attributed to Benjamin Jesty, but he was no scientist and did not repeat or publish his findings. He is considered to be the first to use cowpox as a vaccination, though the term vaccination was not invented yet. During the midst of the smallpox outbreak, Jesty transferred pieces of cow udder which he knew had been infected with cowpox into the skin of his family members in the hopes of protecting them. Jesty did not publicize his findings, and Jenner, who performed his first inoculation 22 years later and publicized his findings, assumed credit. It is said that Jenner made this discovery by himself, possibly without knowing previous accounts 20 years earlier. Although Jesty may have been the first to discover it, Jenner made vaccination widely accessible and has therefore been credited for its invention. Life Cycle The genome for the CPXV is over 220kbp. This makes it the largest genome in the Orthopoxviral species. It can be divided into three different regions. There are two end regions called R1 and R2 and a main central region that is roughly half of the size of the genome. There are also inverted terminal repeats that are located at the terminal sites of the genome and measure around 10kbp. These inverted terminal repeats can then be divided into two more distinct regions. The first section is around 7.5kbp long and includes a coding region. The other section includes a terminal region that can be repeated up to as many times as thirty and is composed of 50 nucleotides. The CPXV genome encodes only 30-40% of products of which are involved in the pathogenesis of the virus. The CPXV genome has the most complete set of genes out of all of the orthopoxviruses. This unique feature of CPXV makes it ideal to be able to mutate into different strains of the virus. It is a double stranded DNA virus. The virus does have an envelope that surrounds the virion. The cowpoxs genome allows the virus to encode its own transcription machinery along with its own DNA replication machinery. The replication then takes place in the cytoplasm after the virus is in the cell and the virion is uncoated. The virion is then assembled and released from the host cell.The genome is arranged so that both of the ends contain the genes responsible for evading the defenses from the immune system of the host which is only activated in the extracellular portion. These receptors are able to be stopped by cytokine and chemokine secretion by blocking the cytokine and chemokine found extracellularly. This is the process responsible for attachment and entry of the virion into the host cell. Because of the large size of the genome, it makes the virus more likely and capable to fight back against the immunes system defenses. Out of all of the poxviruses, CPXV has the most cytokine responses that fight back against the immune system. It encodes cytokine receptors such as TNF, CrmB, CrmC, CrmD, and CrmE proteins. Another set of receptors that CPXV have are lymphotoxins such as IL-1ß, IFN-y, IFN 1, β-chemokines, and IL-18. However, not all of the receptors of CPXV are still not known. CPXV also encodes four tumor necrosis factors (TNF) and lymphotoxin which are the biggest group of homologous receptors for the virus. These receptors play a crucial role that are involved with the immune system. CPXV has two different types of inclusion bodies. All of the poxviruses have basophilic inclusions also called B-type inclusion bodies. The B-type inclusion bodies contain the factory where the virus produces necessary elements for the replication and maturation of the virion. CPXV has another inclusion body that is unique to only some chordopoxviruses called acidophilic inclusion bodies also called A-type inclusion bodies (ATIs). The ATIs are encoded by the cpxv158 gene and is then made the protein ATIP which is a late protein. However, the importance of these ATIs in the life cycle are still not well known or understood and research is still being done to better understand them. It is known that replication can still continue without the cpxv158 gene, and that the replication cycle shows no difference between a fully encoded virion versus the virion that had deleted cwpx158 gene. However, with studies done on mice, the lesions that were caused by the CPXV-BR△ati were able to heal faster due to less tissue that was lost than the CPXV-BR lesions that took longer to heal and lost more tissue. This suggests that this gene helps supports the idea that ATIs are partly involved in how the host responds to the virus infection.Another way that the virus is able to control and infect the host is by regulating cellular signaling pathways. During the infection, CPXV is known to use MEK/ERK/1/2/Egr-1, JNK1/2, and PI3K/Akt pathways. Some of these pathways are not unique only to CPXV, but how they function in response to the host is unique to this virus.One notable protein in the CPXV is the p28 protein. It is made up of 242 amino acids and contains two domains, and N terminal KilA-N and a C-terminal RING domain. One of those domains, the N-terminal KilA-N domain, allows for DNA to bind to it. The KilA-N domain facilitates this p28 protein that is translated early in the replication cycle in the cytoplasm and is then located in the cytoplasm for the rest of the life cycle of the virus. There is current research still being done to determine if the p28 protein could be a requital for an essential macrophage factor that is needed for the DNA replication. Opposition The majority of the population at the time accepted the up-and-coming vaccination. However, there was still opposition from individuals who were reluctant to change from the inoculations. In addition, there became a growing concern from parties who were worried about the unknown repercussions of infecting a human with an animal disease. One way individuals expressed their discontent was to draw comics that sometimes depicted small cows growing from the sites of vaccination. Others publicly advocated for the continuance of the inoculations; however, this was not because of their discontent for the vaccinations. Some of their reluctance had to do with an apprehensiveness for change. They had become so familiar with the process, outcome, positives, and negatives of inoculations that they did not want to be surprised by the outcome or effects of the vaccinations. Jenner soon eased their minds after extensive trials. However, others advocated against vaccinations for different reason. Because of the high price of inoculation, Jenner experienced very few common folk who were not willing to accept the vaccination. Due to this, Jenner found many subjects for his tests. He was able to publish his results in a pamphlet in 1798: An Inquiry into the Causes and Effects of Variolae Vaccinae, a Disease, Discovered in some of the Western Counties of England particularly Gloucestershire, and known by the Name of Cow Pox. Historical use After inoculation, vaccination using the cowpox virus became the primary defense against smallpox. After infection by the cowpox virus, the body (usually) gains the ability to recognize the similar smallpox virus from its antigens and is able to fight the smallpox disease much more efficiently.The cowpox virus contains 186 thousand base pairs of DNA, which contains the information for about 187 genes. This makes cowpox one of the most complicated viruses known. Some 100 of these genes give instructions for key parts of the human immune system, giving a clue as to why the closely related smallpox is so lethal. The vaccinia virus now used for smallpox vaccination is sufficiently different from the cowpox virus found in the wild as to be considered a separate virus. British Parliament While the vaccinations popularity increased exponentially, so did its monetary value. This was realized by the British Parliament, which compensated Jenner 10,000 pounds for the vaccination. In addition, they later compensated Jenner an additional 20,000 pounds. In the coming years, Jenner continued advocacy for his vaccination over the still popular inoculation. Eventually, in 1840, the inoculation became banned in England and was replaced with the cowpox vaccination as the main medical solution to combat smallpox. The cowpox vaccination saved the British Army thousands of soldiers, by making them immune to the effects of smallpox in upcoming wars. The cowpox also saved the United Kingdom thousands of pounds. Kinepox Kinepox is an alternative term for the smallpox vaccine used in early 19th-century America. Popularized by Jenner in the late 1790s, kinepox was a far safer method for inoculating people against smallpox than the previous method, variolation, which had a 3% fatality rate.In a famous letter to Meriwether Lewis in 1803, Thomas Jefferson instructed the Lewis and Clark Expedition to "carry with you some matter of the kine-pox; inform those of them with whom you may be, of its efficacy as a preservative from the smallpox; & encourage them in the use of it..." Jefferson had developed an interest in protecting American Indians from smallpox, having been aware of epidemics along the Missouri River during the previous century. A year before his special instructions to Lewis, Jefferson had persuaded a visiting delegation of North American Indian chieftains to be vaccinated with kinepox during the winter of 1801–1802. Unfortunately, Lewis never got the opportunity to use kinepox during the pairs expedition, as it had become inadvertently inactive—a common occurrence in a time before vaccines were stabilized with preservatives such as glycerol or kept at refrigeration temperatures. Prevention Today, the virus is found in Europe, mainly in the UK. Human cases are very rare (though in 2010 a laboratory worker contracted cowpox) and most often contracted from domestic cats. Human infections usually remain localized and self-limiting, but can become fatal in immunosuppressed patients. The virus is not commonly found in cattle; the reservoir hosts for the virus are woodland rodents, particularly voles. Domestic cats contract the virus from these rodents. Symptoms in cats include lesions on the face, neck, forelimbs, and paws, and, less commonly, upper respiratory tract infections. Symptoms of infection with cowpox virus in humans are localized, pustular lesions generally found on the hands and limited to the site of introduction. The incubation period is nine to ten days. The virus is most prevalent in late summer and autumn. Immunity to cowpox is gained when the smallpox vaccine is administered. Although the vaccine now uses vaccinia virus, the poxviruses are similar enough that the body becomes immune to both cow- and smallpox. Citations General sources Peck DR (2002). Or Perish in the Attempt: Wilderness Medicine in the Lewis & Clark Expedition. Farcountry Press. ISBN 978-1-56037-226-4.
Gestation	Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregnancy can have one or more gestations at the same time, for example in a multiple birth.The time interval of a gestation is called the gestation period. In obstetrics, gestational age refers to the time since the onset of the last menses, which on average is fertilization age plus two weeks. Mammals In mammals, pregnancy begins when a zygote (fertilized ovum) implants in the females uterus and ends once the fetus leaves the uterus during labor or an abortion (whether induced or spontaneous). Humans In humans, pregnancy can be defined clinically or biochemically. Clinically, pregnancy starts from the mothers last missed period. Biochemically, pregnancy starts when a womans human chorionic gonadotropin (hCG) levels rise above 25 mIU/mL.Human pregnancy can be divided into three trimesters, each approximately three months long: the first, second, and third trimester. The first trimester is from the last menstrual period through the 13th week, the second trimester is 14th–28/29th week, and the third trimester is 29/30th–42nd week. Birth normally occurs at a gestational age of about 40 weeks, though it is common for births to occur from 37 to 42 weeks. Labor occurring prior to 37 weeks gestation is considered preterm labor and can result from multiple factors, including previous preterm deliveries.Prenatal care is important for the maintenance of a healthy pregnancy and surveillance of related complications. In high-income countries, prenatal care typically involves monthly visits during the first two trimesters, with an increasing number of visits closer to delivery. At these visits, healthcare providers will evaluate a variety of parental and fetal metrics, including fetal growth and heart rate, birth defects, maternal blood pressure, among others.After birth, health care providers will measure the babys weight, vital signs, reflexes, head circumference, muscle tone, and posture to help determine the gestational age.Various factors can influence the duration of gestation, including diseases in pregnancy and adequate prenatal care. The rates of morbidity and pre-existing diseases that predispose mothers to life-threatening, pregnancy-related complications in the United States are increasing. The brunt of this burden is experienced by non-Hispanic Black women. Inaccessibility of prenatal care may partially explain this ongoing disparity. Other factors that affect prenatal care utilization include socioeconomic status, insurance status, childcare, social support, housing, and immigration status. Non-mammals In viviparous animals, the embryo develops inside the body of the mother, as opposed to outside in an egg (oviparity). The mother then gives live birth. The less developed form of viviparity is called ovoviviparity, in which the mother carries embryos inside eggs. Most vipers exhibit ovoviviparity. The more developed form of viviparity is called placental viviparity; mammals are the best example, but it has also evolved independently in other animals, such as in scorpions, some sharks, and in velvet worms. Viviparous offspring live independently and require an external food supply from birth. Certain lizards also employ this method such as the genera Tiliqua and Corucia. The placenta is attached directly to the mother in these lizards which is called viviparous matrotrophy.Ovoviviparous animals develop within eggs that remain within the mothers body up until they hatch or are about to hatch. It is similar to viviparity in that the embryo develops within the mothers body. Unlike the embryos of viviparous species, ovoviviparous embryos are nourished by the egg yolk rather than by the mothers body. However, the mothers body does provide gas exchange. The young of ovoviviparous amphibians are sometimes born as larvae, and undergo metamorphosis outside the body of the mother.The fish family Syngnathidae has the unique characteristic whereby females lay their eggs in a brood pouch on the males chest, and the male incubates the eggs. Fertilization may take place in the pouch or before implantation in the water. Included in Syngnathidae are seahorses, the pipefish, and the weedy and leafy sea dragons. Syngnathidae is the only family in the animal kingdom to which the term "male pregnancy" has been applied. See also Evolution of mammals (for the evolution of gestation-related features in humans and other mammals) Male pregnancy Nesting instinct Pregnancy Pregnancy in fish Prenatal development Prenatal nutrition and birth weight References External links NSRL.ttu.edu Table listing average animal gestation periods
Azoospermia	Azoospermia is the medical condition of a man whose semen contains no sperm. It is associated with male infertility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be seen in up to 20% of male infertility situations in Canada.In a non-pathological context, azoospermia is also the intended result of a successful vasectomy. Classification Azoospermia can be classified into three major types as listed. Many conditions listed may also cause various degrees of oligospermia rather than azoospermia. Pretesticular and testicular azoospermia are known as non-obstructive azoospermia, whereas post-testicular azoospermia is considered obstructive. Pretesticular Pretesticular azoospermia is characterized by inadequate stimulation of otherwise normal testicles and genital tract. Typically, follicle-stimulating hormone (FSH) levels are low (hypogonadotropic) commensurate with inadequate stimulation of the testes to produce sperm. Examples include hypopituitarism (for various causes), hyperprolactinemia, and exogenous FSH suppression by testosterone. Chemotherapy may suppress spermatogenesis. Pretesticular azoospermia is seen in about 2% of azoospermia. Pretesticular azoospermia is a kind of non-obstructive azoospermia. Testicular Testicular azoospermia means the testes are abnormal, atrophic, or absent, and sperm production severely disturbed to absent. FSH levels tend to be elevated (hypergonadotropic) as the feedback loop is interrupted (lack of feedback inhibition on FSH). The condition is seen in 49–93% of men with azoospermia. Testicular failure includes absence of failure production and low production and maturation arrest during the process of spermatogenesis. Causes for testicular failure include congenital issues such as in certain genetic conditions (e.g. Klinefelter syndrome), some cases of cryptorchidism or Sertoli cell-only syndrome as well as acquired conditions by infection (orchitis), surgery (trauma, cancer), radiation, or other causes. Mast cells releasing inflammatory mediators appear to directly suppress sperm motility in a potentially reversible manner, and may be a common pathophysiological mechanism for many causes leading to inflammation. Testicular azoospermia is a kind of non-obstructive azoospermia. Generally, men with unexplained hypergonadotropic azoospermia need to undergo a chromosomal evaluation. Post-testicular In post-testicular azoospermia, sperm are produced but not ejaculated, a condition that affects 7–51% of azoospermic men. The main cause is a physical obstruction (obstructive azoospermia) of the post-testicular genital tracts. The most common reason is a vasectomy done to induce contraceptive sterility. Other obstructions can be congenital (for example, agenesis of the vas deferens as seen in certain cases of cystic fibrosis) or acquired, such as ejaculatory duct obstruction for instance by infection. Ejaculatory disorders include retrograde ejaculation and anejaculation; in these conditions sperm are produced but not expelled. Unknown Idiopathic azoospermia is where there is no known cause of the condition. It may be a result of multiple risk factors, such as age and weight. For example, a review in 2013 came to the result that oligospermia and azoospermia are significantly associated with being overweight (odds ratio 1.1), obese (odds ratio 1.3) and morbidly obese (odds ratio 2.0), but the cause of this is unknown. The review found no significant relation between oligospermia and being underweight. Genetics Genetic factors can cause pretesticular, testicular, and post-testicular azoospermia (or oligospermia) and include the following situations: The frequency of chromosomal abnormalities is inversely proportional to the semen count, thus males with azoospermia are at risk to have a 10–15% (other sources citing 15–20% incidence) abnormalities on karyotyping versus about <1 % in the fertile male population.Pretesticular azoospermia may be caused by congential hypopituitarism, Kallmann syndrome, Prader-Willi syndrome and other genetic conditions that lead to GnRH or gonadotropin deficiency. Testicular azoospermia is seen in Klinefelter syndrome (XXY) and the XX male syndrome. In addition, 13% of men with azoospermia have a defective spermatogenesis that is linked to defects of the Y chromosome. Such defects tend to be de novo micro-deletions and affect usually the long arm of the chromosome. A section of the long arm of the Y chromosome has been termed Azoospermia Factor (AZF) at Yq11 and subdivided into AZFa, AZFb, AZFc and possibly more subsections. Defects in this area can lead to oligospermia or azoospermia, however, a tight genotype-phenotype correlation has not been achieved. Spermatogenesis is defective with gene defects for the androgen receptor.Post-testicular azoospermia can be seen with certain point mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene commonly associated with congenital vas deferens abnormalities.Genetic counselling is indicated for men with genetic causes of azoospermia. In terms of reproduction, it needs to be considered if the genetic defect could be transmitted to the offspring. BRD7 BRD7, a transcription regulatory protein, is normally highly expressed in the testis. Absent or reduced expression of BRD7 protein was observed in the testes of azoospermia patients exhibiting spermatogenesis arrest. Homozygous knockout mice [BRD7(-/-)] are infertile and have higher levels of apoptosis and DNA damage in their germline cells. Gene polymorphisms The human breast cancer susceptibility gene 2 (BRCA2) is employed in DNA repair. A common single nucleotide polymorphism in BRCA2 is associated with idiopathic male infertility with azoospermia.Four genes involved in DNA double-strand break repair and chromosome synapsis (TEX11, TEX15, MLH1 and MLH3) have key roles in genomic integrity, meiotic recombination and gametogenesis. Polymorphisms in these genes were tested for associations with male infertility. Single nucleotide polymorphisms in two of these genes (TEX11 and MLH3) were found to be associated with male infertility involving azoospermy or oligospermia. Diagnosis Azoospermia is usually detected in the course of an infertility investigation. It is established on the basis of two semen analysis evaluations done at separate occasions (when the seminal specimen after centrifugation shows no sperm under the microscope) and requires a further work-up.The investigation includes a history, a physical examination including a thorough evaluation of the scrotum and testes, laboratory tests, and possibly imaging. History includes the general health, sexual health, past fertility, libido, and sexual activity. Past exposure to a number of agents needs to be queried including medical agents like hormone/steroid therapy, antibiotics, 5-ASA inhibitors (sulfasalazine), alpha-blockers, 5 alpha-reductase inhibitors, chemotherapeutic agents, pesticides, recreational drugs (marijuana, excessive alcohol), and heat exposure of the testes. A history of surgical procedures of the genital system needs to be elicited. The family history needs to be assessed to look for genetic abnormalities.Congenital absence of the vas deferens may be detectable on physical examination and can be confirmed by a transrectal ultrasound (TRUS). If confirmed, genetic testing for cystic fibrosis is in order. Transrectal ultrasound can also assess azoospermia caused by obstruction, or anomalies related to obstruction of the ejaculatory duct, such as abnormalities within the duct itself, a median cyst of the prostate (indicating a need for cyst aspiration), or an impairment of the seminal vesicles to become enlarged or emptied. Retrograde ejaculation is diagnosed by examining a post-ejaculatory urine for presence of sperm after making it alkaline and centrifuging it.Low levels of LH and FSH with low or normal testosterone levels are indicative of pretesticular problems, while high levels of gonadotropins indicate testicular problems. However, often this distinction is not clear and the differentiation between obstructive versus non-obstructive azoospermia may require a testicular biopsy. On the other hand, "In azoospermic men with a normal ejaculate volume, FSH serum level greater than two times the upper limit of the normal range is reliably diagnostic of dysfunctional spermatogenesis and, when found, a diagnostic testicular biopsy is usually unnecessary, although no consensus exists in this matter." Extremely high levels of FSH (>45 ID/mL) have been correlated with successful microdissection testicular sperm extraction.Serum inhibin-B weakly indicates presence of sperm cells in the testes, raising chances for successfully achieving pregnancy through testicular sperm extraction (TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 0.56–0.74) and a specificity of 0.83 (CI: 0.64–0.93) for prediction the presence of sperm in the testes in non-obstructive azoospermia.Seminal plasma proteins TEX101 and ECM1 were recently proposed for the differential diagnosis of azoospermia forms and subtypes, and for prediction of TESE outcome. Mount Sinai Hospital, Canada started clinical trial to test this hypothesis in 2016.Primary hypopituitarism may be linked to a genetic cause. So a genetic evaluation may be done for men with azoospermia as a result. Azoospermic men with testicular failure are advised to undergo karyotype and Y-micro-deletion testing. Treatment Pre- and post-testicular azoospermia are frequently correctible, while testicular azoospermia is usually permanent. In the former the cause of the azoospermia needs to be considered and it opens up possibilities to manage this situation directly. Thus men with azoospermia due to hyperprolactinemia may resume sperm production after treatment of hyperprolactinemia or men whose sperm production is suppressed by exogenous androgens are expected to produce sperm after cessation of androgen intake. In situations where the testes are normal but unstimulated, gonadotropin therapy can be expected to induce sperm production. A major advancement in recent years has been the introduction of IVF with ICSI which allows successful fertilization even with immature sperm or sperm obtained directly from testicular tissue. IVF-ICSI allows for pregnancy in couples where the man has irreversible testicular azoospermia as long as it is possible to recover sperm material from the testes. Thus men with non-mosaic Klinefelters syndrome have fathered children using IVF-ICSI. Pregnancies have been achieved in situations where azoospermia was associated with cryptorchism and sperm where obtained by testicular sperm extraction (TESE).In men with post-testicular azoospermia, different approaches are available. For obstructive azoospermia, IVF-ICSI or surgery can be used and individual factors are considered for the choice of treatment. Medication may be helpful for retrograde ejaculation. References == External links ==
Sex therapy	Sex therapy is a strategy for the improvement of sexual function and treatment of sexual dysfunction. This includes sexual dysfunctions such as premature ejaculation or delayed ejaculation, erectile dysfunction, lack of sexual interest or arousal, and painful sex (vaginismus and dyspareunia), as well as dealing with problems imposed by atypical sexual interests (paraphilias), gender dysphoria and being transgender, highly overactive libido or hypersexuality, a lack of sexual confidence, recovering from sexual abuse such as rape or sexual assault, and sexual issues related to aging, illness, or disability. Practice Modern sex therapy often integrates psychotherapeutic techniques and medical ones, such as Viagra (sildenafil) and Cialis (tadalafil) to increase erectile response and Paxil (paroxetine) to treat premature ejaculation. Sex therapists assist those experiencing problems in overcoming them, in doing so possibly regaining an active sex life. The transformative approach to sex therapy aims to understand the psychological, biological, pharmacological, relational, and contextual aspects of sexual problems.Sex therapy requires rigorous evaluation that includes a medical and psychological examination. The reason is that sexual dysfunction may have a somatic base or a psychogenic basis. A clear example is erectile dysfunction (sometimes still called "impotence"), whose causes may include circulatory problems and performance anxiety. Sex therapy is frequently short term, with duration depending on the causes for therapy.Sex therapy can be provided by licensed psychologists or physicians, who have undergone training and become certified. These trainings and certifications usually begin with a masters degree, and internship, and a license. This can take up to 2 years, and longer if a doctorates degree is desired. Sex therapy is distinct from sex surrogates. Whereas sex therapists discuss and instruct clients in sex-based exercises to be performed at home between sessions, sexual surrogates participate in the exercises with their clients as part of helping them to practice and develop improved skills. Therapists and surrogates sometimes collaborate on cases. Certified sex therapists do not have sexual contact with their clients. Symptoms Sex therapy sessions are focused on the individuals symptoms rather than on underlying psychodynamic conflicts. The sexual dysfunctions which may be addressed by sex therapy include non-consummation, premature ejaculation, erectile dysfunction, low libido, unwanted sexual fetishes, sexual addiction, painful sex, or a lack of sexual confidence, assisting people who are recovering from sexual assault, problems commonly caused by stress, tiredness, and other environmental and relationship factors. Sex therapy can either be on an individual basis or with the sex partner. Sex therapy can be conducted with any adult client, including older adults, any gender expression, and LGBTQ-identified people.A therapists misunderstanding of these conflicts can lead to resistance or serve as a barrier to improving sexual dysfunctions that are directly or indirectly related to sex. The interest in sex therapy among couples has increased along with the number of sexuality educators, counselors, and therapists. Today, sexual problems are no longer regarded as symptoms of hidden deviant, pathological, or psychological defects in maturity or development. Sex therapy has also influenced the emergence of sexual medicine and exploring integrative approaches to sex therapy, in addition to reducing or eliminating sexual problems and increasing sexual satisfaction for individuals of all stages of life. Health therapists, educators, and counselors are conducting research and administering surveys to fully understand normative sexual function – what most people do and experience as they grow older and live longer. Aging and sexuality Both physical and emotional transformation throughout various stages of life can affect the body and sexuality. The subsequent decline in hormone levels and changes in neurological and circulatory functioning may lead to sexual problems such as erectile dysfunction or vaginal pain. These physical changes often affect the intensity of youthful sex and may give way to more subdued responses during middle and later life. Issues with low libido and sexual dysfunction are usually considered to be a byproduct of old age. The emotional byproducts of maturity, however — increased confidence, better communication skills, and lessened inhibitions — can help create a richer, more nuanced, and ultimately satisfying sexual experience. During AARPs last surveys in 1999, 2004, and 2009 statistics show well-being among older adults has increased; however, overall sexual satisfaction has decreased. Nevertheless, older adults believed that an active sexual life offers great pleasure and contributes materially to overall emotional and physical health. Older adults Over the years, little attention has been paid to older adults and sexuality. As the population of older adults and life expectancy continue to grow, there is information about sex therapy but it is often not easily accepted. Cultural and sexual roles are always changing throughout the life-course. As people age, they are often viewed as asexual or as incapable of possessing sexual desires. The presence of sexual dysfunction during old age can be impacted by health problems. There are many endocrine, vascular and neurological disorders that may interfere in sexual function, along with some medications and surgeries. Older men experience changes that occur in sexual physiology and affect both erectile function and ejaculation. While older women experience physiological effects of aging after menopause, resulting in the decreased production of estrogen. This leads to increased vaginal dryness, general atrophy of vaginal tissue, and genital changes (reduced size of clitoral, vulvar, and labial tissue). Cognitive changes and decline is another factor that influences sexual activity. Dementia, Alzheimers and mental health disorders may have an effect on sexual behavior, producing disinhibition or relationship difficulties with subsequent effects on couples sexual relationships.Sex therapy with older adults looks at factors which influence sexuality in older adults, including sexual desire, sexual activity, the value of sexuality, and health. It can include sensate focus, communication, and fantasy exercises as well as psychodynamic therapy.Sex therapy for older adults is similar to sex therapy with other populations. It includes the use of water-based personal lubricants (for decreased vaginal lubrication), hormone therapy, and medications. Sex therapists working with older adults should know about sexuality and aging. They should also be aware of how stereotypes affect their clients. This is especially true for LGBT-identified clients.Older adults may also need more education about their sexuality and sexual functioning. Curriculum for this includes communication, masturbation, body image, and spirituality. It also teaches about talking to a doctor about sexual activity. It is optimal that sex education for older adults includes information about sexually transmitted infections (STDs/STIs), such as HIV/AIDS. History Sex therapy has existed in different cultures throughout time, including ancient India, China, Greece, and Rome. It has taken the form of manuals, spells, anaphrodisiacs or aphrodisiacs, and tantric yoga, among others. Much of sex therapy and sexual dysfunction in Western cultures was limited to scientific discussion, especially throughout the 19th century and into the early 20th century.Sexologists such as Henry Havelock Ellis and Alfred Kinsey began conducting research in the area of human sexuality during the first half of the 20th century. This work was groundbreaking and controversial in the scientific arena.In the 1950s, sex therapy was concerned with "controlling sexual expression" and repressing what was then-considered deviant behaviors, such as homosexuality or having sex too often. Masters and Johnson are credited with revolutionizing sex therapy in the mid-century and included couple therapy and behavioral interventions that focused on being present in the moment such as sensate focus exercises. Dr. Helen Singer Kaplan modified some of Masters and Johnsons ideas to better suit her outpatient practice, including introducing medication. Both integrated cognitive behavioral therapy into their practice and Kaplan used psychodynamic therapy as well. The work of Jack Annon in 1976 also saw the creation of the PLISSIT model that sought to create a structured system of levels for the therapist to follow.The mid-1980s saw the medicalization of sex therapy, with a primary focus on male sexual dysfunction. The 1990s brought penile injections and medications such as Viagra as well as the marketing of antidepressants for their delayed ejaculation side-effects. Hormone therapy was introduced to assist both male and female sexual dysfunction. Dilators were used to treat women with vaginismus and surgical procedures to increase the size of the vaginal opening and treat vulvar pain were also introduced. See also Certified Sex Addiction Therapist Certified Sex Therapist List of sex therapists Sensate focus Society for Sex Therapy and Research References Bibliography Kaplan, Helen Singer, The New Sex Therapy: Active Treatment Of Sexual Dysfunctions, New York, Brunner/Mazel, 1974. ISBN 0-87630-083-2 Robboy, Alex Caroline, "How to Become a Sex Therapist"
Vesical tenesmus	Vesical tenesmus refers to the feeling of incomplete emptying of the bladder following urination. When the word tenesmus is used without modification, it usually refers to rectal tenesmus. Vesical tenesmus is caused by urogenital diaphragm muscle spasms. See also Post-void dribbling Prostate Rectal tenesmus References == External links ==
Paravaccinia virus	Pseudocowpox is a disease caused by the Paravaccinia virus or Pseudocowpox virus, a virus of the family Poxviridae and the genus Parapoxvirus.: 393 Humans can contract the virus from contact with livestock infected with Bovine papular stomatitis and the disease is common among ranchers, milkers, and veterinarians. Infection in humans will present with fever, fatigue, and lesion on the skin. Signs and symptoms Paravaccinia virus presents itself with blisters, nodules, or lesions about 4 mm in diameter, typically in the area that has made contact with livestock that is infected with bovine papular stomatitis. Lesions may begin forming as late as three weeks after contact has been made with an infected animal. In rare cases, lesions may be seen systemic. General signs of infection are also common, such as fever and fatigue. Infected livestock may present with blisters or lesions on their udders or snout. Often, however, infected livestock show little to no symptoms. Mechanism Paravaccinia is a member of the Parapoxvirus family. It has a cylindrical body about 140 X 310 nm in size, with convex ends covered in a criss-cross pattern of rope like structures. The virus is resistant to cold, dehydration, and temperatures up to 56 °C. Upon injecting a cell with its genome, the virus begins transcription in the cytoplasm using viral RNA polymerase. As the virus progresses through the cell, the host begins to replicate the viral genome between 140 minutes and 48 hours. Diagnosis Diagnosis of paravaccinia virus will often come from Polymerase chain reaction screening ordered by their physician. However, due to how common paravaccinia virus is in rural areas, individuals typically do not seek professional help in diagnosis. Instead individuals may refer to people with local knowledge of the cattle in their area such as ranchers, or veterinarians who have some familiarity with the infections in the region.It may appear similar to cowpox and orf. Cause and prevention Paravaccinia virus originates from livestock infected with bovine papular stomatitis. When a human makes physical contact with the livestocks muzzle, udders, or an infected area, the area of contact will become infected. Livestock may not show symptoms of bovine papular stomatitis and still be infected and contagious. Paravaccinia can enter the body though all pathways including: skin contact by mechanical means, through the respiratory tract, or orally. Oral or respiratory contraction may be more likely to cause systemic symptoms such as lesions across the whole bodyA person who has not previously been infected with paravaccinia virus should avoid contact with infected livestock to prevent contraction of disease. There is no commercially available vaccination for cattle or humans against paravaccinia. However, following infection, immunization has been noted in humans, making re-infection difficult. Unlike other pox viruses, there is no record of contracting paravaccinia virus from another human. Further, cattle only show a short immunization after initial infection, providing opportunity to continue to infect more livestock and new human hosts. Treatment and prognosis Lesions of paravaccinia virus will clear up with little to no scarring after 4 to 8 weeks. An antibiotic may be prescribed by a physician to help prevent bacterial infection of the lesion area. In rare cases, surgical removal of the lesions can be done to help increase rate of healing, and help minimize risk of bacterial or fungal infection. Upon healing, no long term side effects have been reported. History Paravaccinia virus was first characterized in by Edward Jenner in 1799 with the presence of lesions on humans, later described as Milkers nodule. Jenner associated the lesions found on human who had contact with infected cattle. Since first being characterized in cows, bovine papular stomatitis has been isolated in sheep, goats, and red deer creating new potential sources for human infection. Bolvine papular stomatitis has been reported in the United States of America, Great Britain, Brazil, Switzerland, and Japan Disease in animals Pseudocowpox is a worldwide disease of cattle. Symptoms include ring or horseshoe shaped scabs on the teats, which usually heal within six weeks. Lesions may also develop on the muzzles and in the mouths of nursing calves. Spread is by fomites, including hands, calves mouths, and milking machines. Lesions may also appear on the hands of milkers, a clinical presentation known as milkers nodule. This disease in humans is nearly identical to orf. == References ==
Heat cramps	Heat cramps, a type of heat illness, are muscle spasms that result from loss of large amount of salt and water through exercise. Heat cramps are associated with cramping in the abdomen, arms and calves. This can be caused by inadequate consumption of fluids or electrolytes. Heavy sweating causes heat cramps, especially when the water is replaced without also replacing salt or potassium.Although heat cramps can be quite painful, they usually dont result in permanent damage, though they can be a symptom of heat stroke or heat exhaustion. Heat cramps can indicate a more severe problem in someone with heart disease or if they last for longer than an hour.In order to prevent them, one may drink electrolyte solutions such as sports drinks during exercise or strenuous work or eat potassium-rich foods like bananas and apples. When heat cramps occur, the affected person should avoid strenuous work and exercise for several hours to allow for recovery. See also Dehydration References External links Heat cramps first aid
Non-Hodgkin lymphoma	Non-Hodgkin lymphoma (NHL), also known as non-Hodgkins lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. Other symptoms may include bone pain, chest pain, or itchiness. Some forms are slow-growing while others are fast-growing.Lymphomas are types of cancer that develop from lymphocytes, a type of white blood cell. Risk factors include poor immune function, autoimmune diseases, Helicobacter pylori infection, hepatitis C, obesity, and Epstein–Barr virus infection. The World Health Organization classifies lymphomas into five major groups, including one for Hodgkin lymphoma. Within the four groups for NHL are over 60 specific types of lymphoma. Diagnosis is by examination of a bone marrow or lymph node biopsy. Medical imaging is done to help with cancer staging.Treatment depends on whether the lymphoma is slow- or fast-growing and if it is in one area or many areas. Treatments may include chemotherapy, radiation, immunotherapy, targeted therapy, stem-cell transplantation, surgery, or watchful waiting. If the blood becomes overly thick due to high numbers of antibodies, plasmapheresis may be used. Radiation and some chemotherapy, however, increase the risk of other cancers, heart disease, or nerve problems over the subsequent decades.In 2015, about 4.3 million people had non-Hodgkin lymphoma, and 231,400 (5.4%) died. In the United States, 2.1% of people are affected at some point in their life. The most common age of diagnosis is between 65 and 75 years old. The five-year survival rate in the United States is 71%. Signs and symptoms The signs and symptoms of non-Hodgkin lymphoma vary depending upon its location within the body. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. Other symptoms may include bone pain, chest pain, or itchiness. Some forms are slow growing, while others are fast growing. Enlarged lymph nodes may cause lumps to be felt under the skin when they are close to the surface of the body. Lymphomas in the skin may also result in lumps, which are commonly itchy, red, or purple. Lymphomas in the brain can cause weakness, seizures, problems with thinking, and personality changes.While an association between non-Hodgkin lymphoma and endometriosis has been described, these associations are tentative. Causes The many different forms of lymphoma probably have different causes. These possible causes and associations with at least some forms of NHL include: Infectious agents: Epstein–Barr virus: associated with Burkitts lymphoma, follicular dendritic cell sarcoma, extranodal NK-T-cell lymphoma and diffuse large B-cell lymphoma. Human T-cell leukemia virus: associated with adult T-cell lymphoma. Helicobacter pylori: associated with gastric lymphoma. HHV-8: associated with primary effusion lymphoma, multicentric Castleman disease. Hepatitis C virus: associated with splenic marginal zone lymphoma, lymphoplasmacytic lymphoma and diffuse large B-cell lymphoma. HIV infection. Some chemicals, like polychlorinated biphenyls (PCBs), diphenylhydantoin, dioxin, and phenoxy herbicides. Medical treatments, like radiation therapy and chemotherapy. Genetic diseases, like Klinefelter syndrome, Chédiak–Higashi syndrome, ataxia–telangiectasia syndrome. Autoimmune diseases, like Sjögren syndrome, celiac disease, rheumatoid arthritis, and systemic lupus erythematosus. Bone trauma and microfractures associated with diffuse large B-cell lymphoma originating in bone marrow. Implants, made from hard metals or silicone, associated with anaplastic large cell lymphoma. Familial component Familial lymphoid cancer is rare. The familial risk of lymphoma is elevated for multiple lymphoma subtypes, suggesting a shared genetic cause. However, a family history of a specific subtype is most strongly associated with risk for that subtype, indicating that these genetic factors are subtype-specific. Genome-wide association studies have successfully identified 67 single-nucleotide polymorphisms from 41 loci, most of which are subtype specific. HIV/AIDS The Centers for Disease Control and Prevention (CDC) included certain types of non-Hodgkin lymphoma as AIDS-defining cancers in 1987. Immune suppression rather than HIV itself is implicated in the pathogenesis of this malignancy, with a clear correlation between the degree of immune suppression and the risk of developing NHL. Additionally, other retroviruses, such as HTLV, may be spread by the same mechanisms that spread HIV, leading to an increased rate of co-infection. The natural history of HIV infection has greatly changed over time. As a consequence, rates of non-Hodgkin lymphoma (NHL) in people infected with HIV has significantly declined in recent years. Treatment The traditional treatment of NHL includes chemotherapy, radiotherapy, and stem-cell transplants. There have also been developments in immunotherapy used in the treatment of NHL. Chemotherapy The most common chemotherapy used for B-cell non-Hodgkin lymphoma is R-CHOP, which is a regimen of four drugs (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab. Treatment complications If participants receive stem-cell transplants, they can develop a graft-versus-host disease. When compared with placebo for treating immune mediated inflammation post transplantation and in autoimmunity, mesenchymal stromal cells (MSCs) may reduce the all-cause mortality if they are used for a therapeutic reason. Moreover, the therapeutic use of MSCs may increase the complete response of acute and chronic GvHD, but the evidence is very uncertain. The evidence suggests that MSCs for prophylactic reason result in little to no difference in the all-cause mortality, in the relapse of malignant diseases, and in the incidence of acute GvHD. The evidence suggests that MSCs for prophylactic reason reduce the incidence of chronic GvHD.Platelet transfusions may be necessary for those who receive chemotherapy or undergo a stem cell transplantation due to the higher risk for bleeding. When comparing therapeutic/non-prophylactic platelet transfusions to prophylactic platelet transfusions there is little to no difference in the mortality secondary to bleeding and they may result in a slight reduction in the number of days on which a significant bleeding event occurred. The evidence suggests that therapeutic platelet transfusions result in a large increase in the number of people with at least one significant bleeding event and they likely result in a large reduction in the number of platelet transfusions. Other It is unclear if including aerobic physical exercise, in addition to the standard treatment for adult patients with haematological malignancies, is effective at reducing anxiety and serious adverse effects. Aerobic physical exercises may result in little to no difference in the mortality, in the quality of life and in the physical functioning. These exercises may result in a slight reduction in depression and most likely reduce fatigue. Prognosis Prognosis depends on the subtype, the staging, a persons age, and other factors. Across all subtypes, 5-year survival for NHL is 71%, ranging from 81% for Stage 1 disease to 61% for Stage 4 disease. Epidemiology Globally, as of 2010, there were 210,000 deaths, up from 143,000 in 1990.Rates of non-Hodgkin lymphoma increase steadily with age. Up to 45 years NHL is more common among males than females. Australia With over 6,000 people being diagnosed yearly, NHL is the fifth most common cancer in Australia. Canada In Canada NHL is the fifth most common cancer in males and sixth most common cancer in females. The lifetime probability of developing a lymphoid cancer is 1 in 44 for males, and 1 in 51 for females. United Kingdom On average, according to data for the 2014–2016 period, around 13,900 people are diagnosed with NHL yearly. It is the sixth most common cancer in the UK, and is the eleventh most common cause of cancer death accounting for around 4,900 deaths per year. United States Age adjusted data from 2012 to 2016 shows about 19.6 cases of NHL per 100,000 adults per year, 5.6 deaths per 100,000 adults per year, and around 694,704 people living with non-Hodgkin lymphoma. About 2.2 percent of men and women will be diagnosed with NHL at some point during their lifetime.The American Cancer Society lists non-Hodgkin lymphoma as one of the most common cancers in the United States, accounting for about 4% of all cancers. History While consensus was rapidly reached on the classification of Hodgkin lymphoma, there remained a large group of very different diseases requiring further classification. The Rappaport classification, proposed by Henry Rappaport in 1956 and 1966, became the first widely accepted classification of lymphomas other than Hodgkin. Following its publication in 1982, the Working Formulation became the standard classification for this group of diseases. It introduced the term non-Hodgkin lymphoma or NHL and defined three grades of lymphoma.NHL consists of many different conditions that have little in common with each other. They are grouped by their aggressiveness. Less aggressive non-Hodgkin lymphomas are compatible with a long survival while more aggressive non-Hodgkin lymphomas can be rapidly fatal without treatment. Without further narrowing, the label is of limited usefulness for people or doctors. The subtypes of lymphoma are listed there.Nevertheless the Working Formulation and the NHL category continue to be used by many. To this day, lymphoma statistics are compiled as Hodgkins versus non-Hodgkin lymphomas by major cancer agencies, including the US National Cancer Institute in its SEER program, the Canadian Cancer Society and the IARC. References External links Non-Hodgkin Lymphoma at American Cancer Society Non-Hodgkins Lymphoma from Cancer.net (American Society of Clinical Oncology)
Abdominal guarding	Abdominal guarding is the tensing of the abdominal wall muscles to guard inflamed organs within the abdomen from the pain of pressure upon them. The tensing is detected when the abdominal wall is pressed. Abdominal guarding is also known as défense musculaire. Guarding is a characteristic finding in the physical examination for an abruptly painful abdomen (an acute abdomen) with inflammation of the inner abdominal (peritoneal) surface due, for example, to appendicitis or diverticulitis. The tensed muscles of the abdominal wall automatically go into spasm to keep the tender underlying tissues from being disturbed. Diagnosis Differential diagnosis Abdominal aortic aneurysm Appendicitis Blunt force trauma to the abdomen Bowel obstruction Diverticulitis Dyspepsia Ectopic pregnancy GERD Ileus Inflammatory bowel disease Intussusception Mesenteric ischemia Nephrolithiasis Ovarian cyst Pancreatitis Pelvic inflammatory disease Perforated peptic ulcer disease Pneumonia Spontaneous bacterial peritonitis (SBP) Urinary tract infection/pyelonephritis Volvulus Zoster Skin lesions may not be visible until another day or two Abdominal migraine Abdominal wall strain/injury Abscess (e.g. iliopsoas) Hepatic or splenic contusion/laceration Incarcerated hernia Insect toxins (e.g. black widow spider) Malingering Pneumoperitoneum secondary to abdominal trauma Septic miscarriage (See Miscarriage) Laboratory findings Complete blood count (CBC) Blood urea nitrogen (BUN)/creatinine Liver function tests (LFTs) Glucose Amylase/lipase Urine culture Urinalysis Beta-human chorionic gonadotropin (beta-hCG) Cervical cultures are recommended to diagnose pelvic inflammatory disease Electrolyte and biomarker studies Electrolytes MRI and CT CT diagnoses: Organ contusion Organ laceration Aneurysm Diverticulitis Appendicitis Echocardiography or ultrasound Pelvic, abdominal and/or transvaginal ultrasound diagnoses: Peritonitis Ectopic pregnancy Ovarian cysts Fluid/blood secondary to trauma Appendicitis Aneurysm Other imaging findings KUB x-ray imaging (kidney, ureter, bladder) could reveal nephrolithiasis and bowel gas pattern Other diagnostic studies Symptomatic relief may be provided by paracentesis, which may also diagnose spontaneous bacterial peritonitis (SBP) Gastrointestinal endoscopy may be used or patients with suspected peptic ulcer disease Helicobacter pylori testing may also be used Trial medications may be beneficial for the diagnosis and treatment of: GERD/dyspepsia: Proton pump inhibitors or H2 blockers Abdominal wall strain: Nonsteriodal anti-inflammatory drugs (NSAIDs) Anxiety: Lorazepam Zoster: Acyclovir Treatment Specific conditions need direct treatment Hemodynamic status and life-threatening disease require immediate attention Volume replacement with a possible blood transfusion, and with normal saline For obstruction and persistent vomiting, place nasogastric (NG) tube Pharmacotherapy If perforated viscus or intra-abdominal infection suspected, administer broad-spectrum empiric antibiotics Surgery and device-based therapy Early sepsis, or evidence of hemorrhage may require surgery (likely to be life-threatening emergency) References Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3
Humerus	The humerus (; pl. humeri) is a long bone in the arm that runs from the shoulder to the elbow. It connects the scapula and the two bones of the lower arm, the radius and ulna, and consists of three sections. The humeral upper extremity consists of a rounded head, a narrow neck, and two short processes (tubercles, sometimes called tuberosities). The body is cylindrical in its upper portion, and more prismatic below. The lower extremity consists of 2 epicondyles, 2 processes (trochlea & capitulum), and 3 fossae (radial fossa, coronoid fossa, and olecranon fossa). As well as its true anatomical neck, the constriction below the greater and lesser tubercles of the humerus is referred to as its surgical neck due to its tendency to fracture, thus often becoming the focus of surgeons. Etymology The word "humerus" is derived from Latin: humerus, umerus meaning upper arm, shoulder, and is linguistically related to Gothic ams shoulder and Greek ōmos. Structure Upper extremity The upper or proximal extremity of the humerus consists of the bones large rounded head joined to the body by a constricted portion called the neck, and two eminences, the greater and lesser tubercles. Head The head (caput humeri), is nearly hemispherical in form. It is directed upward, medialward, and a little backward, and articulates with the glenoid cavity of the scapula to form the glenohumeral joint (shoulder joint). The circumference of its articular surface is slightly constricted and is termed the anatomical neck, in contradistinction to a constriction below the tubercles called the surgical neck which is frequently the seat of fracture. Fracture of the anatomical neck rarely occurs. The diameter of the humeral head is generally larger in men than in women. Anatomical neck The anatomical neck (collum anatomicum) is obliquely directed, forming an obtuse angle with the body. It is best marked in the lower half of its circumference; in the upper half it is represented by a narrow groove separating the head from the tubercles. The line separating the head from the rest of the upper end is called the anatomical neck. It affords attachment to the articular capsule of the shoulder-joint, and is perforated by numerous vascular foramina. Fracture of the anatomical neck rarely occurs.The anatomical neck of the humerus is an indentation distal to the head of the humerus on which the articular capsule attaches. Surgical neck The surgical neck is a narrow area distal to the tubercles that is a common site of fracture. It makes contact with the axillary nerve and the posterior humeral circumflex artery. Greater tubercle The greater tubercle (tuberculum majus; greater tuberosity) is a large, posteriorly placed projection that is placed laterally. The greater tubercle is where supraspinatus, infraspinatus and teres minor muscles are attached. The crest of the greater tubercle forms the lateral lip of the bicipital groove and is the site for insertion of pectoralis major. The greater tubercle is just lateral to the anatomical neck. Its upper surface is rounded and marked by three flat impressions: the highest of these gives insertion to the supraspinatus muscle; the middle to the infraspinatus muscle; the lowest one, and the body of the bone for about 2.5 cm. below it, to the teres minor muscle. The lateral surface of the greater tubercle is convex, rough, and continuous with the lateral surface of the body. Lesser tubercle The lesser tubercle (tuberculum minus; lesser tuberosity) is smaller, anterolaterally placed to the head of the humerus. The lesser tubercle provides insertion to subscapularis muscle. Both these tubercles are found in the proximal part of the shaft. The crest of the lesser tubercle forms the medial lip of the bicipital groove and is the site for insertion of teres major and latissimus dorsi muscles. The lesser tuberosity, is more prominent than the greater: it is situated in front, and is directed medialward and forward. Above and in front it presents an impression for the insertion of the tendon of the subscapularis muscle. Bicipital groove The tubercles are separated from each other by a deep groove, the bicipital groove (intertubercular groove; bicipital sulcus), which lodges the long tendon of the biceps brachii muscle and transmits a branch of the anterior humeral circumflex artery to the shoulder-joint. It runs obliquely downward, and ends near the junction of the upper with the middle third of the bone. In the fresh state its upper part is covered with a thin layer of cartilage, lined by a prolongation of the synovial membrane of the shoulder-joint; its lower portion gives insertion to the tendon of the latissimus dorsi muscle. It is deep and narrow above, and becomes shallow and a little broader as it descends. Its lips are called, respectively, the crests of the greater and lesser tubercles (bicipital ridges), and form the upper parts of the anterior and medial borders of the body of the bone. Shaft The body or shaft of the humerus is triangular to cylindrical in cut section and is compressed anteroposteriorly. It has 3 surfaces, namely: Anterolateral surface: the area between the lateral border of the humerus to the line drawn as a continuation of the crest of the greater tubercle. The antero-lateral surface is directed lateralward above, where it is smooth, rounded, and covered by the deltoid muscle; forward and lateralward below, where it is slightly concave from above downward, and gives origin to part of the Brachialis. About the middle of this surface is a rough, rectangular elevation, the deltoid tuberosity for the insertion of the deltoid muscle; below this is the radial sulcus, directed obliquely from behind, forward, and downward, and transmitting the radial nerve and profunda artery. Anteromedial surface: the area between the medial border of the humerus to the line drawn as a continuation of the crest of the greater tubercle. The antero-medial surface, less extensive than the antero-lateral, is directed medialward above, forward and medialward below; its upper part is narrow, and forms the floor of the intertubercular groove which gives insertion to the tendon of the latissimus dorsi muscle; its middle part is slightly rough for the attachment of some of the fibers of the tendon of insertion of the coracobrachialis muscle; its lower part is smooth, concave from above downward, and gives origin to the brachialis muscle. Posterior surface: the area between the medial and lateral borders. The posterior surface appears somewhat twisted, so that its upper part is directed a little medialward, its lower part backward and a little lateralward. Nearly the whole of this surface is covered by the lateral and medial heads of the Triceps brachii, the former arising above, the latter below the radial sulcus.Its three borders are: Anterior: the anterior border runs from the front of the greater tubercle above to the coronoid fossa below, separating the antero-medial from the antero-lateral surface. Its upper part is a prominent ridge, the crest of the greater tubercle; it serves for the insertion of the tendon of the pectoralis major muscle. About its center it forms the anterior boundary of the deltoid tuberosity, on which the deltoid muscle attaches; below, it is smooth and rounded, affording attachment to the brachialis muscle. Lateral: the lateral border runs from the back part of the greater tubercle to the lateral epicondyle, and separates the anterolateral from the posterior surface. Its upper half is rounded and indistinctly marked, serving for the attachment of the lower part of the insertion of the teres minor muscle, and below this giving origin to the lateral head of the triceps brachii muscle; its center is traversed by a broad but shallow oblique depression, the spiral groove (musculospiral groove). The radial nerve runs in the spiral groove. Its lower part forms a prominent, rough margin, a little curved from backward, forward the lateral supracondylar ridge, which presents an anterior lip for the origin of the brachioradialis muscle above, and extensor carpi radialis longus muscle above, a posterior lip for the triceps brachii muscle, and an intermediate ridge for the attachment of the lateral intermuscular septum. Medial: the medial border extends from the lesser tubercle to the medial epicondyle. Its upper third consists of a prominent ridge, the crest of the lesser tubercle, which gives insertion to the tendon of the teres major muscle. About its center is a slight impression for the insertion of the coracobrachialis muscle, and just below this is the entrance of the nutrient canal, directed downward; sometimes there is a second nutrient canal at the commencement of the radial sulcus. The inferior third of this border is raised into a slight ridge, the medial supracondylar ridge, which became very prominent below; it presents an anterior lip for the origins of the brachialis muscle and the pronator teres muscle, a posterior lip for the medial head of the triceps brachii muscle, and an intermediate ridge for the attachment of the medial intermuscular septum. The Deltoid tuberosity is a roughened surface on the lateral surface of the shaft of the Humerus and acts as the site of insertion of deltoideus muscle. The posterorsuperior part of the shaft has a crest, beginning just below the surgical neck of the humerus and extends till the superior tip of the deltoid tuberosity. This is where the lateral head of triceps brachii is attached. The radial sulcus, also known as the spiral groove is found on the posterior surface of the shaft and is a shallow oblique groove through which the radial nerve passes along with deep vessels. This is located posteroinferior to the deltoid tuberosity. The inferior boundary of the spiral groove is continuous distally with the lateral border of the shaft. The nutrient foramen of the humerus is located in the anteromedial surface of the humerus. The nutrient arteries enter the humerus through this foramen. Distal humerus The distal or lower extremity of the humerus is flattened from before backward, and curved slightly forward; it ends below in a broad, articular surface, which is divided into two parts by a slight ridge. Projecting on either side are the lateral and medial epicondyles. Articular surface The articular surface extends a little lower than the epicondyles, and is curved slightly forward; its medial extremity occupies a lower level than the lateral. The lateral portion of this surface consists of a smooth, rounded eminence, named the capitulum of the humerus; it articulates with the cup-shaped depression on the head of the radius, and is limited to the front and lower part of the bone. Fossae Above the front part of the trochlea is a small depression, the coronoid fossa, which receives the coronoid process of the ulna during flexion of the forearm. Above the back part of the trochlea is a deep triangular depression, the olecranon fossa, in which the summit of the olecranon is received in extension of the forearm. The coronoid fossa is the medial hollow part on the anterior surface of the distal humerus. The coronoid fossa is smaller than the olecranon fossa and receives the coronoid process of the ulna during maximum flexion of the elbow. Above the front part of the capitulum is a slight depression, the radial fossa, which receives the anterior border of the head of the radius, when the forearm is flexed. These fossæ are separated from one another by a thin, transparent lamina of bone, which is sometimes perforated by a supratrochlear foramen; they are lined in the fresh state by the synovial membrane of the elbow-joint, and their margins afford attachment to the anterior and posterior ligaments of this articulation. The Capitulum is a rounded eminence forming the lateral part of the distal humerus. The head of the radius articulates with the capitulum. The trochlea is spool-shaped medial portion of the distal humerus and articulates with the ulna. Epicondyles The epicondyles are continuous above with the supracondylar ridges. The lateral epicondyle is a small, tuberculated eminence, curved a little forward, and giving attachment to the radial collateral ligament of the elbow-joint, and to a tendon common to the origin of the Supinator and some of the Extensor muscles. The medial epicondyle, larger and more prominent than the lateral, is directed a little backward; it gives attachment to the ulnar collateral ligament of the elbow-joint, to the Pronator teres, and to a common tendon of origin of some of the Flexor muscles of the forearm; the ulnar nerve runs in a groove on the back of this epicondyle. The Medial supracondylar crest forms the sharp medial border of the distal humerus continuing superiorly from the medial epicondyle. The Lateral Supracondylar crest forms the sharp lateral border of the distal humerus continuing superiorly from the lateral epicondyle. Borders The medial portion of the articular surface is named the trochlea, and presents a deep depression between two well-marked borders; it is convex from before backward, concave from side to side, and occupies the anterior, lower, and posterior parts of the extremity. The lateral border separates it from the groove which articulates with the margin of the head of the radius. The medial border is thicker, of greater length, and consequently more prominent, than the lateral.The grooved portion of the articular surface fits accurately within the semilunar notch of the ulna; it is broader and deeper on the posterior than on the anterior aspect of the bone, and is inclined obliquely downward and forward toward the medial side. Articulations At the shoulder, the head of the humerus articulates with the glenoid fossa of the scapula. More distally, at the elbow, the capitulum of the humerus articulates with the head of the radius, and the trochlea of the humerus articulates with the trochlear notch of the ulna. Nerves The axillary nerve is located at the proximal end, against the shoulder girdle. Dislocation of the humeruss glenohumeral joint has the potential to injure the axillary nerve or the axillary artery. Signs and symptoms of this dislocation include a loss of the normal shoulder contour and a palpable depression under the acromion. The radial nerve follows the humerus closely. At the midshaft of the humerus, the radial nerve travels from the posterior to the anterior aspect of the bone in the spiral groove. A fracture of the humerus in this region can result in radial nerve injury. The ulnar nerve lies at the distal end of the humerus near the elbow. When struck, it can cause a distinct tingling sensation, and sometimes a significant amount of pain. It is sometimes popularly referred to as the funny bone, possibly due to this sensation (a "funny" feeling), as well as the fact that the bones name is a homophone of humorous. It lies posterior to the medial epicondyle, and is easily damaged in elbow injuries. Function Muscular attachment The deltoid originates on the lateral third of the clavicle, acromion and the crest of the spine of the scapula. It is inserted on the deltoid tuberosity of the humerus and has several actions including abduction, extension, and circumduction of the shoulder. The supraspinatus also originates on the spine of the scapula. It inserts on the greater tubercle of the humerus, and assists in abduction of the shoulder. The pectoralis major, teres major, and latissimus dorsi insert at the intertubercular groove of the humerus. They work to adduct and medially, or internally, rotate the humerus. The infraspinatus and teres minor insert on the greater tubercle, and work to laterally, or externally, rotate the humerus. In contrast, the subscapularis muscle inserts onto the lesser tubercle and works to medially, or internally, rotate the humerus. The biceps brachii, brachialis, and brachioradialis (which attaches distally) act to flex the elbow. (The biceps do not attach to the humerus.) The triceps brachii and anconeus extend the elbow, and attach to the posterior side of the humerus. The four muscles of supraspinatus, infraspinatus, teres minor and subscapularis form a musculo-ligamentous girdle called the rotator cuff. This cuff stabilizes the very mobile but inherently unstable glenohumeral joint. The other muscles are used as counterbalances for the actions of lifting/pulling and pressing/pushing. Other animals Primitive fossils of amphibians had little, if any, shaft connecting the upper and lower extremities, making their limbs very short. In most living tetrapods, however, the humerus has a similar form to that of humans. In many reptiles and some mammals (where it is the primitive state), the lower extremity includes a large opening called the entepicondylar foramen to allow the passage of nerves and blood vessels. Additional images Ossification During embryonic development, the humerus is one of the first structures to ossify, beginning with the first ossification center in the shaft of the bone. Ossification of the humerus occurs predictably in the embryo and fetus, and is therefore used as a fetal biometric measurement when determining gestational age of a fetus. At birth, the neonatal humerus is only ossified in the shaft. The epiphyses are cartilaginous at birth. The medial humeral head develops an ossification center around 4 months of age and the greater tuberosity around 10 months of age. These ossification centers begin to fuse at 3 years of age. The process of ossification is complete by 13 years of age, though the epiphyseal plate (growth plate) persists until skeletal maturity, usually around 17 years of age. See also Humerus fracture References This article incorporates text in the public domain from page 209 of the 20th edition of Grays Anatomy (1918) External links "Humerus" . New International Encyclopedia. 1905. Humerus - BlueLink Anatomy, University of Michigan Medical School
Acanthamoeba	Acanthamoeba is a genus of amoebae that are commonly recovered from soil, fresh water, and other habitats. Acanthamoeba has two evolutive forms, the metabolically active trophozoite and a dormant, stress-resistant cyst. Trophozoites are small, usually 15 to 25 μm in length and amoeboid in shape. In nature, Acanthamoeba species are free-living bacterivores, but in certain situations, they can cause infections (acanthamebiasis) in humans and other animals. Distribution Acanthamoeba spp. are among the most prevalent protozoa found in the environment. They are distributed worldwide, and have been isolated from soil, air, sewage, seawater, chlorinated swimming pools, domestic tap water, bottled water, dental treatment units, hospitals, air-conditioning units, and contact lens cases. Additionally, they have been isolated from human skin, nasal cavities, throats, and intestines, as well as plants and other mammals. Role in disease Diseases caused by Acanthamoeba include keratitis and granulomatous amoebic encephalitis (GAE). The latter is often but not always seen in immunosuppressed patients. GAE is caused by the amoebae entering the body through an open wound and then spreading to the brain. The combination of host immune responses and secreted amoebal proteases causes massive brain swelling resulting in death in about 95% of those infected. Granulomatous amoebic encephalitis (GAE) Granulomatous amoebic encephalitis (GAE) is caused by amoebic infection of the central nervous system (CNS). It is characterized by neurological symptoms including headache, seizures, and mental-status abnormalities. These worsen progressively over weeks to months, leading to death in most patients. Infection is generally associated with underlying conditions such as immunodeficiency, diabetes, malignancies, malnutrition, systemic lupus erythematosus, and alcoholism. The parasite enters the body through cuts in the skin or by being inhaled into the upper respiratory tract. The parasite then spreads through the blood into the CNS. Acanthamoeba crosses the blood–brain barrier by means that are not yet understood. Subsequent invasion of the connective tissue and induction of pro-inflammatory responses leads to neuronal damage that can be fatal within days. Pure granulomatous lesions are rare in patients with AIDS and other related immunodeficiency states, as the patients do not have adequate numbers of CD+ve T-cells to mount a granulomatous response to Acanthamoeba infection in CNS and other organs and tissues. A perivascular cuffing with amoebae in necrotic tissue is usual finding in the AIDS and related T-cell immunodeficiency conditions. Brain biopsy normally reveals severe oedema and hemorrhagic necrosis. A patient who has contracted this illness usually displays subacute symptoms, including altered mental status, headaches, fever, neck stiffness, seizures, and focal neurological signs (such as cranial nerve palsies and coma), all leading to death within one week to several months. Due to the rarity of this parasite and a lack of knowledge, no good diagnoses or treatments for Acanthamoeba infection are now known. Acanthamoeba keratitis cases in the past have resolved from a therapy consisting of atropine and some other drugs with no antimicrobial effects. Recent publications show atropine to interfere with the protists CHRM1 receptor, causing cell death.Infection usually mimics that of bacterial leptomeningitis, tuberculous meningitis, or viral encephalitis. The misdiagnosis often leads to erroneous, ineffective treatment. In the case that the Acanthamoeba is diagnosed correctly, the current treatments, such as amphotericin B, rifampicin, trimethoprim-sulfamethoxazole, ketoconazole, fluconazole, sulfadiazine, or albendazole, are only tentatively successful. Correct and timely diagnosis, as well as improved treatment methods and an understanding of the parasite, are important factors in improving the outcome of infection by Acanthamoeba. A paper published in 2013 has shown substantial effects of some FDA-approved drugs with an in vitro kill rate above 90%. These results were in vitro effects, but as the drugs are already approved, human infections can be targeted after dose calculations in clinical trials done with these diverse groups of drugs. Acanthamoebic keratitis When present in the eye, Acanthamoeba strains can cause acanthamoebic keratitis, which may lead to corneal ulcers or even blindness. This condition occurs most often among contact lens wearers who do not properly disinfect their lenses, exacerbated by a failure to wash hands prior to handling the lenses. Multipurpose contact lens solutions are largely ineffective against Acanthamoeba, whereas hydrogen peroxide-based solutions have good disinfection characteristics.The first cure of a corneal infection was achieved in 1985 at Moorfields Eye Hospital.In May 2007, Advanced Medical Optics, manufacturer of Complete Moisture Plus Contact Lens Solution products, issued a voluntary recall of their Complete Moisture Plus solutions. The fear was that contact lens wearers who used their solution were at higher risk of acanthamoebic keratitis than contact lens wearers who used other solutions. The manufacturer recalled the product after the Centers for Disease Control in the United States found that 21 people had possibly received an Acanthamoeba infection after using Complete Moisture Plus in the month prior to diagnosis. As a bacterial reservoir Several species of bacteria that can cause human disease are also able to infect and replicate within Acanthamoeba species. These include Legionella pneumophila, Pseudomonas aeruginosa, and some strains of Escherichia coli and Staphylococcus aureus. For some of these bacteria, replication inside Acanthamoeba has been associated with enhanced growth in macrophages, and increased resistance to some antibiotics. Furthermore, due to the high prevalence of Acanthamoeba in the environment, these amoebae have been proposed to serve as an environmental reservoir for some human pathogens. Ecology A. castellanii can be found at high densities in various soil ecosystems. It preys on bacteria, but also fungi and other protozoa. This species is able to lyse bacteria and produce a wide range of enzymes, such as cellulases or chitinases, and probably contributes to the breakdown of organic matter in soil, contributing to the microbial loop. Physiology Role as a model organism Because Acanthamoeba does not differ greatly at the ultrastructural level from a mammalian cell, it is an attractive model for cell-biology studies; it is important in cellular microbiology, environmental biology, physiology, cellular interactions, molecular biology, biochemistry, and evolutionary studies, due to the organisms versatile roles in the ecosystem and ability to capture prey by phagocytosis, act as vectors and reservoirs for microbial pathogens, and to produce serious human infections. In addition, Acanthamoeba has been used extensively to understand the molecular biology of cell motility and cancer cell dormancy by in-depth exploration of the process of encystation.The recently available Acanthamoeba genome sequence revealed several orthologs of genes employed in meiosis of sexual eukaryotes. These genes included Spo11, Mre11, Rad50, Rad51, Rad52, Mnd1, Dmc1, Msh, and Mlh. This finding suggests that Acanthamoeba is capable of some form of meiosis and may be able to undergo sexual reproduction. Furthermore, since Acanthamoeba diverged early from the eukaryotic family tree, these results suggest that meiosis was present early in eukaryotic evolution. Owing to its ease and economy of cultivation, the Neff strain of A. castellanii, discovered in a pond in Golden Gate Park in the 1960s, has been effectively used as a classic model organism in the field of cell biology. From just 30 L of simple medium inoculated with A. castellanii, about 1 kg of cells can be obtained after several days of aerated culture at room temperature. Pioneered in the laboratory of Edward D. Korn at the National Institutes of Health (NIH), many important biological molecules have been discovered and their pathways elucidated using the Acanthamoeba model. Thomas Dean Pollard applied this model at the NIH, Harvard Medical School, Johns Hopkins University School of Medicine, and the Salk Institute for Biological Studies to discover and characterize many proteins that are essential for cell motility, not only in amoebae, but also in many other eukaryotic cells, especially those of the human nervous and immune systems, the developing embryo, and cancer cells. Acanthamoeba also has served as a model to study the evolution of certain G-proteins. This unicellular eukaryote expresses few GPCRs over its cell membrane that serve vital role for the microorganism, structural homology bioinformatics tools have been used to show the presence of a homolog of human M1-muscarinic receptor in A. castellanii. Blocking these muscarinic receptors in past studies has proven to be amoebicidal in Acanthamoeba spp. More recently, voltage-gated calcium channels in Acanthamoeba spp. (CavAc) have been reported to have similarities with human voltage-gated calcium channels such as TPC-1 and L-type calcium channels and respond to Ca-channel blockers such as loperamide. This model microbe has been studied to understand complex neurodegenerative states including Alzheimers disease. Scientists have isolated a neurotransmitter acetylcholine in Acanthamoeba and the enzymatic machinery needed for its synthesis. Endosymbionts Acanthamoeba spp. contain diverse bacterial endosymbionts that are similar to human pathogens, so they are considered to be potential emerging human pathogens. The exact nature of these symbionts and the benefit they represent for the amoebic host still have to be clarified. These include Legionella and Legionella-like pathogens. Giant viruses The giant viruses Mimivirus, Megavirus, and Pandoravirus infect Acanthamoeba.Members of the genus Acanthamoeba are unusual in serving as hosts for a variety of giant viruses (that have more than 1000 protein-coding genes; for instance, Pandoravirus, which has about 2500 protein-coding genes in its genome). Diversity Acanthamoeba can be distinguished from other genera of amoebae based on morphological characteristics. However, differentiating one species of Acanthamoeba from another by morphology has proven difficult. Based on 18S rDNA sequencing, known Acanthamoeba strains can be organized into 12 groups, denoted T1-T12. Most disease-causing isolates belong to type T4.Below is a list of described species of Acanthamoeba, with sequence types noted where known. Species that have been identified in diseased patients are marked with . A. astronyxis (Ray & Hayes 1954) Page 1967 (T7) A. byersi Qvarnstrom, Nerad & Visvesvara 2013 * A. castellanii Volkonski 1931 * (T4) [A. terricola Pussard 1964] A. comandoni Pussard 1964 (T9) A. culbertsoni (Singh & Das 1970) Griffin 1972 * (T10) A. divionensis Pussard & Pons 1977 (T4) A. echinulata Pussard & Pons 1977 A. gigantea Schmöller 1964 A. glebae (Dobell 1914) A. gleichenii Volkonsky 1931 A. griffini Sawyer 1971 (T3) A. hatchetti Sawyer, Visvesvara & Harke 1977 * (T11) A. healyi Moura, Wallace & Visvesvara 1992 (T12) A. hyalina Dobel & Oconnor 1921 A. jacobsi Sawyer, Nerad & Visvesvara 1992 A. keratitis * A. lenticulata Molet & Ermolieff-braun 1976 (T3) A. lugdunensis Pussard & Pons 1977 * (T4) A. mauritaniensis Pussard & Pons 1977 (T4) A. micheli Corsaro et al. 2015 A. palestinensis (Reich 1933) Page 1977 * (T1) A. paradivionensis Pussard & Pons 1977 (T4) A. pearcei Nerad et al. 1995 A. polyphaga (Puschkarew 1913) Volkonsky 1931 * (T4) A. pustulosa Pussard & Pons 1977 (T2) A. pyriformis (Olive & Stoianovitch 1969) Spiegel & Shadwick 2016 A. quina Pussard & Pons 1977 * A. rhysodes (Singh 1952) Griffin 1972 * (T4) A. royreba Willaert, Stevens & Tyndall 1978 A. sohi Kyung-il & Shin 2003 A. stevensoni Sawyer et al. 1993 (T11) A. triangularis Pussard & Pons 1977 (T4) A. tubiashi Lewis & Sawyer 1979 (T8) Etymology From the Greek akantha (spike/thorn), which was added before "amoeba" (change) to describe this organism as having a spine-like structure (acanthopodia). This organism is now well known as Acanthamoeba, an amphizoic, opportunistic, and nonopportunistic protozoan protist widely distributed in the environment. See also Acanthamoeba infection Balamuthia mandrillaris References External links Acanthamoeba – Centers for Disease Control and Prevention Video of Acanthamoeba from contact lens keratitis Marciano-Cabral F, Cabral G (April 2003). "Acanthamoeba spp. as agents of disease in humans". Clinical Microbiology Reviews. 16 (2): 273–307. doi:10.1128/CMR.16.2.273-307.2003. PMC 153146. PMID 12692099. Comprehensive resource on Amoeba Eye health and Acanthamoeba Acanthamoeba pictures and illustrations
Creutzfeldt–Jakob disease	Creutzfeldt–Jakob disease (CJD), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is an invariably fatal degenerative brain disorder. Early symptoms include memory problems, behavioral changes, poor coordination, and visual disturbances. Later symptoms include dementia, involuntary movements, blindness, weakness, and coma. About 70% of people die within a year of diagnosis. The name Creutzfeldt–Jakob disease was introduced by Walther Spielmeyer in 1922, after the German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob.CJD is caused by a type of abnormal protein known as a prion. Infectious prions are misfolded proteins that can cause normally folded proteins to also become misfolded. About 85% of cases of CJD occur for unknown reasons, while about 7.5% of cases are inherited in an autosomal dominant manner. Exposure to brain or spinal tissue from an infected person may also result in spread. There is no evidence that sporadic CJD can spread among people via normal contact or blood transfusions, although this is possible in variant Creutzfeldt–Jakob disease. Diagnosis involves ruling out other potential causes. An electroencephalogram, spinal tap, or magnetic resonance imaging may support the diagnosis.There is no specific treatment for CJD. Opioids may be used to help with pain, while clonazepam or sodium valproate may help with involuntary movements. CJD affects about one person per million people per year. Onset is typically around 60 years of age. The condition was first described in 1920. It is classified as a type of transmissible spongiform encephalopathy. Inherited CJD accounts for about 10% of prion disease cases. Sporadic CJD is different from bovine spongiform encephalopathy (mad cow disease) and variant Creutzfeldt–Jakob disease (vCJD). Signs and symptoms The first symptom of CJD is usually rapidly progressive dementia, leading to memory loss, personality changes, and hallucinations. Myoclonus (jerky movements) typically occurs in 90% of cases, but may be absent at initial onset. Other frequently occurring features include anxiety, depression, paranoia, obsessive-compulsive symptoms, and psychosis. This is accompanied by physical problems such as speech impairment, balance and coordination dysfunction (ataxia), changes in gait, and rigid posture. In most people with CJD, these symptoms are accompanied by involuntary movements. The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks. Most affected people die six months after initial symptoms appear, often of pneumonia due to impaired coughing reflexes. About 15% of people with CJD survive for two or more years.The symptoms of CJD are caused by the progressive death of the brains nerve cells, which are associated with the build-up of abnormal prion proteins forming in the brain. When brain tissue from a person with CJD is examined under a microscope, many tiny holes can be seen where the nerve cells have died. Parts of the brain may resemble a sponge where the prions were infecting the areas of the brain. Cause CJD is a type of transmissible spongiform encephalopathy (TSE), which are caused by prions. Prions are misfolded proteins that occur in the neurons of the central nervous system (CNS). They are thought to affect signaling processes, damaging neurons and resulting in degeneration that causes the spongiform appearance in the affected brain.The CJD prion is dangerous because it promotes refolding of native prion protein into the diseased state. The number of misfolded protein molecules will increase exponentially and the process leads to a large quantity of insoluble protein in affected cells. This mass of misfolded proteins disrupts neuronal cell function and causes cell death. Mutations in the gene for the prion protein can cause a misfolding of the dominantly alpha helical regions into beta pleated sheets. This change in conformation disables the ability of the protein to undergo digestion. Once the prion is transmitted, the defective proteins invade the brain and induce other prion protein molecules to misfold in a self-sustaining feedback loop. These neurodegenerative diseases are commonly called prion diseases.People can also develop CJD because they carry a mutation of the gene that codes for the prion protein (PRNP). This occurs in only 5–10% of all CJD cases. In sporadic cases, the misfolding of the prion protein is a process that is hypothesized to occur as a result of the effects of aging on cellular machinery, explaining why the disease often appears later in life. An EU study determined that "87% of cases were sporadic, 8% genetic, 5% iatrogenic and less than 1% variant." Transmission The defective protein can be transmitted by contaminated harvested human brain products, corneal grafts, dural grafts, or electrode implants and human growth hormone.It can be familial (fCJD); or it may appear without clear risk factors (sporadic form: sCJD). In the familial form, a mutation has occurred in the gene for PrP, PRNP, in that family. All types of CJD are transmissible irrespective of how they occur in the person.It is thought that humans can contract the variant form of the disease by eating food from animals infected with bovine spongiform encephalopathy (BSE), the bovine form of TSE also known as mad cow disease. However, it can also cause sCJD in some cases.Cannibalism has also been implicated as a transmission mechanism for abnormal prions, causing the disease known as kuru, once found primarily among women and children of the Fore people in Papua New Guinea, who previously engaged in funerary cannibalism. While the men of the tribe ate the muscle tissue of the deceased, women and children consumed other parts, such as the brain, and were more likely than men to contract kuru from infected tissue.Prions, the infectious agent of CJD, may not be inactivated by means of routine surgical instrument sterilization procedures. The World Health Organization and the US Centers for Disease Control and Prevention recommend that instrumentation used in such cases be immediately destroyed after use; short of destruction, it is recommended that heat and chemical decontamination be used in combination to process instruments that come in contact with high-infectivity tissues. Thermal depolymerization also destroys prions in infected organic and inorganic matter, since the process chemically attacks protein at the molecular level, although more effective and practical methods involve destruction by combinations of detergents and enzymes similar to biological washing powders. Diagnosis Testing for CJD has historically been problematic, due to nonspecific nature of early symptoms and difficulty in safely obtaining brain tissue for confirmation. The diagnosis may initially be suspected in a person with rapidly progressing dementia, particularly when they are also found with the characteristic medical signs and symptoms such as involuntary muscle jerking, difficulty with coordination/balance and walking, and visual disturbances. Further testing can support the diagnosis and may include: Electroencephalography – may have characteristic generalized periodic sharp wave pattern. Periodic sharp wave complexes develop in half of the people with sporadic CJD, particularly in the later stages. Cerebrospinal fluid (CSF) analysis for elevated levels of 14-3-3 protein could be supportive in the diagnosis of sCJD. However, a positive result should not be regarded as sufficient for the diagnosis. The Real-Time Quaking-Induced Conversion (RT-QuIC) assay has a diagnostic sensitivity of more than 80% and a specificity approaching 100%, tested in detecting PrPSc in CSF samples of people with CJD. It is therefore suggested as a high-value diagnostic method for the disease. MRI of the brain – often shows high signal intensity in the caudate nucleus and putamen bilaterally on T2-weighted images.In recent years, studies have shown that the tumour marker neuron-specific enolase (NSE) is often elevated in CJD cases; however, its diagnostic utility is seen primarily when combined with a test for the 14-3-3 protein. As of 2010, screening tests to identify infected asymptomatic individuals, such as blood donors, are not yet available, though methods have been proposed and evaluated. Imaging Imaging of the brain may be performed during medical evaluation, both to rule out other causes and to obtain supportive evidence for diagnosis. Imaging findings are variable in their appearance, and also variable in sensitivity and specificity. While imaging plays a lesser role in diagnosis of CJD, characteristic findings on brain MRI in some cases may precede onset of clinical manifestations.Brain MRI is the most useful imaging modality for changes related to CJD. Of the MRI sequences, diffuse-weighted imaging sequences are most sensitive. Characteristic findings are as follows: Focal or diffuse diffusion-restriction involving the cerebral cortex and/or basal ganglia. In about 24% of cases DWI shows only cortical hyperintensity; in 68%, cortical and subcortical abnormalities; and in 5%, only subcortical anomalies. The most iconic and striking cortical abnormality has been called "cortical ribboning" or "cortical ribbon sign" due to hyperintensities resembling ribbons appearing in the cortex on MRI. The involvement of the thalamus can be found in sCJD, is even stronger and constant in vCJD. Varying degree of symmetric T2 hyperintense signal changes in the basal ganglia (i.e., caudate and putamen), and to a lesser extent globus pallidus and occipital cortex. Cerebellar atrophyBrain FDG PET-CT tends to be markedly abnormal, and is increasingly used in the investigation of dementias. Patients with CJD will normally have hypometabolism on FDG PET. Histopathology Testing of tissue remains the most definitive way of confirming the diagnosis of CJD, although it must be recognized that even biopsy is not always conclusive.In one-third of people with sporadic CJD, deposits of "prion protein (scrapie)", PrPSc, can be found in the skeletal muscle and/or the spleen. Diagnosis of vCJD can be supported by biopsy of the tonsils, which harbor significant amounts of PrPSc; however, biopsy of brain tissue is the definitive diagnostic test for all other forms of prion disease. Due to its invasiveness, biopsy will not be done if clinical suspicion is sufficiently high or low. A negative biopsy does not rule out CJD, since it may predominate in a specific part of the brain.The classic histologic appearance is spongiform change in the gray matter: the presence of many round vacuoles from one to 50 micrometers in the neuropil, in all six cortical layers in the cerebral cortex or with diffuse involvement of the cerebellar molecular layer. These vacuoles appear glassy or eosinophilic and may coalesce. Neuronal loss and gliosis are also seen. Plaques of amyloid-like material can be seen in the neocortex in some cases of CJD.However, extra-neuronal vacuolization can also be seen in other disease states. Diffuse cortical vacuolization occurs in Alzheimers disease, and superficial cortical vacuolization occurs in ischemia and frontotemporal dementia. These vacuoles appear clear and punched-out. Larger vacuoles encircling neurons, vessels, and glia are a possible processing artifact. Classification Types of CJD include: Sporadic (sCJD), caused by the spontaneous misfolding of prion-protein in an individual. This accounts for 85% of cases of CJD. Familial (fCJD), caused by an inherited mutation in the prion-protein gene. This accounts for the majority of the other 15% of cases of CJD. Acquired CJD, caused by contamination with tissue from an infected person, usually as the result of a medical procedure (iatrogenic CJD). Medical procedures that are associated with the spread of this form of CJD include blood transfusion from the infected person, use of human-derived pituitary growth hormones, gonadotropin hormone therapy, and corneal and meningeal transplants. Variant Creutzfeldt–Jakob disease (vCJD) is a type of acquired CJD potentially acquired from bovine spongiform encephalopathy or caused by consuming food contaminated with prions. Treatment As of 2022, there is no cure or effective treatment for CJD. Some of the symptoms like twitching can be managed, but otherwise treatment is palliative care. Psychiatric symptoms like anxiety and depression can be treated with sedatives and antidepressants. Myoclonic jerks can be handled with clonazepam or sodium valproate. Opiates can help in pain. Seizures are very uncommon but can nevertheless be treated with antiepileptic drugs. Prognosis The condition is universally fatal. As of 1981, no one is known to have lived longer than 2.5 years after the onset of CJD symptoms. The longest recorded survivor of variant Creutzfeldt–Jakob disease (vCJD) was Jonathan Simms, a Northern Irish man who lived 10 years after his diagnosis. Epidemiology CDC monitors the occurrence of CJD in the United States through periodic reviews of national mortality data. According to the CDC: CJD occurs worldwide at a rate of about 1 case per million population per year. On the basis of mortality surveillance from 1979 to 1994, the annual incidence of CJD remained stable at approximately 1 case per million people in the United States. In the United States, CJD deaths among people younger than 30 years of age are extremely rare (fewer than five deaths per billion per year). The disease is found most frequently in people 55–65 years of age, but cases can occur in people older than 90 years and younger than 55 years of age. In more than 85% of cases, the duration of CJD is less than one year (median: four months) after the onset of symptoms.Further information from the CDC: Risk of developing CJD increases with age. CJD incidence was 3.5 cases per million among those over 50 years of age between 1979 and 2017. Approximately 85% of CJD cases are sporadic and 10-15% of CJD cases are due to inherited mutations of the prion protein gene. CJD deaths and age-adjusted death rate in the United States indicate an increasing trend in the number of deaths between 1979 and 2017.Although not fully understood, additional information suggests that CJD rates in African American and nonwhite groups are lower than in whites. While the mean onset is approximately 67 years of age, cases of sCJD have been reported as young as 17 years and over 80 years of age. Mental capabilities rapidly deteriorate and the average amount of time from onset of symptoms to death is 7 to 9 months.According to a 2020 systematic review on the international epidemiology of CJD: Surveillance studies from 2005 and later show the estimated global incidence is 1–2 cases per million population per year. Sporadic CJD (sCJD) incidence increased from the years 1990–2018 in the UK. Probable or definite sCJD deaths also increased from the years 1996–2018 in twelve additional countries. CJD incidence is greatest in those over the age of 55 years old, with an average age of 67 years old.The intensity of CJD surveillance increases the number of reported cases, often in countries where CJD epidemics have occurred in the past and where surveillance resources are greatest. An increase in surveillance and reporting of CJD is most likely in response to BSE and vCJD. Possible factors contributing to an increase of CJD incidence are an aging population, population increase, clinician awareness, and more accurate diagnostic methods. Since CJD symptoms are similar to other neurological conditions, it is also possible that CJD is mistaken for stroke, acute nephropathy, general dementia, and hyperparathyroidism. History The disease was first described by German neurologists Hans Gerhard Creutzfeldt in 1920 and shortly afterward by Alfons Maria Jakob, giving it the name Creutzfeldt–Jakob. Some of the clinical findings described in their first papers do not match current criteria for Creutzfeldt–Jakob disease, and it has been speculated that at least two of the people in initial studies had a different ailment. An early description of familial CJD stems from the German psychiatrist and neurologist Friedrich Meggendorfer (1880–1953). A study published in 1997 counted more than 100 cases worldwide of transmissible CJD and new cases continued to appear at the time.The first report of suspected iatrogenic CJD was published in 1974. Animal experiments showed that corneas of infected animals could transmit CJD, and the causative agent spreads along visual pathways. A second case of CJD associated with a corneal transplant was reported without details. In 1977, CJD transmission caused by silver electrodes previously used in the brain of a person with CJD was first reported. Transmission occurred despite the decontamination of the electrodes with ethanol and formaldehyde. Retrospective studies identified four other cases likely of similar cause. The rate of transmission from a single contaminated instrument is unknown, although it is not 100%. In some cases, the exposure occurred weeks after the instruments were used on a person with CJD. In the 1980s it was discovered that Lyodura, a dura mater transplant product, was shown to transmit CJD from the donor to the recipient. This led to the product being banned in Canada but it was used in other countries such as Japan until 1993.A review article published in 1979 indicated that 25 dura mater cases had occurred by that date in Australia, Canada, Germany, Italy, Japan, New Zealand, Spain, the United Kingdom, and the United States.By 1985, a series of case reports in the United States showed that when injected, cadaver-extracted pituitary human growth hormone could transmit CJD to humans.In 1992, it was recognized that human gonadotropin administered by injection could also transmit CJD from person to person.Stanley B. Prusiner of the University of California, San Francisco (UCSF) was awarded the Nobel Prize in Physiology or Medicine in 1997 "for his discovery of Prions—a new biological principle of infection".Yale University neuropathologist Laura Manuelidis has challenged the prion protein (PrP) explanation for the disease. In January 2007, she and her colleagues reported that they had found a virus-like particle in naturally and experimentally infected animals. "The high infectivity of comparable, isolated virus-like particles that show no intrinsic PrP by antibody labeling, combined with their loss of infectivity when nucleic acid–protein complexes are disrupted, make it likely that these 25-nm particles are the causal TSE virions". Australia Australia has documented 10 cases of healthcare-acquired CJD (iatrogenic or ICJD). Five of the deaths resulted after the patients, who were in treatment either for infertility or short stature, were treated using contaminated pituitary extract hormone but no new cases have been noted since 1991. The other five deaths occurred due to dura grafting procedures that were performed during brain surgery, in which the covering of the brain is repaired. There have been no other ICJD deaths documented in Australia due to transmission during healthcare procedures. New Zealand A case was reported in 1989 in a 25-year-old man from New Zealand, who also received dura mater transplant. Five New Zealanders have been confirmed to have died of the sporadic form of Creutzfeldt–Jakob disease (CJD) in 2012. United States In 1988, there was a confirmed death from CJD of a person from Manchester, New Hampshire. Massachusetts General Hospital believed the person acquired the disease from a surgical instrument at a podiatrists office. In September 2013, another person in Manchester was posthumously determined to have died of the disease. The person had undergone brain surgery at Catholic Medical Center three months before his death, and a surgical probe used in the procedure was subsequently reused in other operations. Public health officials identified thirteen people at three hospitals who may have been exposed to the disease through the contaminated probe, but said the risk of anyones contracting CJD is "extremely low". In January 2015, former speaker of the Utah House of Representatives Rebecca D. Lockhart died of the disease within a few weeks of diagnosis. John Carroll, former editor of The Baltimore Sun and Los Angeles Times, died of CJD in Kentucky in June 2015, after having been diagnosed in January. American actress Barbara Tarbuck (General Hospital, American Horror Story) died of the disease on December 26, 2016. José Baselga, clinical oncologist having headed the AstraZeneca Oncology division, died in Cerdanya, March 21, 2021, from CJD. Research Diagnosis In 2010, a team from New York described detection of PrPSc in sheeps blood, even when initially present at only one part in one hundred billion (10−11) in sheeps brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay (SOFIA) and some specific antibodies against PrPSc. The technique allowed improved detection and testing time for PrPSc. In 2014, a human study showed a nasal brushing method that can accurately detect PrP in the olfactory epithelial cells of people with CJD. Treatment Pentosan polysulphate (PPS) was thought to slow the progression of the disease, and may have contributed to the longer than expected survival of the seven people studied. The CJD Therapy Advisory Group to the UK Health Departments advises that data are not sufficient to support claims that pentosan polysulphate is an effective treatment and suggests that further research in animal models is appropriate. A 2007 review of the treatment of 26 people with PPS finds no proof of efficacy because of the lack of accepted objective criteria, but it was unclear to the authors whether that was caused by PPS itself. In 2012 it was claimed that the lack of significant benefits has likely been caused because of the drug being administered very late in the disease in many patients. Use of RNA interference to slow the progression of scrapie has been studied in mice. The RNA blocks production of the protein that the CJD process transforms into prions. Both amphotericin B and doxorubicin have been investigated as treatments for CJD, but as yet there is no strong evidence that either drug is effective in stopping the disease. Further study has been taken with other medical drugs, but none are effective. However, anticonvulsants and anxiolytic agents, such as valproate or a benzodiazepine, may be administered to relieve associated symptoms. Quinacrine, a medicine originally created for malaria, has been evaluated as a treatment for CJD. The efficacy of quinacrine was assessed in a rigorous clinical trial in the UK and the results were published in Lancet Neurology, and concluded that quinacrine had no measurable effect on the clinical course of CJD. Astemizole, a medication approved for human use, has been found to have anti-prion activity and may lead to a treatment for Creutzfeldt–Jakob disease. A monoclonal antibody (code name PRN100) targeting the prion protein (PrP) was given to six people with Creutzfeldt–Jakob disease in an early-stage clinical trial conducted from 2018 to 2022. The treatment appeared to be well-tolerated and was able to access the brain, where it might have helped to clear PrPC. While the treated patients still showed progressive neurological decline, and while none of them survived longer than expected from the normal course of the disease, the scientists at University College London who conducted the study see these early-stage results as encouraging and suggest to conduct a larger study, ideally at the earliest possible intervention. See also Chronic traumatic encephalopathy Chronic wasting disease Kuru References External links Creutzfeldt–Jakob disease at Curlie
Carcinoma in situ	Carcinoma in situ (CIS) is a group of abnormal cells. While they are a form of neoplasm, there is disagreement over whether CIS should be classified as cancer. This controversy also depends on the exact CIS in question (i.e. cervical, skin, breast). Some authors do not classify them as cancer, however, recognizing that they can potentially become cancer. Others classify certain types as a non-invasive form of cancer. The term "pre-cancer" has also been used. These abnormal cells grow in their normal place, thus "in situ" (from Latin for "in its place"). For example, carcinoma in situ of the skin, also called Bowens disease, is the accumulation of dysplastic epidermal cells within the epidermis only, that has failed to penetrate into the deeper dermis. For this reason, CIS will usually not form a tumor. Rather, the lesion is flat (in the skin, cervix, etc.) or follows the existing architecture of the organ (in the breast, lung, etc.). Exceptions include CIS of the colon (polyps), the bladder (preinvasive papillary cancer), or the breast (ductal carcinoma in situ or lobular carcinoma in situ). Many forms of CIS have a high probability of progression into cancer, and therefore removal may be recommended; however, progression of CIS is known to be highly variable and not all CIS becomes invasive cancer. In the TNM classification, carcinoma in situ is reported as TisN0M0 (stage 0). Terminology These terms are related since they represent the steps of the progression toward cancer: Dysplasia is the earliest form of precancerous lesion recognizable in a biopsy. Dysplasia can be low-grade or high-grade. High-grade dysplasia may also be referred to as carcinoma in situ. Invasive carcinoma, usually simply called cancer, has the potential to invade and spread to surrounding tissues and structures, and may eventually be lethal. Examples Cervical squamous intraepithelial lesion (SIL), previously called cervical intraepithelial neoplasia (CIN), is a form of dysplasia that can progress to cervical cancer. The term carcinoma in situ may be used interchangeably with high-grade SIL. Ductal carcinoma in situ of the breast is the most common precancer in women. Bowens disease is a squamous carcinoma in situ of the skin. Colon polyps often contain areas of CIS that will almost always transform into colon cancer if left untreated. High-grade prostatic intraepithelial neoplasia is equivalent to CIS of the prostate. Bronchioloalveolar carcinoma (BAC) of the lung is the only form of CIS that can kill directly because, in rare cases (the "pneumonic form"), it expands greatly and fills the lungs, preventing breathing and causing other dire effects on the host. Thus, the pneumonic form of BAC is a true malignant entity, but is not "invasive" in the classical sense. For this reason, it is considered a form of CIS by pathologists, but not by oncologists or surgeons, and inclusion of this form of cancer among the types of CIS is controversial. Treatment Carcinoma in situ is, by definition, a localized phenomenon, with no potential for metastasis unless it progresses into cancer. Therefore, its removal eliminates the risk of subsequent progression into a life-threatening condition. Some forms of CIS (e.g., colon polyps and polypoid tumours of the bladder) can be removed using an endoscope, without conventional surgical resection. Dysplasia of the uterine cervix is removed by excision (cutting it out) or by burning with a laser. Bowens disease of the skin is removed by excision. Other forms require major surgery, the best known being intraductal carcinoma of the breast (also treated with radiotherapy). References == External links ==
Pannus	Pannus is an abnormal layer of fibrovascular tissue or granulation tissue. Common sites for pannus formation include over the cornea, over a joint surface (as seen in rheumatoid arthritis), or on a prosthetic heart valve. Pannus may grow in a tumor-like fashion, as in joints where it may erode articular cartilage and bone. In common usage, the term pannus is often used to refer to a panniculus (a hanging flap of tissue). Pannus in rheumatoid arthritis The term "pannus" is derived from the Latin for "tablecloth". Inflammation and exuberant proliferation of the synovium leads to formation of pannus and destruction of cartilage, bone, tendons, ligaments, and blood vessels. Basically, the hypertrophied synovium is called pannus. Pannus tissue is composed of aggressive macrophage- and fibroblast-like mesenchymal cells, macrophage-like cells and other inflammatory cells that release collagenolytic enzymes. In people suffering from rheumatoid arthritis, pannus tissue eventually forms in the joint affected by the disease, causing loss of bone and cartilage. From Autoimmunity and Disease by Harley Y. Tse and Michail K. Shaw:Chronic stages of the disease typically coincide with the formation of a structure known as a pannus. A pannus is a membrane of granulation tissue composed of mesenchyme- and bone marrow-derived cells. Formation of the pannus stimulates the release of IL-1, platelet-derived growth factor, prostaglandins, and substance P by macrophages, which ultimately cause cartilage destruction and bone erosion. Pannus in ophthalmology In ophthalmology, pannus refers to the growth of blood vessels into the peripheral cornea. In normal individuals, the cornea is avascular. Chronic local hypoxia (such as that occurring with overuse of contact lenses) or inflammation may lead to peripheral corneal vascularization, or pannus. Pannus may also develop in diseases of the corneal stem cells, such as aniridia. It is often resolved by peritomy. == References ==
Holoprosencephaly	Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy. The condition also occurs in other species. Holoprosencephaly is estimated to occur in approximately 1 in every 250 conceptions and most cases are not compatible with life and result in fetal death in utero due to deformities to the skull and brain. However, holoprosencephaly is still estimated to occur in approximately 1 in every 8,000 live births.When the embryos forebrain does not divide to form bilateral cerebral hemispheres (the left and right halves of the brain), it causes defects in the development of the face and in brain structure and function. The severity of holoprosencephaly is highly variable. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip. Signs and symptoms Symptoms of holoprosencephaly range from mild (no facial/organ defects, anosmia, or only a single central incisor) to moderate to severe (cyclopia). The symptoms are dependent upon the classification type.There are four classifications of holoprosencephaly as well as a mild "microform". Alobar Most severe form includes formation of synophthalmia (a single central eye), proboscis, and severe impairment. Semilobar Can present with severely decreased distance between eyes, a flat nasal bridge, eye defects, cleft lip and palate, and severe impairment. Lobar Can present with decreased distance between eyes, a flat nasal bridge, closely spaced nostrils, mental and locomotion delays may be present. Syntelencephaly or middle interhemispheric variant of holoprosencephaly (MIHV) Mild phenotypic presentation which can present with flat nasal bridge, metopic prominence, shallow philtrum, and possible mental and locomotion delays. "Microform" Mild phenotypic presentation with reduced distance between eyes, sharp nasal bridge, single maxillary central incisor. Diagnosis Holoprosencephaly is typically diagnosed during fetal development when there are abnormalities found on fetal brain imaging, however it can also be diagnosed after birth. The Protocol for diagnosis includes neuroimaging (Ultrasound or fetal MRI prior to birth or Ultrasound, MRI or CT post birth), syndrome evaluation, cytogenetics, molecular testing, and genetic counseling.There are four classifications of holoprosencephaly as well as a “microform". These classifications can be distinguished by their anatomical differences. Alobar holoprosencephaly Small single forebrain ventricle No interhemispheric division Absence of olfactory bulbs and tracts Absence of corpus callosum Non separation of deep gray nuclei Semilobar holoprosencephaly Rudimentary cerebral lobes Incomplete interhemispheric division Absence or hypoplasia of olfactory bulbs and tracts Absence of corpus callosum Varying non separation of deep gray nuclei Lobar holoprosencephaly Fully-developed cerebral lobes Distinct interhemispheric division Midline continuous frontal neocortex Absent, hypoplasic or normal corpus callosum Separation of deep gray nuclei Syntelencephaly, or middle interhemispheric variant of holoprosencephaly (MIHV) Failure of separation of the posterior frontal and parietal lobes Callosal genu and splenium normally formed Absence of corpus callosum Hypothalamus and lentiform nuclei normally separated Heterotopic gray matter Microform Subtle defects of corpus callosum Subtle midline brain defects Causes In Holoprosencephaly, the neural tube fails to segment, resulting in incomplete separation of the prosencephalon at the fifth week of gestation.The exact cause(s) of HPE are yet to be determined. Mutations in the gene encoding the SHH protein, which is involved in the development of the central nervous system (CNS), can cause holoprosencephaly. In other cases, it often seems that there is no specific cause at all. Genetics Armand Marie Leroi describes the cause of cyclopia as a genetic malfunctioning during the process by which the embryonic brain is divided into two. Only later does the visual cortex take recognizable form, and at this point an individual with a single forebrain region will be likely to have a single, possibly rather large, eye (at such a time, individuals with separate cerebral hemispheres would form two eyes). Increases in expression of such genes as Pax-2, as well as inhibition of Pax-6, from the notochord have been implicated in normal differentiation of cephalic midline structures. Inappropriate expression of any of these genes may result in mild to severe forms of holoprosencephaly. Other candidate genes have been located, including the SHH (holoprosencephaly type 3 a.k.a. HPE3), TGIF, ZIC2, SIX3 and BOC genes.Although many children with holoprosencephaly have normal chromosomes, specific chromosomal abnormalities have been identified in some patients (trisomy of chromosome 13, also known as Patau syndrome). There is evidence that in some families, HPE is inherited (autosomal dominant as well as autosomal or X-linked recessive inheritance). Features consistent with familial transmission of the disease (e.g., a single central maxillary incisor) should be carefully assessed in parents and family members. Non-genetic factors Numerous possible risk factors have been identified, including gestational diabetes, transplacental infections (the "TORCH complex"), first trimester bleeding, and a history of miscarriage. As well, the disorder is found twice as often in female babies. However, there appears to be no correlation between HPE and maternal age.There is evidence of a correlation between HPE and the use of various drugs classified as being potentially unsafe for pregnant and lactating mothers. These include insulin, birth control pills, aspirin, lithium, thorazine, retinoic acid, and anticonvulsants. There is also a correlation between alcohol consumption and HPE, along with nicotine, the toxins in cigarettes and toxins in cigarette smoke when used during pregnancy. Prognosis HPE is not a condition in which the brain deteriorates over time. Although serious seizure disorders, autonomic dysfunction, complicated endocrine disorders and other life-threatening conditions may sometimes be associated with HPE, the mere presence of HPE does not mean that these serious problems will occur or develop over time without any previous indication or warning. These abnormalities are usually recognized shortly after birth or early in life and only occur if areas of the brain controlling those functions are fused, malformed or absent.Prognosis is dependent upon the degree of fusion and malformation of the brain, as well as other health complications that may be present. The more severe forms of encephalopathy are usually fatal. This disorder consists of a spectrum of defects, malformations and associated abnormalities. Disability is based upon the degree in which the brain is affected. Moderate to severe defects may cause intellectual disability, spastic quadriparesis, athetoid movements, endocrine disorders, epilepsy and other serious conditions; mild brain defects may only cause learning or behavior problems with few motor impairments. Seizures may develop over time with the highest risk before 2 years of age and the onset of puberty. Most are managed with one medication or a combination of medications. Typically, seizures that are difficult to control appear soon after birth, requiring more aggressive medication combinations/doses. Most children with HPE are at risk of having elevated blood sodium levels during moderate-severe illnesses, that alter fluid intake/output, even if they have no previous diagnosis of diabetes insipidus or hypernatremia. See also Cephalic disorder Cyclopia Prenatal development References External links GeneReview/NIH/UW entry on Holoprosencephaly Overview holoprosencephaly at NINDS What do we know about holoprosencephaly - Genome.gov
Cardiac allograft vasculopathy	Cardiac allograft vasculopathy (CAV) is a progressive type of coronary artery disease in people who have had a heart transplant. As the donor heart has lost its nerve supply there is typically no chest pain, and CAV is usually detected on routine testing. It may present with symptoms such as tiredness and breathlessness.It arises when the blood vessels supplying the transplanted heart change in structure. They gradually narrow and restrict its blood flow, subsequently leading to impairment of the heart muscle or sudden death. In addition to the same risk factors for coronary artery disease due to the build up of plaque, CAV is more likely to occur if the donor was older or died from explosive brain death, and if there is cytomegalovirus infection. Its mechanism involves immunological (innate and adaptive) and nonimmunological factors, with distinct features on histological samples of coronary arteries. Other major causes of death following heart transplantation include graft failure, organ rejection and infection.Diagnosis is by regular follow-up and monitoring of the transplanted heart for early signs of disease. Tests include coronary angiography, intravascular ultrasound, dobutamine stress echocardiography, positron emission tomography, computed tomographic angiography (CT angiography) and several biomarkers.Statins and aspirin are commenced early after transplantation and on detection of CAV. Medications including sirolimus and everolimus can slow disease progression. A repeat heart transplantation may be required.CAV affects around half of heart transplant recipients within 10 years. It contributes to the death of 11-13% one year from heart transplantation. Definition Cardiac allograft vasculopathy is an accelerated type of coronary artery disease in people who have had a heart transplantation. Signs and symptoms Unlike the chest tightness of angina in those who have not had a heart transplant, people with CAV typically do not experience chest pain because the donor heart has lost its nerve supply. A few regain nerves some years later and may develop unusual chest pain. People with CAV may present with a broad spectrum of symptoms including tiredness, nausea, or abdominal discomfort or may have no symptoms at all. Shortness of breath and arrythmias may also occur. Risk factors Similar to coronary artery disease in those who have not had a heart transplant, risk factors to CAV include high blood pressure, high cholesterol, and diabetes mellitus. Other risk factors exclusive to CAV include older donors, cytomegalovirus infection and circulating antibodies after heart transplantation. The mechanism of donor brain death, particularly explosive brain death in the donor has been shown to be a significant factor. It is probably the combination of injuries to the allograft that determine the risk of developing CAV. Mechanism Immunological (innate and adaptive) and nonimmunological factors contribute to the complex pathogenesis of CAV.In those nontransplanted people who develop coronary artery disease due to atherosclerosis, progression of disease is slow, histological changes are confined mainly to the main coronary arteries and arterial dilatation is observed as a form of compensatory remodelling. However, in CAV, histology specimens typically show concentric thickening of the intimal layer of the main coronary arteries on the surface of the heart and in intramyocardial arteries which can become obliterated within a few years. There is smooth muscle cell migration, foamy macrophages and lymphocytic infiltrates. This can be seen to affect the whole length of the coronary arteries and often the smaller arteries. Calcification does not always occur in CAV and if it does appear, it happens late. The compensatory arterial dilation does not occur in CAV. Unlike in nontransplanted people with coronary artery disease due to atherosclerosis, in CAV occlusion with thrombus of the vessel lumen is rare.Inflammation and endothelial injury can be triggered by the donor arrest, organ procurement, and allograft ischaemia and reperfusion. Diagnosis As symptoms are so variable and often absent, diagnosis has been a challenge. Hence, regular follow-up and monitoring of the allograft for early signs of disease is advocated. Coronary angiography Surveillance is performed by regularly repeating coronary angiography in the cardiac catheterization laboratory, the diagnostic test of choice. This is typically performed annually for the first five years after transplantation. Angiography in CAV characteristically demonstrates diffuse stenoses in large coronary arteries and a reduced number of smaller coronary arteries, also known as "peripheral pruning". However, because CAV frequently affects the entire length of the coronary artery, CAV may not be apparent by angiography alone. Intravascular ultrasound (IVUS) Intravascular ultrasound (IVUS) is more sensitive at reliably detecting subtle changes in the thickness of the intimal layer of the artery walls and provide measurements of artery lumen. Following transplantation, serial measurements are compared to the baseline. A greater than 0.5 mm increase in intimal thickness one year after transplantation is predictive of CAV changes on angiography within five years. The paradoxical reduction in the number of blood vessels, can also be detected by intravascular ultrasound.IVUS, however, tends to be used for research due to its drawbacks of being invasive, requiring the use of contrast material and cost. Dobutamine stress-echocardiography (DSE) Alternatively, dobutamine stress echocardiography (DSE) is commonly performed and has an 85% sensitivity for the presence of CAV. A negative DSE correlates with a good prognosis.Other noninvasive diagnostics include positron emission tomography and computed tomographic angiography (CT angiography). In addition, ECGs may show atypical features of ischaemia. Biomarkers Biomarkers for increased risk of CAV include C-reactive protein, serum brain natriuretic peptide and troponin I have been suggested. Classification The degree of CAV after heart transplantation has been obtained from a variety of sources including The Cardiac Transplant Research Database, the ISHLT registry and The United Network for Organ Sharing registry.The International Society for Heart and Lung Transplantation (ISHLT) have formulated and standardized a terminology, based on diagnostic findings, to define the presence and severity of CAV, which in turn reflects prognosis. The severity of CAV is defined by the degree of narrowing of the coronary arteries and the presence of restrictive heart disease. Treatment Statins Prevention of CAV progression is important as once developed, CAV existing treatments are often ineffective. Commencing the statins pravastatin and simvastatin early after transplantation reduces the incidence and severity of CAV. Vitamins When combined with immunosuppressants, the progression of CAV could possibly be slowed by vitamins C and E. Aspirin Since the role of aspirin is already established in coronary artery disease in those who have not had a heart transplant, it is usually given after heart transplantation too. Antiproliferative agents On detection of CAV, medications including mTOR inhibitors sirolimus and everolimus have been shown to slow disease progression. Other treatment options Clinically significant CAV may require percutaneous coronary interventions for focal disease, but the likelihood of restenosis is high. A repeat heart transplantation may be considered. Outcome Once there is reduced left ventricular ejection fraction and symptoms of heart failure, the outcome is typically poor. The risk of major adverse cardiovascular events is increased by 3.4 fold if CAV is present on angiography. Epidemiology The frequency of CAV after heart transplantation has been obtained from a variety of sources including The Cardiac Transplant Research Database, the ISHLT registry and The United Network for Organ Sharing registry. In comparison to between 1994 and 2001, there has been a decline in incidence of CAV between 2001 and 2007. ISHLT figures show an incidence of CAV of around 50% at 10 years after heart transplantation.CAV is a leading cause of late mortality following heart transplantation. Most are not severe but it contributes to the death of 11-13% one year from heart transplantation. History Unlike rejection and infection, CAV in the transplanted heart was not initially a predicted outcome. Early survivors of heart transplants soon developed this form of vasculopathy of their coronary arteries, initially identified at post-mortems. There were early suggestions that preventing cytomegalovirus (CMV) infection could decrease the prevalence of CAV. The impact of CAV has changed over time, with early recipients being younger, having more rejection and cardiovascular risk factors and less use of statins. Later recipients used statins routinely and were introduced to the immunosuppressive agent mycophenolate mofetil (MMF) and CMV prophylaxis. In addition, the later recipients were monitored for antibody-mediated cardiac allograft rejection (AMR).Before 2010 there was no uniform international standards for the nomenclature of CAV. A consensus statement on a standard language for CAV was first published in 2010 by the ISHLT. This was devised in a similar way to the earlier acute rejection grading system by endomyocardial biopsy. Research directions Antibody-mediated cardiac allograft rejection (AMR) is a significant factor leading to the rapid progression of CAV. Future research directions in this area may include prospective databases that correlate clinical factors with surveillance of the incidence and severity of AMR, the frequency of CMV infection, and the use of immunosuppressants. The role of inducing immune tolerance has yet to be established. == References ==
Erectile dysfunction	Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men. Through its connection to self-image and to problems in sexual relationships, erectile dysfunction can cause psychological harm. In about 80% of cases, physical causes can be identified. These include cardiovascular disease; diabetes mellitus; neurological problems, such as those following prostatectomy; hypogonadism; and drug side effects. About 10% of cases are psychological impotence, caused by thoughts or feelings; here, there is a strong response to placebo treatment. The term erectile dysfunction is not used for other disorders of erection, such as priapism. Treatment involves addressing the underlying causes, lifestyle modifications, and addressing psychosocial problems. In many cases, treatment is attempted by drugs, specifically PDE5 inhibitors (such as sildenafil), which dilate blood vessels, allowing more blood to flow through the spongy tissue of the penis (akin to opening a valve further in order to allow more water to enter a fire hose). Other treatments, less commonly used, include prostaglandin pellets, inserted in the urethra; smooth-muscle relaxants and vasodilators, injected into the penis; penile implants; penis pumps; and vascular reconstructive surgery. Signs and symptoms ED is characterized by the regular or repeated inability to achieve or maintain an erection of sufficient rigidity to accomplish sexual activity. It is defined as the "persistent or recurrent inability to achieve and maintain a penile erection of sufficient rigidity to permit satisfactory sexual activity for at least 3 months." Psychological impact ED often has an impact on the emotional well-being of both men and their partners. Many men do not seek treatment due to feelings of embarrassment. About 75% of diagnosed cases of ED go untreated. Causes Causes of or contributors to ED include the following: Diets high in saturated fat are linked to heart diseases, and men with heart diseases are more likely to experience ED. By contrast, plant-based diets show a lower risk for ED. Prescription drugs (e.g., SSRIs, beta blockers, antihistamines, alpha-2 adrenergic receptor agonists, thiazides, hormone modulators, and 5α-reductase inhibitors) Neurogenic disorders (e.g., diabetic neuropathy, temporal lobe epilepsy, multiple sclerosis, Parkinsons disease, multiple system atrophy) Cavernosal disorders (e.g., Peyronies disease) Hyperprolactinemia (e.g., due to a prolactinoma) Psychological causes: performance anxiety, stress, and mental disorders Surgery (e.g., radical prostatectomy) Ageing: after age 40 years, ageing itself is a risk factor for ED, although numerous other pathologies that may occur with ageing, such as testosterone deficiency, cardiovascular diseases, or diabetes, among others, appear to have interacting effects Kidney disease: ED and chronic kidney disease have pathological mechanisms in common, including vascular and hormonal dysfunction, and may share other comorbidities, such as hypertension and diabetes mellitus that can contribute to ED Lifestyle habits, particularly smoking, which is a key risk factor for ED as it promotes arterial narrowing. Due to its propensity for causing detumescence and erectile dysfunction, some studies have described tobacco as an anaphrodisiacal substance. COVID-19: preliminary research indicates that COVID-19 viral infection may affect sexual and reproductive healthSurgical intervention for a number of conditions may remove anatomical structures necessary to erection, damage nerves, or impair blood supply. ED is a common complication of treatments for prostate cancer, including prostatectomy and destruction of the prostate by external beam radiation, although the prostate gland itself is not necessary to achieve an erection. As far as inguinal hernia surgery is concerned, in most cases, and in the absence of postoperative complications, the operative repair can lead to a recovery of the sexual life of people with preoperative sexual dysfunction, while, in most cases, it does not affect people with a preoperative normal sexual life.ED can also be associated with bicycling due to both neurological and vascular problems due to compression. The increased risk appears to be about 1.7-fold.Concerns that use of pornography can cause ED have little support in epidemiological studies, according to a 2015 literature review. According to Gunter de Win, a Belgian professor and sex researcher, "Put simply, respondents who watch 60 minutes a week and think theyre addicted were more likely to report sexual dysfunction than those who watch a care-free 160 minutes weekly." Pathophysiology Penile erection is managed by two mechanisms: the reflex erection, which is achieved by directly touching the penile shaft, and the psychogenic erection, which is achieved by erotic or emotional stimuli. The former involves the peripheral nerves and the lower parts of the spinal cord, whereas the latter involves the limbic system of the brain. In both cases, an intact neural system is required for a successful and complete erection. Stimulation of the penile shaft by the nervous system leads to the secretion of nitric oxide (NO), which causes the relaxation of the smooth muscles of the corpora cavernosa (the main erectile tissue of the penis), and subsequently penile erection. Additionally, adequate levels of testosterone (produced by the testes) and an intact pituitary gland are required for the development of a healthy erectile system. As can be understood from the mechanisms of a normal erection, impotence may develop due to hormonal deficiency, disorders of the neural system, lack of adequate penile blood supply or psychological problems. Spinal cord injury causes sexual dysfunction, including ED. Restriction of blood flow can arise from impaired endothelial function due to the usual causes associated with coronary artery disease, but can also be caused by prolonged exposure to bright light. Diagnosis In many cases, the diagnosis can be made based on the persons history of symptoms. In other cases, a physical examination and laboratory investigations are done to rule out more serious causes such as hypogonadism or prolactinoma.One of the first steps is to distinguish between physiological and psychological ED. Determining whether involuntary erections are present is important in eliminating the possibility of psychogenic causes for ED. Obtaining full erections occasionally, such as nocturnal penile tumescence when asleep (that is, when the mind and psychological issues, if any, are less present), tends to suggest that the physical structures are functionally working. Similarly, performance with manual stimulation, as well as any performance anxiety or acute situational ED, may indicate a psychogenic component to ED.Another factor leading to ED is diabetes mellitus, a well known cause of neuropathy). ED is also related to generally poor physical health, poor dietary habits, obesity, and most specifically cardiovascular disease, such as coronary artery disease and peripheral vascular disease. Screening for cardiovascular risk factors, such as smoking, dyslipidemia, hypertension, and alcoholism, is helpful.In some cases, the simple search for a previously undetected groin hernia can prove useful since it can affect sexual functions in men and is relatively easily curable.The current diagnostic and statistical manual of mental diseases (DSM-IV) lists ED. Ultrasonography Penile ultrasonography with doppler can be used to examine the erect penis. Most cases of ED of organic causes are related to changes in blood flow in the corpora cavernosa, represented by occlusive artery disease (in which less blood is allowed to enter the penis), most often of atherosclerotic origin, or due to failure of the veno-occlusive mechanism (in which too much blood circulates back out of the penis). Before the Doppler sonogram, the penis should be examined in B mode, in order to identify possible tumors, fibrotic plaques, calcifications, or hematomas, and to evaluate the appearance of the cavernous arteries, which can be tortuous or atheromatous.Erection can be induced by injecting 10–20 µg of prostaglandin E1, with evaluations of the arterial flow every five minutes for 25–30 min (see image). The use of prostaglandin E1 is contraindicated in patients with predisposition to priapism (e.g., those with sickle cell anemia), anatomical deformity of the penis, or penile implants. Phentolamine (2 mg) is often added. Visual and tactile stimulation produces better results. Some authors recommend the use of sildenafil by mouth to replace the injectable drugs in cases of contraindications, although the efficacy of such medication is controversial.Before the injection of the chosen drug, the flow pattern is monophasic, with low systolic velocities and an absence of diastolic flow. After injection, systolic and diastolic peak velocities should increase, decreasing progressively with vein occlusion and becoming negative when the penis becomes rigid (see image below). The reference values vary across studies, ranging from > 25 cm/s to > 35 cm/s. Values above 35 cm/s indicate the absence of arterial disease, values below 25 cm/s indicate arterial insufficiency, and values of 25–35 cm/s are indeterminate because they are less specific (see image below). The data obtained should be correlated with the degree of erection observed. If the peak systolic velocities are normal, the final diastolic velocities should be evaluated, those above 5 cm/s being associated with venogenic ED. Other workup methods Penile nerves function Tests such as the bulbocavernosus reflex test are used to ascertain whether there is enough nerve sensation in the penis. The physician squeezes the glans (head) of the penis, which immediately causes the anus to contract if nerve function is normal. A physician measures the latency between squeeze and contraction by observing the anal sphincter or by feeling it with a gloved finger in the anus.Nocturnal penile tumescence (NPT) It is normal for a man to have five to six erections during sleep, especially during rapid eye movement (REM). Their absence may indicate a problem with nerve function or blood supply in the penis. There are two methods for measuring changes in penile rigidity and circumference during nocturnal erection: snap gauge and strain gauge. A significant proportion [give us the percentage] of men who have no sexual dysfunction nonetheless do not have regular nocturnal erections.Penile biothesiometry This test uses electromagnetic vibration to evaluate sensitivity and nerve function in the glans and shaft of the penis.Dynamic infusion cavernosometry (DICC) Technique in which fluid is pumped into the penis at a known rate and pressure. It gives a measurement of the vascular pressure in the corpus cavernosum during an erection.Corpus cavernosometry Cavernosography measurement of the vascular pressure in the corpus cavernosum. Saline is infused under pressure into the corpus cavernosum with a butterfly needle, and the flow rate needed to maintain an erection indicates the degree of venous leakage. The leaking veins responsible may be visualized by infusing a mixture of saline and x-ray contrast medium and performing a cavernosogram. In Digital Subtraction Angiography (DSA), the images are acquired digitally.Magnetic resonance angiography (MRA) This is similar to magnetic resonance imaging. Magnetic resonance angiography uses magnetic fields and radio waves to provide detailed images of the blood vessels. The doctor may inject into the patients bloodstream a contrast agent, which causes vascular tissues to stand out against other tissues, so that information about blood supply and vascular anomalies is easier to gather. Treatment Treatment depends on the underlying cause. In general, exercise, particularly of the aerobic type, is effective for preventing ED during midlife. Counseling can be used if the underlying cause is psychological, including how to lower stress or anxiety related to sex. Medications by mouth and vacuum erection devices are first-line treatments,: 20, 24 followed by injections of drugs into the penis, as well as penile implants.: 25–26 Vascular reconstructive surgeries are beneficial in certain groups. Treatments, other than surgery, do not fix the underlying physiological problem, but are used as needed before sex. Medications The PDE5 inhibitors sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis) are prescription drugs which are taken by mouth.: 20–21 As of 2018, sildenafil is available in the UK without a prescription. Additionally, a cream combining alprostadil with the permeation enhancer DDAIP has been approved in Canada as a first line treatment for ED. Penile injections, on the other hand, can involve one of the following medications: papaverine, phentolamine, and prostaglandin E1, also known as alprostadil. In addition to injections, there is an alprostadil suppository that can be inserted into the urethra. Once inserted, an erection can begin within 10 minutes and last up to an hour. Medications to treat ED may cause a side effect called priapism. Prevalence of medical diagnosis In a study published in 2016, based on US health insurance claims data, out of 19,833,939 US males aged ≥18 years, only 1,108,842 (5.6%), were medically diagnosed with erectile dysfunction or on a PDE5I prescription (μ age 55.2 years, σ 11.2 years). Prevalence of diagnosis or prescription was the highest for age group 60–69 at 11.5%, lowest for age group 18–29 at 0.4%, and 2.1% for 30–39, 5.7% for 40–49, 10% for 50–59, 11% for 70–79, 4.6% for 80–89, 0.9% for ≥90, respectively. Focused shockwave therapy Focused shockwave therapy involves passing short, high frequency acoustic pulses through the skin and into the penis. These waves break down any plaques within the blood vessels, encourage the formation of new vessels, and stimulate repair and tissue regeneration.Focused shockwave therapy appears to work best for men with vasculogenic ED, which is a blood vessel disorder that affects blood flow to tissue in the penis. The treatment is painless and has no known side effects. Treatment with shockwave therapy can lead to a significant improvement of the IIEF (International Index of Erectile Function). Testosterone Men with low levels of testosterone can experience ED. Taking testosterone may help maintain an erection. Men with type 2 diabetes are twice as likely to have lower levels of testosterone, and are three times more likely to experience ED than non-diabetic men. Pumps A vacuum erection device helps draw blood into the penis by applying negative pressure. This type of device is sometimes referred to as penis pump and may be used just prior to sexual intercourse. Several types of FDA approved vacuum therapy devices are available under prescription. When pharmacological methods fail, a purpose-designed external vacuum pump can be used to attain erection, with a separate compression ring fitted to the base of the penis to maintain it. These pumps should be distinguished from other penis pumps (supplied without compression rings) which, rather than being used for temporary treatment of impotence, are claimed to increase penis length if used frequently, or vibrate as an aid to masturbation. More drastically, inflatable or rigid penile implants may be fitted surgically. Surgery Often, as a last resort, if other treatments have failed, the most common procedure is prosthetic implants which involves the insertion of artificial rods into the penis.: 26 Some sources show that vascular reconstructive surgeries are viable options for some people. Alternative medicine The Food and Drug Administration (FDA) does not recommend alternative therapies to treat sexual dysfunction. Many products are advertised as "herbal viagra" or "natural" sexual enhancement products, but no clinical trials or scientific studies support the effectiveness of these products for the treatment of ED, and synthetic chemical compounds similar to sildenafil have been found as adulterants in many of these products. The FDA has warned consumers that any sexual enhancement product that claims to work as well as prescription products is likely to contain such a contaminant. A 2021 review indicated that ginseng had "only trivial effects on erectile function or satisfaction with intercourse compared to placebo". History Attempts to treat ED date back well over 1,000 years. In the 8th century, men of Ancient Rome and Greece wore talismans of rooster and goat genitalia, believing these talismans would serve as an aphrodisiac and promote sexual function. In the 13th century Albertus Magnus recommended ingesting roasted wolf penis as a remedy for impotence.During the late 16th and 17th centuries in France, male impotence was considered a crime, as well as legal grounds for a divorce. The practice, which involved inspection of the complainants by court experts, was declared obscene in 1677.The first successful vacuum erection device, or penis pump, was developed by Vincent Marie Mondat in the early 1800s. A more advanced device, based on a bicycle pump, was developed by Geddings Osbon, a Pentecostal preacher, in the 1970s. In 1982, he received FDA approval to market the product as the ErecAid®.John R. Brinkley initiated a boom in male impotence cures in the U.S. in the 1920s and 1930s. His radio programs recommended expensive goat gland implants and "mercurochrome" injections as the path to restored male virility, including operations by surgeon Serge Voronoff. Modern drug therapy for ED made a significant advance in 1983, when British physiologist Giles Brindley dropped his trousers and demonstrated to a shocked Urodynamics Society audience his papaverine-induced erection. The drug Brindley injected into his penis was a non-specific vasodilator, an alpha-blocking agent, and the mechanism of action was clearly corporal smooth muscle relaxation. The effect that Brindley discovered established the fundamentals for the later development of specific, safe, and orally effective drug therapies.The current first-line treatment for ED, the oral PDE5 inhibitor, was introduced by Pfizer in 1999. Anthropology Anthropological research presents ED not as a disorder but, as a normal, and sometimes even welcome sign of healthy aging. Wentzells study of 250 Mexican men in their 50s and 60s found that “most simply did not see decreasing erectile function as a biological pathology”. The men interviewed described the decrease in erectile function “as an aid for aging in socially appropriate ways”. A common theme amongst the interviewees showed that respectable older men shifted their focus toward the domestic sphere into a “second stage of life”. The Mexican men of this generation often pursued sex outside of marriage; decreasing erectile function acted as an aid to overcoming infidelity thus helping to attain the ideal “second stage” of life. A 56-year-old about to retire from the public health service said he would now "dedicate myself to my wife, the house, gardening, caring for the grandchildren—the Mexican classic". Wentzell found that treating ED as a pathology was antithetical to the social view these men held of themselves, and their purpose at this stage of their lives. In the 20th and 21st centuries, anthropologists investigated how common treatments for ED are built upon assumptions of institutionalized social norms. In offering a range of clinical treatments to ‘correct’ a persons ability to produce an erection, biomedical institutions encourage the public to strive for prolonged sexual function. Anthropologists argue that a biomedical focus places emphasis on the biological processes of fixing the body thereby disregarding holistic ideals of health and aging. By relying on a wholly medical approach, Western biomedicine can become blindsided by bodily dysfunctions which can be understood as appropriate functions of age, and not as a medical problem. Anthropologists understand that a biosocial approach to ED considers a persons decision to undergo clinical treatment more likely a result of "society, political economy, history, and culture" than a matter of personal choice. In rejecting biomedical treatment for ED, men can challenge common forms of medicalized social control by deviating from what is considered the normal approach to dysfunction. Lexicology The Latin term impotentia coeundi describes simple inability to insert the penis into the vagina; it is now mostly replaced by more precise terms, such as erectile dysfunction (ED). The study of ED within medicine is covered by andrology, a sub-field within urology. Research indicates that ED is common, and it is suggested that approximately 40% of males experience symptoms compatible with ED, at least occasionally. The condition is also on occasion called phallic impotence. Its antonym, or opposite condition, is priapism. References Further reading Carson, Culley; Faria, Geraldo; Hellstrom, Wayne J. G.; Krishnamurti, Sudhakar; Minhas, Suks; Moncada, Ignacio; Montague, Drogo K. (1 January 2010). "Implants, Mechanical Devices, and Vascular Surgery for Erectile Dysfunction". Journal of Sexual Medicine. Wiley. 7 (1): 501–523. doi:10.1111/j.1743-6109.2009.01626.x. PMID 20092450. External links Erectile dysfunction at Curlie
Athelia (disease)	Athelia is the congenital absence of one or both nipples. It is a rare condition. It sometimes occurs on one side in children with the Poland sequence and on both sides in certain types of ectodermal dysplasia. Sources == External links ==