Medical outliers present a medical, psychological, social, and economic challenge to the physicians who care for them. The determinism of Stoic thought is explored as an intellectual basis for the pursuit of a correct mental attitude that will provide aid and comfort to physicians who care for medical outliers, thus fostering continued physician engagement in their care.The Stoic topics of good, the preferable, the morally indifferent, living consistently, and appropriate actions are reviewed. Furthermore, Zeno's cardinal virtues of Justice, Temperance, Bravery, and Wisdom are addressed, as are the Stoic passions of fear, lust, mental pain, and mental pleasure. These concepts must be understood by physicians if they are to comprehend and accept the Stoic view as it relates to having the proper attitude when caring for those with long-term and/or costly illnesses.Practicing physicians, especially those that are hospital based, and most assuredly those practicing critical care medicine, will be emotionally challenged by the medical outlier. A Stoic approach to such a social and psychological burden may be of benefit. Medical outliers are defined in health care reimbursement, especially in the prospective payment system, as those patients who require an unusually long hospital stay or whose stay generates unusually high costs, i.e., the most severely ill . AccordiFinancial concerns have overwhelmed the American medical educational system and hospitals ,5. MedicEric Cassell has pointed out that medical practice is now being shaped by commercial considerations; the issue of financing health care dominates all facets of medicine, including education, research, the relationships between physicians, and the relationships between physicians and their patients . NonetheIn a previous debate an argument was made, using the works of Kant and Hegel, that physicians have an obligation to treat medical outliers . Here anStoics will argue that becoming a physician is predetermined by Nature, or God, and, that having occurred, it must also be predetermined that a physician will care for medical outliers. Thus, the only thing physicians can alter, or control, is their attitude. Zeno, the founder of Stoicism, explains,"A man's excellence or virtue does not depend on his success in obtaining anything in the external world; it depends entirely on having the right mental attitude toward things" .logos, the ability of humans to think, plan, and express themselves, was inherent in the cosmos. Therefore, logos is part of Nature, or God,Stoicism teaches that the universe is rational, that it can be explained rationally, and organized rationally. Stoics taught that "God and man are related to each other at the heart of their being rational agents. If a man fully recognizes the implications of this relationship, he will act in a manner which wholly accords with human rationality at its best, the excellence of which is guaranteed by its willing agreement with nature. This is what it is to be wise...." .Stoics believed that a cosmic thread related every event to another and that such a premise allows a human to live a life at one with Nature, or God. In acquiring such an understanding a human could strike an accord between his or her attitudes, actions, and the course of events.The reason for having a good mental attitude and the understanding that a cosmic thread relates all actions and events, according to the Stoics, is that God rules all and nothing can occur unless God wills it. Accepting everything that happens to one's self will bring contentment,"So the good man will accept everything, knowing that it is not only unalterable, since Fate determines all, but also the work of God, the perfect being; namely that his happiness depends entirely upon himself, and not at the mercy of other persons or the play of outside forces. What brings happiness is to have the right attitude, to choose the right actions, to aim correctly at the mark" .Therefore, to "try" is within a man's power, and good intentions are indeed enough according to Stoic philosophy. The ability to succeed is not necessarily within man's grasp, but his attitude is his own doing. If a person does his or her best and has no self-reproach for this effort, then he or she is one with Nature, or God.There are difficulties with accepting Stoic philosophy, which will be reviewed later. Nonetheless, the Stoic view of a physician's approach to the care of the medical outlier will be advocated as one that may allow a physician to be successful in outlier care. Success does not refer to monetary remuneration, but an approach that will allow a physician mental comfort (a good attitude) in such an advocacy.Physicians must understand the concepts of good, the preferable, the morally indifferent, living consistently, appropriate actions, the cardinal virtues, and the passions to successfully apply the Stoic view.What is good? Any physician pondering this question may come up with answers such as a lucrative medical practice, minimal on-call days, or passing medical board examinations. These things are good, especially when compared to poverty, sickness, or unemployment. However, the Stoics believed what was "good", was also morally perfect . Virtue and virtuous things belonged in a league of their own. If you were virtuous, according to the Stoics, you were "good", therefore happy, and this was moral perfection. If you were virtuous you always did what was morally right. Things that are "bad" are morally imperfect (not virtuous); here we speak of evil and wickedness, not poverty, illness, or death.The Stoics' view of good and bad were extremes of perfection and imperfection. Beauty, wealth, a good job, and a good marriage were things that were preferable, but not morally "good". Illness, poverty, and death were less preferable, but not morally "bad". However, neither the preferable, nor the less preferable were considered "good" or "evil"; they were considered morally indifferent,Right action  is a matter of choice concerned with morally indifferent things – will you look for wealth or accept poverty, marry or remain a bachelor, live or die? – and choice between absolutely different alternatives would not involve knowledge or reason.... Virtue then can consist in the effort to obtain these things that have value and avoid their contraries, and knowledge can be knowledge of what is to be preferred. But since things of this sort are not "good" or "bad", it is of no importance whether one has them or does not have them, as far as goodness is concerned. The good intention is enough; achievement may be impeded by forces outside a man's control" ["Goodness, however, and knowledge, although they had value of a unique kind, could not be the only things to have value. control" .It can generally be agreed upon that caring for medical outliers, ideally, is a "right action" because we are dealing with sickness and economics, i.e., morally indifferent things that are not preferable. Many times caring for medical outliers is something we must do to keep our position, fulfill our contract, or to avoid a lawsuit. However, if we speak of doing what is right in the virtuous, or morally perfect sense, caring for medical outliers must be more than moral indifference. It must be an act of virtue, but can only be so if the physician is doing it out of the deepest sense of duty. Virtue in this case means having the right mental attitude toward outlier care and understanding that it is more than an ordinary good, it is an action that stands morally in a class of its own.Philosophers in ancient Greece would inquire, "What is the goal of a perfect life" . The StoZeno explained that "the single plan by which life should be lived must be a plan formed by correct reason, and this would be one that is natural in the sense that it accords both with man's nature and with universal nature" . In advoTo be happy or content in the care of medical outliers a physician must have this consistency of life and an absence of conflict in this regard. To be able to understand this concept and accept it, the physician must be aware that he or she is a part of the whole. For example, let us say a flower flourishes in a garden; we understand what "to flourish" means. Also, let us say we observe a group of birds, some are healthy and some are not. Therefore, we know what the natural condition, or norm, for a flower and a bird should be. This norm is good. So each thing, flower, or bird has a good that is a universal. There is a universal condition or nature that is appropriate for each thing,"Eating hay is natural to horses, but not to men. It accords with universal nature that horses should eat hay and that men should speak a language. But the former is inappropriate to men and the latter to horses. Universal Nature sanctions a norm for particular things – the nature of plants, animals and men – by reference to which they can be said to attain or not to attain their individual ends" .Thus we can understand what is meant by "the part". Man is born and man will die. Man fights the Universal Nature of death, a particular "norm" of humans. In struggling against his role, or his "part" in nature, man may do extraordinary things to keep himself healthy or alive. A man may decide to preserve his home or his child's education by not having (paying for) health insurance. A physician, for example, may decide that a patient needs an organ transplant. The physician will engage this struggle whether or not the patient has health insurance, and the end result may make the patient a medical outlier, physiologically and/or economically. Universal Nature may sanction a norm for particular things, but humans, and especially physicians, often struggle against their role as a "part" and come into conflict with nature.Each flower, bird, person, or physician is a part of Nature's whole. Contrary events may happen to an individual "part". Birds are hunted and eaten, flowers are cut and put into a vase, and severely ill humans may end up on long-term ventilatory support. The Stoics believed that such events are part of nature's order. Such a view may be contrary to a human observing the whole of nature. However, if the human perspective is removed from an event then, "From the perspective of the whole even such conditions are not unnatural, because all natural events contribute to the universal well-being" .The Stoics combine their views of the part and the whole. They view the whole as perfect and the nature of perfect requires inequities and incompatibilities; nothing that happens to a human is disadvantageous to him or her, nor is it a disadvantage to nature. Nature is perfect, so according to Stoicism, suffering does not occur for its own sake, but "it is necessary to the economy of the whole" .For physicians to live consistently they must understand their place in nature. Stoics would explain to today's physician that their contentment in dealing with medical outliers depends on this understanding of nature. If this is understood and accepted there will be no conflict and "living consistently" will be attainable.appropriately is not in itself either good or bad in the sense of being morally "good" or "bad" [Most physicians hope to make the right, or moral, decisions in regard to their actions. Caring for medical outliers is a choice that has to be made by many physicians. Stoics believed it was always appropriate to act virtuously, but acting virtuously can only occur when a man is "perfectly good", and since men are not "perfectly good" then physicians cannot act virtuously, in other words, be morally perfect. However, Stoicism has made a niche for appropriate actions, "to act virtuously is always morally good, and to act faultily is always bad, to act or "bad" . Even thA physician may care for a medical outlier, but it is not necessarily a morally good action if he or she does it without the complete understanding of why it is the right thing to do. In other words, taking care of a medical outlier is a just action, and thus an appropriately good action, but only if the physician is doing it without duress or not being mandated to attend to the patient .Irrational forces plague a man's mind according to Plato, and these forces have to be controlled before a man could have the needed knowledge to act virtuously. The Stoics, however, did not feel this was true. They felt that if a man could be trained to think correctly, then he could learn to act virtuously.Justice was wisdom concerned with distribution. Temperance (self-control) was wisdom concerned with acquisition. Bravery was wisdom concerned with endurance. Wisdom was defined as "knowledge of what should and should not be done, or knowledge of what is good or bad or neither" [Zeno went on to define four cardinal virtues that were necessary for a man to acquire to be successfully trained to think correctly so that he could act virtuously. He used Plato's work as a basis and he defined the four virtues in terms of the fourth virtue, wisdom. neither" .Medical outliers require justice. Physicians must be able to distribute their actions  fairly and equitably to all those who are in need of such services. Temperance, or self-control, must be learned or acquired. Physicians have to control their emotions when assigned to a medical outlier, having their patients turn into medical outliers, or seeing other parties' responses to medical outliers. Physicians should allow neither anger, frustration, anxiety, nor fear to overtake them. Enduring the endless days, weeks, or months of caring for a medical outlier certainly requires bravery and stamina. Fielding the unending phone calls and the constant re-tuning of a patient's hemodynamic status can be of marathon proportions. Wisdom is what should or should not be done and what is good or bad must not only apply to the type and amount of medical care, but it should also encompass the virtue of the acts of justice, compassion, and care given to the medical outlier.pathos) or what many of them called a mental disturbance. The Stoic "passion" is defined as an excessive uncontrollable drive due to an overestimation of the worth of the "indifferent" things (or events) mentioned previously. Nonetheless Stoics taught that to have great affection was indeed desirable, but at the same time one should remain passionless. Animals are driven to an action because of a stimulus, but in man such a stimulus (or impulse) requires the mind to accede to the stimulus. The Stoics found this to be important because they felt it to be a point of distinction between humans and animals. To the Stoics all living animals were compelled to respond to stimuli by their psyche, a mix of fire and air that was responsible for the functions of living animals . There are times, however, when a man's mind is out of control and his passions become excessive [Physicians need emotion. The Stoics did not disagree, but they wished to eliminate passion . The passions were explained by F.H. Sanbach,"Fear is a contraction of the psyche caused by the belief that something bad is impending. It causes paleness, shivering, and thumping of the heart. But the belief is false: what is feared is not what a Stoic calls "bad", but one of the morally indifferent things, e.g. death, pain, ill-repute. Fear is the result of exaggerating their importance, of believing they will bring real harm, whereas they do not affect man's essential moral being and if they come are to be accepted as part of the great plan of nature. Lust is a longing for something believed to be good, but again is falsely so believed, since the supposed good is morally of the psyche. Mental pain is a contraction of the psyche resulting from the belief, again erroneous, that something bad is present.... Pleasure was defined as an irrational expansion of the psyche caused by the supposed presence of something good.... What is thought to be good is not in fact good, but at the best acceptable" .In many instances the passions do come into play when a physician cares for a medical outlier. Fear affects the physician from several perspectives. Physicians fear for adverse outlier outcomes, not only for the patient's sake and that of the family, but also out of concern for potential litigation, non-reimbursement for services rendered, and long hours incurred in the care of the patient.In regard to lust (desire), something believed to be good, but falsely so, several points can be made. The Stoics spoke of many types, or species, of lust, anger being foremost among them. This species of lust is very appropriate to discuss in regard to care of the medical outlier. Physicians do get angry and occasionally act out when challenged. Outliers involve a large investment of emotion, time, and a potential loss of income on the part of the physician . Also, hostility toward staff for small deviations from the plan of care may occur more frequently than the staff would like. As the patient's course of illness drags on physicians may have anger for the patient and the family . Such anger occurs because the patient does not improve or improves too slowly. There may also be anger towards the family for asking too many questions or questioning the plan of care the physician is following. In addition, the family may also want other physicians consulted or more time from their current physician. What is, in fact, happening is that the family is merely trying to exert control over what little they can yet control.Mental pain or anguish is self evident in medical outlier care. The previous passions of fear and lust (the species of anger) contribute to the burden of mental pain. The species of mental pain that Stoics address include grief and pity, two potentially powerful distorters of judgment for physicians.Mental pleasure in caring for those that are seriously and/or chronically ill is not as self-evident. Again we do not speak here of physical pleasure. The species of mental pleasure include "pleasure at unexpected 'benefits', pleasure at other people's misfortunes, pleasures caused by deceit and magic" . PhysiciThere is no doubt that medical outlier care evokes passions. There is little for a physician to do but his or her best in regard to giving health care. Much is out of the physician's control, and therefore much of Stoic thought is applicable; control the passions, keep a good attitude, have an open mind about plans of care, have an open mind as to who can participate in decisions , understand what is a reasonable outcome, and remember that is does not matter who gets credit for good outcomes .If all human events and actions are predetermined how are human freedoms and free will to be addressed? Universal causation is the bedrock of Stoic philosophy. If human attitudes and beliefs are within an individual's power or sphere of influence, is this truly congruent with Stoic determinism?Robert L. Arrington illustrates the human attitude towards sickness as a foible in Stoic thought . Illnessit is not possible for us to perceive it as a matter of indifference. If, on the contrary, the causes lead us to assume the attitude of indifference, then it becomes impossible for us to see the illness as misfortune. Either one of the sets of courses or the other must exist, from which it follows that it is either impossible for us to feel misfortune or impossible for us to feel indifference. If one of these options is impossible, the attitude we take is necessary in which case we really didn't have any options at all. And without options or choices, there is no thing as freedom or voluntary behavior. And, so it seems, our attitudes and beliefs are not in our power" ["And if the causes that exist prior to our forming the attitude lead us to perceive the illness as misfortune, r power" .This argument regarding whether universal causation and determinism is consistent with a free will has been debated for over 20 centuries. Today there are philosophers on both sides of the issue.Another flaw is the Stoic approach to evil. Stoics simply tell us it does not exist; events may seem evil, but they are not. Stoics teach that only the human perspective allows the interpretation that evil exists. Religions of the world, many philosophers, and people who have viewed and/or endured suffering cannot agree with the Stoics.A further distortion in Stoic thought involves the idea that the life of virtue is the only "good" life. What about the "preferred" things that we as humans know make our lives better? What is wrong with "attaining the goals of impulse" ? There wAnd, finally, the Stoics felt the universe was rational and in unity. A divine thread ran through the cosmos connecting everything and everybody. Many philosophers cannot accept this concept. However, as we see the progression of this line of reasoning as it regards the study of the "string" theory in physics and the further work and modification of Einstein's views of relativity, we realize that there may be a mathematical basis to existence. The Stoics may be criticized about their "thread" through the cosmos, but when we discuss how time "bends" and describe gravity as "curved space" the critics of Stoicism may be tightrope-walking this same thread.The health care rendered to medical outliers can be for a substantial length of time and cost to the medical practitioner. The intensive interaction with the patient, his or her family, consultants, nurses, other ancillary staff, and the institution can sap the performance of involved physicians.Placing the argument for the predetermination of events aside, if one is a physician that is involved in a hospital-based specialty, critical care medicine, or as surgeon, the fact of the matter is that medical outliers will come to your door. By fate or by choice physicians in the above-mentioned areas will be engaged with outliers. As the Stoics point out, the future is coming at you and there is nothing you can do about it, except adjust your attitude.While engaged in such an endeavor physicians will "try" to do their best, hopefully without self-reproach as to their efforts. Physicians, as humans, cannot be "good", or morally perfect. They become tired, hungry, worry about the bills, their children, their practice, hospital policies, etc. Nonetheless, most physicians realize and understand what appropriate actions are necessary in regard to the most ill and poorest of patients. Also, though physicians may not be morally perfect (virtuous in the Stoic sense), they know what is "preferable" for their patients, i.e., to get well, go home and be with their families. These are morally "indifferent" things, but as Stoics point out, "virtue then can consist in the effort to obtain these things that have value and avoid their contraries, and knowledge can be knowledge of what is to be preferred" .As mentioned previously, physicians frequently struggle against their role as a "part". By the mere fact that physicians acknowledge struggles with or against insurers, patients, families, colleagues, ancillary staff, and institutions there is realization that they are part of a "whole", but at the same to "live consistently" requires an understanding of one's role in nature and the need for absence of conflict. In the struggle to help the critically ill, the chronically ill, or the incredibly poor, avoiding conflict is challenging.The cardinal virtues of justice, temperance, bravery, and wisdom come with upbringing, education, and life experiences. Lacking the proper intellectual or nurturing environment will not allow the flourishing of these virtues in an individual. In schools of medicine the faculty attempt to inculcate these virtues in the students, although they are not always successful.The Accreditation Council for Graduate Medical Education (ACGME) has recently mandated six core competencies for resident education . One of Justice is a far-reaching concept that more physicians need to embrace. It is difficult to teach and is best acquired through experience of its antithesis. Temperance, or self-control, can be mandated by medical staff guidelines and licensing boards, but this virtue actually needs to have been ingrained before medical school. Bravery is something that residency training seeds in a physician through the frequent facing of dying or hostile patients that come through a medical practice, especially at an academic institution that cares for the disenfranchised. Wisdom will come with time and maturity. Both are needed to acquire wisdom. Physicians, medical students, and residents can, indeed, be taught to think correctly, as the Stoics emphasized. However, individuals will have varying degrees of success depending their rearing/nurturing and educational environment.Emotion is necessary to physicians, but the passions, those uncontrollable mental disturbances due to overestimation of the value of "indifferent" things, may blind them in their judgment and decision-making. It is important that when making important decisions in regard to medical outliers that the passions be "checked".To avoid frustration, disappointment and unhappiness in the practice of medicine as it regards medical outliers, physicians must do two things: (1) control things that are within their power , and (2) be indifferent to the things that they cannot control  .Even though Stoicism has evoked controversy for over twenty centuries it is relevant to a physician who must juggle patients, procedures, therapies, and colleagues in the care of a patient who has maximally taxed medical insurers, institutions, other practitioners, and their own families.Insurers and institutions may have financial burdens, but those providing patient care, especially physicians, bear a disproportionate slice of the mental anguish associated with the care of medical outliers. Here an argument has been made that applying the philosophical tenets of Stoicism to the physician's intellectual pursuit of how to deal mentally with the care of medical outliers is appropriate. Physicians that are hospital based and those practicing critical care medicine may well be the providers most emotionally challenged by outliers. A Stoic approach to such a social and psychological burden may be helpful.The author(s) declare that they have no competing interests.TJP is responsible for the manuscript in its entirety.The pre-publication history for this paper can be accessed here:


H. pylori infection using only non-invasive tests. We compared the diagnostic value of non-invasive and endoscopy based H. pylori tests in a late post-treatment setting.Guidelines for management of peptic ulcer patients after the treatment are largely directed to detection of 13C-UBT tests were performed.Altogether 34 patients with dyspeptic complaints were referred for gastroscopy 5 years after the treatment of peptic ulcer using a one-week triple therapy scheme. The endoscopic and histologic findings were evaluated according to the Sydney classification. Bacteriological, PCR and cytological investigations and H. pylori positive by 13C-UBT test, PCR and histological examination. On endoscopy, peptic ulcer persisted in 4 H. pylori positive cases. Among the 6 cases with erosions of the gastric mucosa, only two patients were H. pylori positive. Mucosal atrophy and intestinal metaplasia were revealed both in the H. pylori positive and H. pylori negative cases. Bacteriological examination revealed three clarithromycin resistant H. pylori strains. Cytology failed to prove validity for diagnosing H. pylori in a post-treatment setting.Seventeen patients were defined H. pylori colonisation, PCR and bacteriology as they have shown good concordance with 13C-UBT. Moreover, endoscopy and histological investigation of a gastric biopsy have proved to be the methods with an additional diagnostic value, providing the physician with information about inflammatory, atrophic and metaplastic lesions of the stomach in dyspeptic H. pylori positive and negative patients. Bacteriological methods are suggested for detecting the putative antimicrobial resistance of H. pylori, aimed at successful eradication of infection in persistent peptic ulcer cases.In a late post-treatment setting, patients with dyspepsia should not be monitored only by non-invasive investigation methods; it is also justified to use the classical histological evaluation of  Endoscopic biopsies alone are not considered adequate for confirming eradication of bacteria, although they might provide additional information about gastritis and dysplasia [H. pylori status [Treatment of peptic ulcer in accordance with relevant guidelines is becoming a common task for general practitioners -6. In a 13C-UBT) -5. In a er cases . Moreoveysplasia . Use of i status .13C-UBT) and endoscopy-based diagnostic methods  for monitoring patients after eradication therapy in a late post-treatment setting.Our aim was to assess the diagnostic value of different non-invasive . The studied patients were not NSAID users.The study group was formed of 134 consecutive peptic ulcer outpatients who had been treated by 7-day triple therapy with metronidazole, amoxicillin and omeprazole in 1996. The group was observed at the outpatient department of Tartu University Hospital at 4 weeks, at 1 year (1997) and at 5 (2001) years after treatment . Five yeThe patients passed the Gastrointestinal Symptoms Rating Scale (GSRS) test  in a val13C-UBT drinking 100 mg 13C-urea; the test meal was citric acid and the time of specimen collection was 30 min. The test was provided, according to a standard protocol, from the Helsinki Keskuskatu Laboratory, Finland. The ratio of 13CO2 to 12CO2 in expired breath was measured by mass spectrometry and expressed in ml/mmol/kg (δ). An automated breath 13C analyser (ABCA) with chromatographic purification and a single inlet isotope ratio mass spectrometer (IRMS) were used. A difference of 5‰ in the content (δ13C) was considered positive for H. pylori infection.The subjects passed The procedure was performed with the gastroscope Olympus-GIF 21. All mucosal defects were registered according to the Sydney classification for endoscopic evaluation . GastricH. pylori colonisation were evaluated on a three-grade scale both for the antrum and the corpus [Five specimens from the antrum mucosa and five from the corpus mucosa were taken with medium-sized forceps. Two specimens were embedded in paraffin and the paraffin sections were stained using haematoxylin-eosin and Giemsa methods. The mucosal specimens were evaluated histologically according to the Sydney classification: presence of neutrophil infiltration, chronic lymphocytic inflammation, surface epithelial damage, atrophy, intestinal metaplasia, lymphoid follicles and e corpus -14.2 and diluted in the Brucella broth (Oxoid). H. pylori was isolated on the Columbia Agar Base supplemented with 7% horse blood and 1% Vitox (Oxoid) or Isovitalex (BBL). The plates were incubated for 3–7 days at 37°C under microaerobic conditions . H. pylori was identified by Gram staining and by oxidase, catalase and urease reactions [H. pylori strains to clarithromycin was estimated by E-test. The antibiotic cut-off points employed for the E-test were 1.0 mg/l .One specimen from the antrum and one from the corpus were placed in the Stuart Transport Medium (Oxoid) and taken to the laboratory within two hours for bacteriological examination. The biopsy samples were homogenised with sterile glass powder and under a stream of COeactions . The senH. pylori cells on the gastric mucosa and in the mucus layer.One specimen was used for imprinting the cytology slides from the antrum and corpus mucosa, fixed with 96% ethanol and stained by Acridine Orange  . The cytH. pylori from a frozen gastric biopsy specimen, a previously described procedure was used [glmM gene in each strain was established by PCR using primers, the reaction mixture, and thermal cycling [H. pylori NCTC 11637  and the DNA-free reaction mixture were assayed in separate tubes in each PCR and were run as the positive and negative controls of the reaction, respectively. The PCR products were identified by electrophoresis on 2% agarose gels.For DNA extraction of was used . The pre cycling ,20. DNA H. pylori was assessed positive if at least two tests were positive according to golden standard [standard .The data were analysed by Fisher's exact tests using the Jandel SigmaStat 2.0 program. Measurements from the GSRS were expressed as the mean values for dyspeptic syndrome.The study was carried out in accordance with the Helsinki Declaration and was approved by the Ethics Committee of the University of Tartu.Dyspeptic syndrome was found in all 34 cases. The mean GSRS score for the patients varied from 1.2 to 4.3.H. pylori infection in half of the investigated patients: positive 13C-UBT was found in 17 out of 34 cases. There was no difference between the mean GSRS score values for the H. pylori positive and negative cases .The applied non-invasive test revealed H. pylori status and of the endoscopic finding are presented in Table On endoscopy, among the 34 patients, no ulcer or other mucosal defects were observed in 24 cases; erosions in the duodenal bulb were revealed in 6 cases and peptic ulcer was found in 4 cases . The data of H. pylori . The gastric and duodenal mucosa was visually normal in 11 H. pylori positive cases out of 17. On the contrary, only in 4 H. pylori positive cases did the endoscopic examination reveal the above mentioned peptic ulcers. Among the 6 cases with erosions of the duodenal mucosa, only two patients were H. pylori positive.A poor concordance was found between the visual examination of the gastric and duodenal mucosa on endoscopy and the applied non-invasive and invasive tests of H. pylori is shown in Table 13C-UBT and PCR were consistent with the data of histological examination both in 17H. pylori positive and 17 negative cases. On bacteriological examination, only one case, which was H. pylori positive both by PCR and the histological tests, was H. pylori negative. In contrast, cytological examination assessed typical H. pylori bacterial cells in only 4 of the 17H. pylori positive cases (24%), while all other cases (both positive and negative for H. pylori by the other methods) displayed abundant bacteria of different morphotypes.Comparison of the different diagnostic methods used for the detection of H. pylori was detected in 17 patients out of 34. Neutrophil infiltration, chronic inflammation, and surface epithelial damage both in the antrum and corpus mucosa were significantly expressed in the H. pylori positive cases (p < 0.001). Glandular atrophy and intestinal metaplasia were rarely observed both in the antrum and corpus mucosa of the H. pylori negative cases in comparison with the H. pylori positive cases, but the difference was not statistically significant (p > 0.05). Lymphoid follicles were more frequent in the antrum colonised with H. pylori (p < 0.05).The data of the histological findings are presented in Table H. pylori in 16 biopsy samples of the antral mucosa, while highly (> 256 mg/l) clarithromycin resistant H. pylori strains were found in 3 cases.Bacteriological investigation revealed H. pylori eradication therapy is of utmost importance for physicians as well for patients [H. pylori tests used before treatment, while post-treatment testing is not yet adequately studied. However, in the case of long-lasting recurrent dyspepsia after H. pylori eradication therapy, endoscopy has been strongly recommended [H. pylori status. Since persistent H. pylori positivity is always associated with possible peptic ulcer recurrence, the second line treatment according to bacterial susceptibility should be recommended. In the remaining cases where H. pylori is absent, the gastric mucosa is normal and no ulcer is detected, management of such patients should be aimed at establishment of other possible reasons for their complaints. Usually, a normal endoscopic finding reassures both the doctor and the patient [Proper diagnostic and therapeutic management of patients with dyspeptic syndrome after patients . Severalpatients ,23 have ommended . Our stu patient .H. pylori infection. On the contrary, our results demonstrate that although all patients with recurrent peptic ulcer were H. pylori positive, the minor visual findings in the other cases were not in concordance with H. pylori colonisation. Usually, the mucosa was visually normal even when H. pylori was found, and, on the contrary, most duodenal erosions occurred in H. pylori negative patients. The clinical data of our patients did not suggest earlier use of NSAID, which would have been one of the main reasons for H. pylori negative erosions. Therefore, after treatment, in presence of complaints, it is important to obtain samples for the investigation of gastric mucosa specimens to enhance the value of endoscopic examination. We completely agree with the opinion that the value of using mucosal specimens for histological evaluation of late post-treatment H. pylori eradication is sometimes underestimated [H. pylori test alone cannot solve the clinical problem of these patients. In our study, H. pylori negative patients had dyspeptic syndrome as well as gastric mucosal erosions, glandular atrophy and intestinal metaplasia. The last two lesions can presumably be associated with previous H. pylori infection and the follow-up of severe mucosal changes is recommended [H. pylori negative cases in accordance with endoscopic and histological findings.A recent study of Ohkusa et al.  showed tstimated . The nonommended . Hence iH. pylori infection even after treatment, and that the diagnostic value of a histology-based decision is high. Today, the value of mucosal specimens for the post-treatment histological diagnosis of H. pylori is considered low assuming that H. pylori colonisation may be patchy, or coccoid forms are difficult to detect [13C-UBT in parallel with histological investigation.Our study demonstrates that evaluation of the gastric mucosa with a focus on neutrophil and lymphocyte infiltration and epithelial damage is specific and sensitive for diagnosing o detect . We haveH. pylori completely correlates with the results of 13C-UBT and PCR both in H. pylori positive and negative cases. This confirms the validity of the histological evaluation of mucosal specimens in the case of recurrent peptic ulcer or erosions. Moreover, in countries with a high rate of H. pylori infection and gastric cancer, it is especially important to follow up patients for detecting dysplasia and malignancies [Next, for detecting the coccoid forms of the bacteria, we used additionally PCR method. Our results show that the histological finding of gnancies -29.H. pylori in cases where it was found by other methods. Cytology is highly evaluated for detection of H. pylori infection, as its agreement with histology is considered to be 100% [H. pylori detection, as different forms of the bacteria were found. The morphology of the helicobacters could have been modified for coccoid or otherwise non-typical forms. It is possible that some other bacteria might have colonised the mucosa due to reduced colonisation resistance after antibacterial treatment, failure of some intestinal functions or usage of medicines administered to relieve the feeling of discomfort [Surprisingly, brush cytology from the mucosa failed to detect  be 100% . Our resscomfort -33.H. pylori strains, which may result in the failure of repeat triple therapy. As the macrolide clarithromycin is chemically stable and well tolerated [Bacteriological investigation enabled to find a few clarithromycin resistant olerated , physiciH. pylori colonisation, PCR and bacteriology as they have shown good concordance with 13C-UBT. Moreover, endoscopy and histological investigation of a gastric biopsy have proved to be the methods with an additional diagnostic value, providing the physician with information about inflammatory, atrophic and metaplastic lesions of the stomach in dyspeptic H. pylori positive and negative patients. Bacteriological methods are suggested for detecting the putative antimicrobial resistance of H. pylori, aimed at successful eradication of infection in persistent peptic ulcer cases.In a late post-treatment setting, patients with dyspepsia should not be monitored only by non-invasive investigation methods; it is also justified to use the classical histological evaluation of The author(s) declare that they have no competing interests.13C-urea breath tests, and performed GSRS. KLõ carried out bacteriological examination. PH performed cytological examination. HA carried out molecular analysis and participated in the writing of the manuscript. HIM performed histological examination and statistical analysis, and participated in the design of the study and in the writing of the manuscript. MM coordinated the study and participated in the completion of the manuscript. All authors have read and approved the final version of the manuscript.HIM, IK and KLa carried out GSRS, endoscopy and gastrobiopsy. HK recruited patients, collected The pre-publication history for this paper can be accessed here:


However, when ThT assays were repeated using Aβ1-42, modest, but statistically significant, profibrillogenic activity was detected in both apolipoprotein E ε3- and apolipoprotein E ε4-containing media and was similar in magnitude for the two isoforms. These data demonstrate that native apolipoprotein E possesses "pathological chaperone"-type activity for Aβ: in other words, the data indicate that a chaperone-like misfolding reaction can occur between native apolipoprotein E and Aβ. However, the equipotent activities of the apolipoprotein E ε3 and ε4 isoforms suggests the possibility that either extended co-incubation of apolipoprotein E and Aβ, or, perhaps, the inclusion in the reaction of other fibrillogenesis-modulation co-factors  may be required for modeling in vitro the apolipoprotein E-isoform-specific-regulation of extracellular Aβ accumulation that occurs in vivo. Alternatively, other events, such as differential apolipoprotein E-isoform-mediated clearance of Aβ or of apolipoprotein E/Aβ complexes may underlie apolipoprotein E-isoform-dependent Aβ accumulation.The apolipoprotein E ε4 allele contributes to the genetic susceptibility underlying a large proportion (~40–60%) of typical, sporadic Alzheimer disease. Apolipoprotein E deficient mice made transgenic for human apolipoprotein E ε4 accumulate excess cerebral amyloid when compared to similarly prepared mice expressing human apolipoprotein E ε3. Therefore, it is important to search for relevant interactions(s) between apolipoprotein E ε4 and Aβ in order to clarify the biological role for apolipoprotein E ε4 in Alzheimer disease. Using a thioflavine T (ThT)-based assay, we have investigated the effects of native human apolipoprotein E isoforms on the kinetics of Aβ fibrillogenesis. No obvious profibrillogenic activity was detected in Aβ Using a thioflavine T (ThT)-based assay [Genetic-neuropathological correlation indicates that the apolipoprotein E type ε4 isoform specifies increased cerebral ,2 and ceed assay  we have 1-40 or Aβ1-42  was freshly prepared for each assay at a concentration of 16 mg/ml in distilled, deionized water and diluted with phosphate-buffered saline (PBS) to generate a 5 mg/ml working solution. The "aggregation step" consisted of a reaction mixture containing 8 μl Aβ peptide  and 32 μl of either apolipoprotein E ε3- or ε4-containing conditioned medium or control conditioned medium from SV40 empty vector-transfected cells.Synthetic AβFor the investigation of native apolipoprotein E preparations, apolipoprotein E isoforms were generated in the conditioned medium of stably-transfected SV40-apolipoprotein E ε3-, or SV40-apolipoprotein E ε4-, expressing Chinese hamster ovary (CHO) cells . All conditioned media were prepared using Dulbecco's minimal essential medium supplemented with 0.2% (wt/vol) bovine serum albumin only . Apolipoprotein E isoform levels were determined by quantitative immunoblotting of conditioned medium and apolipoprotein E-containing serum standards, the latter having been kindly provided by Dr. Petar Alaupovic of the Oklahoma Medical Research Foundation (Oklahoma City OK). Conditioned medium apolipoprotein E concentrations were then standardized using control medium conditioned by SV40 empty vector-transfected cells as diluent, yielding a final concentration of apolipoprotein E of 14 μg/ml, within the range of that reported in human cerebrospinal fluid. Since the final concentration of Aβ peptide was 1 mg/ml, the Aβ/apolipoprotein E stoichiometry (molar ratio) was ~500:1, suggesting models for the Aβ/apolipoprotein E interaction based either on a "catalytic" "pathological chaperoning" model of apolipoprotein E action on Aβ, or with a "seeding" model of Aβ folding. Detailed biochemical characterization of this native apolipoprotein E preparation has been reported .The "aggregation step" fibrillogenesis reaction  was incu1-40, either in physiological phosphate buffer alone or in the presence of metal ions , indicating that our Aβ preparations were capable of metal ion-induced fibrillogenesis. Metals were not present during assessment of profibrillogenic effects of apolipoprotein E isoforms.In order to standardize the ThT assay in our Laboratory, we performed studies of Aβ fibrillogenesis following 1–7 day incubations of Aβnal conc . ThT flunal conc   may be required for modeling in vitro the apolipoprotein E-isoform-specific-regulation of extracellular Aβ accumulation that occurs in vivo.These data demonstrate that native apolipoprotein E possesses "pathological chaperone"-type activity for Aβ: in other words, the data indicate that a chaperone-like misfolding reaction can occur between native apolipoprotein E and Aβ, at least at the concentrations and proportions evaluated herein. However, the equipotent activities of the apolipoprotein E ε3 and ε4 isoforms suggests the possibility that either extended co-incubation of apolipoprotein E and Aβ, or, perhaps, the inclusion in the reaction of other fibrillogenesis-modulation co-factors (such as metal ions, or inflammatory mediators such as reactive oxygen species, αin vivo.Alternatively, other events, such as differential apolipoprotein E-isoform-mediated clearance of Aβ or of apolipoprotein E/Aβ complexes ,9,14 mayThT, thioflavine T; Aβ, amyloid-β peptide; PBS, phosphate-buffered saline; CHO, Chinese hamster ovary cells.None declared.DS performed all assays, including the ThT assay, which was originated by HL. HL also oversaw the transfer of the assay from his lab to ours. RM prepared standard conditioned media from transfected cells provided by JDS. SG oversaw the project, supported the project as noted below, and wrote the manuscript.


The University of Edinburgh encourages its Ph.D. students to participate in a broad programme of science communication activities, designed to enhance public engagement in science The need for effective communication of research and the promotion of science is more important then ever. Public scepticism of research is high, and the number of students studying science continues to dwindle. In an attempt to combat this, the University of Edinburgh encourages its Ph.D. students to participate in a broad programme of science communication activities, designed to develop transferable skills they can use outside pure research and to enhance public engagement in science (PES).Included as part of the transferable skills programme, the University hosts a science communication module. The course provides an introduction to the different media, educational, ethical, and political issues surrounding the communication of science to a nonspecialist audience. Initially, the course addresses the presentation of science in written and oral forms. However, as the presentation of science to the public is not simply a practical skill, part of the course is dedicated to the tactical communication of science in society and the relationship between scientists and the media. Finally, students are introduced to ongoing PES opportunities. Any involvement requires the approval of supervisors, to ensure no adverse effects on academic performance. The activities available are diverse and flexible, and they enable students to undertake projects that reflect personal interest and availability.What opportunities are available? For enthusiastic students, membership of the Nikon–University of Edinburgh Post-Graduate Science Communication Team (PGSCT) is possible. The PGSCT requires a commitment of 15 days per academic year to paid science communication projects and events, including compulsory support of SCI-FUN, the University's established science and technology roadshow. The team is recruited annually from students of the Science and Engineering, Medicine, and Veterinary Medicine Colleges and takes a leading role in PES activities. Team members are supported by other graduate students who participate on a more casual basis.To ensure that a broad spectrum of activities is available to audiences, the PGSCT members are actively encouraged to design and develop their own ideas. An opportunity to do this is provided through the University's Science Zone, at the Royal Museum of Scotland, for the duration of the Edinburgh International Science Festival. From successful workshops, originally piloted at the science festival, several ex-PGSCT members have gone on to establish their own projects. One example of this is the Natural Environment Science Education scheme, which later received recognition through the Royal Society of Edinburgh/Scottish Executive ‘Science in the Community’ Award for 2003. A primary aim of this scheme was to deliver in isolated and remote communities innovative hands-on earth science- and natural science-based activities beyond city venues. For students, developing and presenting workshops are incredibly rewarding and allow them to experience the enthusiasm of participants and fellow presenters.Some activities are transferred from the Science Zone to the classroom, where students can communicate with children at all stages of their schooling. At primary school age (5–11 years) after-school science clubs, led by graduate students, provide an opportunity for presenters to share with pupils their enthusiasm for science. Alternative activities are directed at secondary school children (12–18 years), with a variety of workshops available across the different scientific disciplines. In particular, The Scottish Institute for Biotechnology Education (SIBE) has been set up within the University to facilitate PES activities such as the popular ‘Green Fingerprinting’ workshop where the principles of DNA fingerprinting are applied to an ecological scenario in the form of a practical activity . The majThe presentations may be in person or utilise new technologies such as video conferencing. A BBSRC Dialogue Award has recently been granted to SIBE to design, develop and deliver video-conferences addressing bio-ethical issues surrounding recent advances in biotechnology. Together, the two approaches of in-person and virtual presenting, enhance the schools' curriculum and facilitate dialogue between scientists and the public at a stage where promotion of science can influence the choice of further study and career options.The promotion of biotechnology within schools does not stop with the encouragement of school children's enthusiasm; SIBE also works closely with organisations such as ‘Science and Plants for Schools’ (SAPS) to assist with continuing professional development of biology teachers through the organisation of training days aimed at curriculum enhancement and the practical application of biotechnology in the classroom. Interested graduate students can co-present the workshops, though they are led by permanent staff. The students introduce their own research to highlight the applications of biotechnology and provide a useful technical resource.For students who prefer to communicate through the written word, though no guarantee of publication can be given, the University is in a position to highlight science-writing opportunities, usually as a contribution to publications specifically concerned with science communication or within the scientific press. At the Institute of Cell and Molecular Biology at the University a ‘press-gang’ meets on a monthly basis to discuss research carried out in the Institute and generate press releases for publication in the university press and national newspapers where appropriate.Complementing the University's efforts, many other organisations, such as UK Research Councils and the British Association for the Advancement of Science, endorse graduate students spending time on PES activities. Several schemes have been put in place to facilitate this; Researchers in Residence, the Science and Engineering Ambassadors Scheme and science communication courses. Hosted at the University's science campus—Kings Buildings—‘pgscicom’ provides up-to-date information on opportunities for PES at the University and beyond through regular email communications.As a PhD student and PGSCT member, I believe the approach of the University of Edinburgh to PES is of benefit to all involved. The combination of training and practical experience provides graduate students with new and valuable skills and opportunities to develop them further. The events and activities enthuse and engage audiences with the presentation of science in an informal but informative manner.


The GOLD.db (Genomics of Lipid-Associated Disorders Database) was developed to address the need for integrating disparate information on the function and properties of genes and their products that are particularly relevant to the biology, diagnosis management, treatment, and prevention of lipid-associated disorders. provides a reference for pathways and information about the relevant genes and proteins in an efficiently organized way. The main focus was to provide biological pathways with image maps and visual pathway information for lipid metabolism and obesity-related research. This database provides also the possibility to map gene expression data individually to each pathway. Gene expression at different experimental conditions can be viewed sequentially in context of the pathway. Related large scale gene expression data sets were provided and can be searched for specific genes to integrate information regarding their expression levels in different studies and conditions. Analytic and data mining tools, reagents, protocols, references, and links to relevant genomic resources were included in the database. Finally, the usability of the database was demonstrated using an example about the regulation of Pten mRNA during adipocyte differentiation in the context of relevant pathways.The GOLD.db The GOLD.db will be a valuable tool that allow researchers to efficiently analyze patterns of gene expression and to display them in a variety of useful and informative ways, allowing outside researchers to perform queries pertaining to gene expression results in the context of biological processes and pathways. The excessive consumption of high calorie, high fat diets and the adoption of a sedentary life style have made obesity and atherosclerosis major health problems in Western societies. In the USA, over 50% of the population are over-weight BMI > 25) and close to 25% are considered obese (BMI > 30) ,2. As a 5 and cloAt the root of obesity and atherosclerosis is an excessive deposition of neutral lipids. Adipose tissue accumulates predominantly triglycerides, whereas macrophages along the blood vessel wall mainly accumulate cholesterol and cholesteryl esters. Accordingly, a detailed understanding of the molecular mechanisms that govern the balance between lipid deposition and mobilization is fundamentally important for the prevention and improved treatment of disease. In addition to the apparent environmental components involved in the pathogenesis of disorders related to lipid and energy metabolism, a large number of studies have provided undisputed evidence that susceptibility genes contribute around 50% of the phenotype. These genes encode products involved in the cellular uptake, synthesis, deposition and/or mobilization of lipids. However, characterization of many if not most of these genes and their products remains rudimentary. Deficiencies in the current level of understanding extend to key enzymes such as important triglyceride hydrolases in adipose tissue  or choleWhile medical molecular biology traditionally associates single genes and gene products with diseases, a growing body of evidence suggests that several common disease phenotypes arise from the delicate interaction of many genes as well as gene-environment interactions. To elucidate the development of obesity and atherosclerosis, it will be necessary to analyze patterns of gene expression and relate them to various metabolic states. To discover novel genes, processes and pathways that regulate lipid deposition and mobilization, a departure from hypothesis-driven research and turn to a discovery-driven approach is necessary. The application of high-throughput technologies and genome-based analysis will provide the tools for the analysis of gene-gene and gene-environment interactions in a systematic and comprehensive manner.To facilitate genomic research we have initiated the development of a system for storing, integrating, and analyzing relevant data needed to decipher the molecular anatomy of lipid associated disorders. In order to provide a reference for pathways and information of the relevant genes and proteins in an efficiently organized way, we have created the Genomics Of Lipid-Associated Disorders database (GOLD.db). The GOLD.db integrates disparate information on the function and properties of genes and their protein products that are particularly relevant to the biology, diagnosis management, treatment, and prevention of lipid-associated disorders.The main goal of the GOLD.db was to provide biological pathways with image maps and visual pathway information. For each element in the pathway, specific information exists including structured information about a gene, protein, function, literature, and links. The GOLD.db provides also the possibility to map gene expression data individually to each pathway. Additionally, analytic and data mining tools, reagents, protocols, references, and links to relevant genomic resources were included in the database.The GOLD.db was implemented in Java technology . Hence, For tracking the repository of the reagents like clone resources and libraries which can be used for microarray studies, we have developed a relational database. Information about the vector, the sequence and length of the clone insert, primers for the PCR amplification, tissue, organism, accession number, library, container, storage information, date and person and access to other clone bases (e.g. IMAGE Consortium) can be stored. Users of the GOLD.db can list these clones and get all the information about each available clone. With restricted access, clone information or even clone lists can be uploaded and selection lists can be created and deleted. The input mask is designed in such way that the user can choose one of the elements of the created selection lists.In order to deal with the huge amount of data associated with large scale studies and to perform sequence based and microarray analysis, several bioinformatic tools were integrated or can be downloaded. Sequence similarity search against databases can be performed with BLAST  , FASTA  or HMM  to the corresponding elements of the available pathways similar to previous efforts . Either As key for the mapped relation the RefSeq number  is used. or ArrayExpress , it is still very difficult for researchers to obtain the original data. Web sites with Supplementary information are not maintained and/or not further developed. Hence, a database with a large collection of curated datasets will be enormously valuable for the community. Approaches to upload and retrieve gene expression data were pursued within the GOLD.db. Large scale gene expression data sets can be uploaded in form of tab delimited text files (Stanford file format) [Analysis of gene expression patterns in animal and cell models for lipid-associated disorders will help to understand the fundamental gene relations and regulatory mechanisms responsible for the development of obesity related diseases. The huge amount of data associated with the analysis of large scale gene expression analysis raises the demand of tools for storing, processing and retrieving complex information. Although a number of studies have been published and despite the requirements of some journals to deposit microarray data in public databases like GEO  format)  as used Recently, it was shown that insulin sensitivity, energy expenditure, and thermogenesis were enhanced in adipose-specific Pten-deficient (AdipoPten-KO) mice. Body and adipose tissues weight in these mice were significantly lower than those of control mice in spite of a larger food intake . We addrDuring adipocyte differentiation cyclin dependent kinase inhibitors, like p21 leads to a hypophosphorylation of the Retinoblastoma protein (Rb) which allows binding to the E2F transcription factor, causing cells to permanently exit the cell cycle – a required step in adipocyte differentiation called mitotic clonal expansion – before entering the terminal differentiation state. pRb interacts physically with adipogenic CCAAT/enhancer-binding proteins and positively regulates transactivation by C/EBPβ and therefore plays a pivotal role in adipocyte differentiation ,25. HencThus, using recently identified key player for food intake and weight control and using the GOLD.db, it is possible to address relevant questions and generate testable hypotheses on the molecular mechanisms of fat cell development.The vast quantity of gene expression data generated in genomic studies presents a number of challenges for their effective analysis and interpretation. In order to fully understand the changes in expression that will be observed, we must correlate these data with phenotype, genotype, metabolism and other information including the tissue distribution and time course expression data gleaned from previous studies. The goal of our work was the development of a specialized database and tools that allow researchers to efficiently analyze patterns of gene expression and to display them in a variety of useful and informative ways, allowing outside researchers to perform queries pertaining to gene expression results in the context of biological processes and pathways. The uniqueness of the GOLDdb database we have developed is threefold: 1) the inclusion of annotated pathways, 2) the availability of curated datasets and 3) the possibility to map experimental data on biological pathways. The upcoming challenges will be to include data from functional analysis and proteomics data, which will give us new opportunities in understanding mechanisms of different applications and lipid-associated disorders in particular.. The pathway editor and the clone tracker are available free of charge to academic, government, and other nonprofit institutions.The GOLD.db database should be cited with the present publication as a reference. Access to GOLD.db is possible through the world wide web at HH was responsible for the content, the annotation process, webdesign, and processing of data sets. MM was responsible for the implementation of the database and web application as well as the relational database for the clone tracker. BM and JH had implemented the mapping of expression data to pathways. GS is involved in providing of sequence analysis tools and server software. DMS has annotated the insulin signaling pathway. ZT was responsible for the design of the study and for overall project coordination.


The recent primary care policy debate in Australia has centred on access to primary medical  services. In Australia, access is heavily influenced by Commonwealth Government patient rebates that provide incentives for general practitioners not to charge copayments to patients (bulk billing). A steady decline in key access indicators (bulk billing) has led the Howard Government to introduce a set of changes that move Medicare from a universal scheme, to one increasingly targeted at providing services to more disadvantaged Australians. In doing so, another scene in the story of the contest between universal health care and selective provision in Australia has been written. This paper explores the immediate antecedents and consequences of the changes and sets them in the broader context of policy development for primary care in Australia. Primary health care and community care can be thought of as a set of health programs and services. Most discussions of the primary health and community care services sector suggest that it has the following characteristics: (1) It is the first point of contact with the health system. This may occur through general practice, community health services, and pharmacies. There is also some overlap between primary care and hospital emergency departments, particularly for less complex and intensive presentations. (2) Services are provided in community and ambulatory settings and at home. (3) There is an emphasis on continuing relationships between service providers and consumers over extended periods of time. (4) Services have a more comprehensive and holistic approach. (5) There is an emphasis on early detection and illness prevention services such as maternal and child health programs and population health programs including health promotion.Primary health and community care is the most visible and commonly used part of the health system. In 1999–00 the Commonwealth provided approximately $6 billion through the Commonwealth Medical Benefits and Pharmaceutical Benefits Schemes. States and Local Government provided approximately $1.8 billion for 'community and public health' which includes allied health, counselling, nursing and a range of primary and secondary prevention and health promotion programs. The Commonwealth, through direct outlays ($6 million) and private health insurance premium rebates ($97 million), also provided $103 million for dental services, with the States and Territories contributing $305 million. This does not include the substantial funds committed to the various forms of community support for people with disabilities, chronic illness and mental illness [Primary health and community care services face unique challenges. Over the past three decades primary health services have come under significant pressure to address a more complex and diverse range of community needs.Deinstitutionalisation, the introduction of new health and information technologies, the increasing prevalence of chronic disease and more general social and economic trends have had a significant impact on primary health and community support services. This has resulted in concerns about the equity, quality and efficiency of services and programs. Arguably, there is a need for a national primary health care policy in Australia. One that would address system integration, care pathways and team practice, work force development, payment arrangements, governance, performance management and accountability. However, current Commonwealth reforms are focused on important, but relatively, narrowly focused solutions to the decreasing affordability and access for general medical services. This article focuses primarily on the recent debate that surrounds this issue.Medicare is a Commonwealth Government, tax funded, social insurance scheme that provides rebates for general (primary) and specialist medical services and optometry. In Australia, it is the principal national program for ensuring equitable access to primary medical services. Over the last two years there has been a fiercely contested debate about the future of Medicare.Medicare was introduced to provide universal access to affordable medical care. Up until recently Medicare simply provided a rebate of 85% of the Commonwealth Government determined schedule fee for medical and diagnostic services. Practitioners were free to charge patients a copayment as well. Where they did not apply a copayment, they could bill the Commonwealth for the rebate and receive bulk payments direct from the Commonwealth for these services, thereby avoiding administrative costs and delay. This payment method, which became known as bulk billing, ensured that services were effectively free to the patient at the point of service.Medicare has been very successful, particularly for general practice services. It is strongly supported by the Australia community because it provides affordable access to medical services. Despite historical resistance by the Australian Medical Association, it has been widely supported by practitioners because it provides them with a universal, simple and predictable revenue stream.Bulk billing increased steadily from the introduction of Medicare in 1984/85 to approximately 70% in the mid-1990s. Bulk-billing rates for GP services have generally been about 10% higher than the overall bulk-billing rates over the last decade, reaching a plateau of about 80% in the mid-1990s. They declined significantly after 2000. Average GP bulk billing fell to 68% by September 2003. GP bulk billing rates are now similar to the overall CMBS bulk billing rates for all services [As bulk billing rates declined, disquiet and concern about access to medical services rose amongst stakeholder interests. More generally, the overall decline in bulk billing came on top of considerable disparity in equity of access between rural and urban settings. Bulk billing rates in inner city areas with high per capita GP ratios were 30% higher than those in rural settings with low per capita ratios. A number of remote rural areas had difficulty attracting any GPs at all.Analysis of the reasons for the decline in bulk billing and the disparities between rural and metropolitan settings suggest a strong relationship between the supply of GPs and the capacity to charge copayments and the importance of the steady decline in the relative value of Commonwealth rebates for GP services over time.There is considerable evidence that GPs manage demand for their services to maintain their income . As the In the decade to 2003, changes to GP training, migration and demographic ageing lead to a stabilization and decline in the supply of GP services. Over the same period, the relative value of Medicare rebate income for GP services fell by about 10 percent compared with average weekly ordinary time earnings. A decline that was probably even greater when compared to specialist incomes. In response, GPs began to experiment with price increases (co-payments) to improve their relative incomes .Interestingly, bulk billing rates in relatively under supplied rural settings remained relatively stable at about 50% of consultations. This is about the level of consultations one would expect people on low incomes, who are eligible for concessional welfare benefits, to use. A finding that suggests that patient capacity to pay sets a 'floor' bulk billing rate at about this level .It is worth noting that many of these effects were predictable from the reforms to General Practice introduced in the early 1990s. In particular, tight management of GP supply through changes to training programs and restrictions on overseas trained medical practitioners were introduced in order to reduce growth in aggregate Medicare expenditure. However, the reforms recognised that a move away from fee for service payment would also be required in the longer term. To this end a Better Practice Program to pay GPs on a per capita basis was introduced.Over time, it was intended that a significant proportion of Medicare payments would be made by practice based, per capita payments. Progressively this would have allowed a shift toward more comprehensive, integrated practice and a greater focus on quality and preventive services. However, while the supply of GPs was successfully constrained, per capita payments remained a marginal component of the payment system.In response to concerns about the fall in the bulk billing rate, the Commonwealth Government proposed a "Fairer Medicare" package in April 2003. The package introduced a participating practice scheme. GP practices that agreed to charge a no gap fee to concessional patients were to be eligible for increased Medicare rebates for these patients. The level of the proposed increase for the rebate was $1 in metropolitan city practices, $2.95 in non-metropolitan city practices, $5.30 in rural centre practices, and $6.30 in outer rural and remote areas.Participating practices were to continue to have the capacity to determine fees for non-concession cardholders, including the option of bulk billing. However, if they chose not to bulk bill these patients, they were to be able to charge the patient the co-payment and claim the Medicare rebate direct from the Health Insurance Commission through HIC online billing facilities. Effectively, non-concession cardholders were to be charged a gap payment thereby avoiding the transaction costs involved in claiming a rebate through the Medicare scheme themselves.A new MBS safety net was to be available for those covered by concession cards with out-of-pocket costs greater than $500 in a calendar year. Charges in excess of the scheduled fee were to be included, as were the costs of specialist and diagnostic services. Eighty per cent of out-of-pocket costs above the $500 threshold were to be met through this safety net.Private health insurers were to be able to offer insurance coverage for the cumulative cost of out-of-hospital medical services over $1,000 for a family in a calendar year. This included costs above the scheduled fee across a range of out-of-hospital services, including GP and specialist consultations and diagnostic tests. The Commonwealth estimated that insurance products for this coverage were likely to cost around $50 per year for families, and the 30% private health insurance rebate was to apply to these products.The Government's package also included proposals to introduce additional medical school places, additional GP training places, additional nurses and allied health professionals in general practice, and measures for veterans.The Fairer Medicare package resulted in considerable debate and criticism, much of which was considered by the Senate Select Committee on Medicare . In part• Equitable access to general practice services regardless of income or geography is fundamental to good health care.• GP income from bulk billing had not kept pace with increases in average weekly ordinary time earnings and this had contributed to declining bulk billing rates and increased out of pocket charges.• Shortages in the supply of GPs are emerging as result of compositional changes in the workforce, changes in practice patterns and population ageing.• The Commonwealth's 'Fairer Medicare' proposals were inconsistent with the principles of Medicare.• The differential rebate payments for concessional patients were unnecessary because these patients were already largely receiving bulk billed services• The introduction of the new safety net arrangements creates a two tier system of access to GP servicesIt became apparent that the Senate would not pass the legislation required to enact the Commonwealth's package. Consequently, the Commonwealth presented its 'MedicarePlus' extensions and revisions to the original proposal in November 2003 . This paThe MedicarePlus proposals dropped the participating practice scheme. Instead the Commonwealth proposed to increase the rebate for all concessional patients by $5 in metropolitan areas and $7.50 in remote, rural and regional areas (including the State of Tasmania). The increased rebate was also extended to children under 16. The safety net provisions were modified to provide an 80% rebate for out of hospital medical costs for concessional patients and those whose income fell below specified tax thresholds after $300 of out of pocket expenses and after $700 for the remainder of the population.Other aspects of the original proposal were largely retained and extended. These included training places for GPs, medical graduates and nurses. Additionally, it was proposed to introduce a Medicare Benefits Schedule item for nursing support in general practice and improved internet access and online billing for GPs. MedicarePlus also provides rebates for up to five allied health consultations delivered to patients with a chronic condition or complex care needs, for and on behalf of a GP. Similarly, dental treatment care plans will be funded for these patients where they have significant dental problems that exacerbate their condition. The total estimated cost for MedicarePlus to 2006/07 was estimated at $2.85 billion.Initial reactions to the Commonwealth's proposals were mixed. A number of patient and provider groups have criticized the new arrangements as undermining the principle of universality that underpins Medicare. Criticisms have also focused on the narrow focus of MedicarePlus on fees for general practitioners.More specifically, MedicarePlus is likely to have differential effects on affordability and access to GP services in rural and metropolitan settings. In metropolitan settings, the introduction of a $5 differential rebate for bulk billing concessional payments is sufficient to increase net GP incomes to about the AWOTE relativities that applied prior to the decline in bulk billing.However, with current levels of bulk billing still at over 65% in metropolitan areas, virtually all concessional patients are already bulk billed. The proposal is therefore subject to substantial dead weight loss. No incentives to bulk bill non concessional patients  are included.In metropolitan areas, the gap between the average Medicare rebate and the average patient billed service is around $13 for patients not covered by the differential rebate, compared to $8 for concessional patients and children under 16. Within system constraints, GP incomes are optimized by bulk billing concessional patients and children under 16 and charging copayments for other patients. Doing so also largely addresses patient capacity to pay issues. In the absence of major changes to supply or GP costs, it is therefore likely that bulk billing rates in metropolitan areas will continue to decline over time, until they stabilise at around the level of services for concessional patients plus non concessional children under 16 .The proportion of children is highest in outer metropolitan regions and lowest in the inner city. Bulk billing rates have declined most in outer metropolitan areas. It is therefore plausible that this measure will have the greatest differential impact in outer metropolitan regions.In rural settings, where there are GP shortages, the differential rebate (which is higher than in metropolitan settings) could substantially increase GP incomes. However, GP supply factors ensure GPs have considerable capacity to increase copayments within the limits of patient capacity to pay. In general, bulk billing rates in rural settings are now at or below the consultation rate for concessional patients. The new arrangements are therefore likely to protect bulk billing rate for concessional patients and are likely to see the rate increase to the level of concessional consultations (around 55 – 60%).The effect of differential rebates for non concessional children under 16 on overall bulk billing rates is less clear in rural settings. With the increased rebate, there remains a gap of approximately $5.50 between the new rebate and the average patient billed service. As for metropolitan settings, there are no additional incentives to bulk bill other non concessional patients. Given the greater capacity to charge copayments, this measure may be less successful in encouraging bulk billing than in metropolitan areas.The safety net provisions in MedicarePlus have significant inflationary potential for out of hospital medical service fees. Concessional patients and those who qualify for Family Tax Benefit A are eligible for an 80% rebate on out of hospital costs once they incur $300 of out of pocket costs. There is no cap on the rebate under the safety net. Average out of pocket costs for patient billed GP services are currently about $13. The safety net is therefore reached in 20–25 consultations. The safety net provisions will be invoked more quickly when specialist medical practitioners, diagnostic imaging services and pathology are required. Average copayments are two or three times higher for specialist medical practitioners than for GPs.Effectively, the introduction of the safety net removes constraints on medical practitioners associated with concerns about patient capacity to pay. This introduces moral hazard for practitioners and consumers. Practitioners have incentives to increase their fees and provide more services than necessary knowing the safety net will protect patients. Patients have incentives to consume more services than are necessary because they are effectively insured by the safety net.However, the initial threshold and value of copayments act as balancing disincentives for utilization. Clearly if the initial threshold and the copayments were less, the hazard would be greater and vice versa. This trade off is likely to impact differently depending on need, capacity to pay and supply factors.For example, there may be paradoxical adverse effects for patients with significant ongoing health costs who are currently bulk billed because GPs and specialists have concerns about their capacity to meet aggregate out of pocket costs over time. This is particularly true for aged pension recipients with chronic illness. With the introduction of the safety net, the potential for incurring unmanageable costs is significantly reduced and therefore bulk billing rates for this group may decline. Whether effects like these are experienced in practice will depend on factors such as the real value of GP rebates, patient need, capacity to pay, GP supply and regulatory constraints.Overall, the design features of the Howard Government recent changes to Medicare are intended to, and will produce a two tier system. Access to primary medical services for people on low incomes will be relatively well protected, but those above the income threshold will see a steady decline in bulk billing and an increase in out of pocket costs for these services. Additionally, the poorly designed safety net will have inflationary consequences.The policy and political contest around Medicare has an extended pedigree. The conservative Liberal/National Party Coalition has long held the position that government should primarily provide health services for those who are unable to provide for themselves and that those who are able to make their own way should do so, particularly by taking out private health insurance. From this perspective the role of government is to provide an appropriate regulatory environment, incentives and sanctions to take up private insurance and a targeted safety net for the disadvantaged. Their preferred model was developed and refined in the 1950s and 1960s during the period of the Menzies Government and reintroduced in stages during the late 1970s and early 1980s by the Fraser Government [On the other hand, the Australian Labor Party has advocated tax funded, universal access to publicly funded health care provided on the basis of need, rather than capacity to pay. The Whitlam Government settled the basic architecture of Labor's approach in the early 1970s. Setting aside the brief flirtation with a national community health program for primary care, it established a universal system of public hospital access through the States and a tax funded, social insurance scheme to underwrite equitable access to medical and related services.Notwithstanding Howard Government claims of strong support for Medicare, the pendulum has now swung a considerable distance back toward the traditional Liberal/National Party preferred model. If history is a guide, now that the incentives to take out private health insurance and the safety net is in place, the next steps are regulatory mechanisms to exclude higher income earners from accessing publicly funded health services.While debates about access and equity are critical, they are only part of the overall picture. Recontesting the basic access and equity principles of the health system every decade or so misses a number of important emerging issues.There is now emerging evidence that closer integration of clinical decision-making and purchasing for enrolled populations in primary care settings through funds pooling and local agreements and contracts has the potential to increase innovation, reduce costs and improve outcomes. These principles are being explored or actively implemented in a number of countries comparable to Australia, including the United Kingdom and New Zealand .There is clearly a need to reconsider the development of a national policy for primary health and community support services. Such a policy might include the following elements to address the issues which have been discussed above:• National primary health and community care goals and objectives. For example, these might broadly set out equity, efficiency and quality criteria for the Australian primary health and community support system.• National performance indicators. For example, these indicators could be used to report on and benchmark the quality, access, efficiency and utilisation of the primary health and community support system and its impact on acute, sub acute and residential care.• Population based planning, allocation and monitoring. For example, funding allocation models and system governance arrangements based on the health care needs of geographically defined residential populations  that promote continuity of care and service integration could be considered.• Coordinated service pathways for health issues and conditions. For example, consistent best practice models linking prevention, early intervention, primary care, acute care, rehabilitation and community support should be developed for all major chronic diseases, mental illness and alcohol and drug problems.• Payment systems. For example a program to develop integrated payment models and systems for primary and community support services could be established and linked to Commonwealth/State agreements  and own purpose funding streams. This might include consideration of capitated, case based, and contract funding to replace or compliment existing arrangements for primary care services.• National workforce planning and analysis for primary health and community support services.• A national evaluation, research and development program in primary health and community support services.• National planning and priority setting processes for primary health and community care to ensure greater alignment of Commonwealth and State priorities.


Wolbachia have a thing against males. A member of one of the most diverse groups of bacteria, called Proteobacteria, this parasitic “endosymbiont” lives inside the reproductive cells of a wide variety of the nearly 1 million species of arthropods, including insects, spiders, and crustaceans. It has also been found in worms. Wolbachia's preferred habitat is the cytoplasm of its host's gametes. Since sperm have very little cytoplasm, Wolbachia seek out the company of females, securing its survival by hitching a ride to the next generation in the cytoplasm of the mother's eggs. Wolbachia's effects range from beneficial to pathological, depending on which species infects which invertebrate host, but since most species are not beneficial, Wolbachia infections often turn out badly if the host is male. On the other hand, if female, the host could very well live longer, produce more eggs, and have higher hatching rates than its noninfected cousins—thereby facilitating Wolbachia's transmission from mother to offspring.Wolbachia have evolved an impressive repertoire of “reproductive parasitic” strategies to adapt its host's physiology to its own advantage. One strategy involves inducing “cytoplasmic incompatibility” between sperm and egg, which in effect uses infected males to keep uninfected females from producing viable offspring. Another causes infected females to reproduce asexually, creating a new generation of infected clones. Another turns developing male embryos into females. And, in a pinch, some Wolbachia simply kill developing males. The biochemical mechanisms that trigger different strategies in different hosts are unclear, however, in part because it's so far been impossible to cultivate sufficient quantities of these obligate endosymbionts . But now that Scott O'Neill, Jonathan Eisen, and colleagues have sequenced the complete genome of one strain of Wolbachia pipientis, scientists investigating the biology and evolution of Wolbachia–host interactions have a valuable new research tool. The strain they sequenced, W. pipientiswMel, lives inside the fruitfly Drosophila melanogaster, the favorite model organism of geneticists for nearly 100 years. This strain causes cytoplasmic incompatibility in its host.wMel genome, the O'Neill and Eisen groups note, is strikingly different from any other obligate intracellular species. While its genome is compact, it nonetheless contains large amounts of repetitive DNA and “mobile” DNA elements. Mobile genetic elements, as the name implies, are DNA sequences that move around the genome and are often acquired from other species. Most of the repetitive and mobile elements in Wolbachia do not appear in other α-Proteobacteria species and were probably introduced some time after Wolbachia split off from its evolutionary ancestors. Wolbachia, unlike other obligate intracellular bacteria, seem quite amenable to incorporating foreign DNA, which the authors speculate was introduced by the bacteria-infecting virus called phage.The structure of the Wolbachia genome sheds light on the mechanisms that might help the parasite manipulate the host cell's physiology to its own advantage. One likely bacterial weapon for host exploitation is the abundance of predicted genes encoding ankyrin repeat domains, amino acid sequences characteristic of proteins important for protein–protein interactions in eukaryotes . In bacteria, ankyrin repeats might regulate host cell-cycle pathways, which one wasp-infecting Wolbachia strain modifies to induce cytoplasmic incompatibility. Other molecular interactions between wMel and its host, the researchers propose, might also rely on proteins with these ankyrin repeats.Analysis of the Wolbachia genome also provides insight into mitochondrial evolution. It is widely believed that these intracellular energy-metabolizing centers were once free-living bacteria belonging to the α-Proteobacteria group, though it's not clear which branch of the α-Proteobacteria tree they inhabit. Complete genome analysis of various α-Proteobacteria—including wMel, the first non-Rickettsia species sequenced in the Rickettsiales group—provides no evidence that mitochondria are more related to Rickettsia species than to Wolbachia, as was previously thought. In fact, further analysis failed to consistently connect mitochondria to any particular species or group within the α-Proteobacteria.The Wolbachia genome seems to raise as many issues as it settles, biologists studying a wide range of problems—from the evolution and biology of Wolbachia and endosymbiont–host interactions to the origin of mitochondria—have a valuable new tool to explore their questions. The Wolbachia genome will also provide important molecular guidance for efforts to suppress insect pests and control filariasis, a human disease caused by worms. Since beneficial Wolbachia live in both insect and worm, applying antibiotics to target the Wolbachia will ultimately kill the insect pest and infecting worm, which both depend on the bacteria to survive.While the information hidden in the