Self-monitoring of blood pressure is effective in reducing blood pressure in hypertension. However previous meta-analyses have shown a considerable amount of heterogeneity between studies, only part of which can be accounted for by meta-regression. This may be due to differences in design, recruited populations, intervention components or results among patient subgroups. To further investigate these differences, an individual patient data (IPD) meta-analysis of self-monitoring of blood pressure will be performed.We will identify randomised trials that have compared patients with hypertension who are self-monitoring blood pressure with those who are not and invite trialists to provide IPD including clinic and/or ambulatory systolic and diastolic blood pressure at baseline and all follow-up points where both intervention and control groups were measured. Other data requested will include measurement methodology, length of follow-up, cointerventions, baseline demographic  and psychosocial factors , setting, intensity of self-monitoring, self-monitored blood pressure, comorbidities, lifestyle factors  and presence or not of antihypertensive treatment. Data on all available patients will be included in order to take an intention-to-treat approach. A two-stage procedure for IPD meta-analysis, stratified by trial and taking into account age, sex, diabetes and baseline systolic BP will be used. Exploratory subgroup analyses will further investigate non-linear relationships between the prespecified variables. Sensitivity analyses will assess the impact of trials which have and have not provided IPD.This study does not include identifiable data. Results will be disseminated in a peer-reviewed publication and by international conference presentations.IPD analysis should help the understanding of which self-monitoring interventions for which patient groups are most effective in the control of blood pressure. This study will gather all available individual patient data from previous trials examining the effectiveness of self-monitoring of blood pressure in hypertension totalling up to 10 000 randomised patients.It will be powered to compare the effectiveness of self-monitoring in different subgroups which was not previously possible.This study is inherently retrospective but all proposed analyses will be agreed prior to conducting the investigation.Across Europe and the USA, around 30% of adults have or are being treated for hypertension, which is a key risk factor for cardiovascular disease, the largest cause of death worldwide.9–142=71.9%, Diastolic I2=42.1%) that could not be accounted for by meta regression.17Previous systematic reviews and meta-analyses have found that self-monitoring reduces clinic BP by an average of around 4 mm Hg for systolic pressure and by around 1.5 mm Hg for diastolic pressure, small, but significant reductions compared to conventional care.et al suggested that when self-monitoring was accompanied by a cointervention, participants were more likely to meet target BP but this did not explain remaining heterogeneity. Key issues in understanding this include differences in study populations such as age, gender, body mass index (BMI), a previous cardiovascular event and socioeconomic situation. Subgroup analyses from a previous summary meta-analysis suggests that the observed heterogeneity can be explained in part, due to cointerventions such as telemonitoring and use of self-titration and the setting in which the intervention is delivered.Analysis by Bray An individual patient data meta-analysis of these data may allow better discrimination of the causes of the underlying heterogeneity.systolic and diastolic clinic BP at 12-month follow-upsystolic and diastolic ambulatory BP at 12 months follow-upproportion controlled below the target specified in the individual trial at 12 months follow-upThe primary objectives are to estimate the effect of self-monitoring BP compared to standard care on:This study will undertake an individual patient data meta-analysis of randomised trials of self-monitoring BP using an intention-to-treat approach where possible. It will assess the evidence for the effectiveness of self-monitoring blood pressure, examine the effects of mediators of such effects and examine if particular subgroups would particularly benefit from self-monitoring intervention. In addition we will aim to develop a prospective register of trials to facilitate on going analyses.To use individual patient data to further explore the heterogeneity found previously and to assess the effect on outcome of the following where data allow: length of follow-up, cointerventions, baseline demographic  and psychosocial factors , setting, intensity of self-monitoring intervention, comorbidities , lifestyle factors  and presence or not of antihypertensive treatment and the number of antihypertensive medications prescribed. This will allow better definition of which intervention to use with whom so as to better operationalise implementation of self-monitoring.To develop a prospective register of trials to facilitate on going meta-analysis.The effects at 6 and 18 months will also be examined as the data allows as a secondary objective.Population—patients with hypertension being managed on an outpatient basis.Intervention—self-measurement of BP without medical professional input plus or minus other cointerventions.Comparator—no organised self-measurement of BP, although there may be some ad hoc measurement which would be difficult to prevent or assess.Outcome—systolic and/or diastolic BP measured in clinic, or by daytime ambulatory measurement.Study design—randomised trial of at least 100 participants followed up for at least 24 weeks.Publication Date since 2000 (because changes in the technology used for self-monitoring make comparisons prior to this date less relevant).All published and unpublished controlled trials where the authors are able to provide individual patient data will be included that fulfil the following criteria:supplementary material appendix A and searches of reference lists of all retrieved papers will be performed. Articles for inclusion will be assessed independently by two reviewers. Non-randomised designs will be excluded. Data will be extracted independently by two team members with disagreements adjudicated by a third. We will study the reference lists of included articles and ask contributing authors if they have, or are aware of any unpublished data which might be included in the review.Relevant electronic databases  will be searched for articles published from 2000. The search strategy has been designed to capture all the relevant literature concerning schedules for self-monitoring of blood pressure. The MEDLINE search strategy is given in online All published and unpublished controlled trials will be included that assess self-measurement of BP without medical professional input, if usual care did not include organised self-monitoring and if a BP outcome was available that had been taken independently of self-measurement (clinic or ambulatory measurement).Assessment of the quality of included trials is controversial.Approaches will be made to all authors of trials that meet the inclusion criteria. The following data will be requested (if available);Setting (primary or secondary care)Inclusion and exclusion criteriaPopulationMonitor usedMonitor validated?Arm usedNumber of readings used in analysisOther measurement criteria, for example, were repeated readings at least 1 min apart?Method of BP outcome measurementAllocation groupsMethod of generation of randomisation listMethod of concealment of randomisationStratification factorsDetails about randomisationDetails of training/education given (both for control and intervention)Targets used for intervention and control groups; if not specified for control concurrent national target will be usedType and frequency of self-monitoringAny additional allocated intervention Who titrates medication Timing of trial follow-up appointmentsInterventionDetails about cost of interventionAge and genderDemographic detailsMedical history Number of medications prescribed at baseline and follow-upBaselineFollow-upBP readings Allocation groupSmokingAlcohol consumptionDietWeightPhysical activityLifestyle factorsMeasures of deprivation, for example, Indices of Multiple DeprivationMeasures of anxiety and depressionMeasures of quality of life, for example, EQ-5D, SF-36Psychosocial factors includingPatient satisfactionResource useConsultationsAdmissionsCostsAny new incidence of cardiovascular events or deathAny clustering factors, for example, by practiceData will be requested either in electronic or paper form and a desired format and coding will be specified. Trialists may supply data in the most convenient way open to them provided details of coding are supplied. The co-ordinating centre will ensure that data items are consistently derived, labelled and coded. Each trial group will be asked to nominate a trialist to lead in the collaboration.Original data will be transferred and stored in a secure environment at the University of Oxford and copies will be made for use in the analyses. Trial details and summary measures will be cross-checked against published articles by two reviewers and inconsistencies will be discussed with the original trialist. Data from each trial will remain the property of each individual group.The primary outcomes will be the change in mean office systolic and diastolic blood pressure, change in ambulatory systolic and diastolic BP and proportion of patients with office BP below target between baseline and follow-up. The primary outcome will be 12 months and outcomes will also be assessed at 6 and 18 months. Reporting of outcomes in the original trial report is not an eligibility requirement provided data are available.Data will be initially tabulated to include important attributes of each trial and to assess comparability, for example of treatment targets.A two-stage procedure for IPD meta-analysis (described below) will be adopted. Handling of missing data will be by complete case analysis, with sensitivity analyses using other methods including multiple imputation if possible.2 statistics for heterogeneity. Analyses will be reported in subgroups, by level of self-monitoring intervention. This will be defined according to levels based on those previously described by Uhlig et al,The two-stage analysis will use linear regression for continuous outcomes and logistic regression for proportions, aggregated across studies by random effects inverse variance methods. Intention-to-treat comparisons of outcomes between self-monitoring arm and comparator arm will be summarised as forest plots with IFurther analyses will explore the effects of age (in 10-year age bands), sex, BMI (dichotomised around BMI of 30), baseline BP (in 10 mm Hg bands), number of medications prescribed at baseline and the presence of comorbidities at baseline  on mean BP change and BP control at follow-up. Exploratory analyses will be conducted (where data are available) including the use and nature of cointerventions , planned intensity of self-monitoring , psychosocial factors , setting and type of healthcare professional involved , lifestyle factors  and changes in antihypertensive treatment at follow-up and the impact on mean arterial BP (MAP).In case of non-linear relationships between the prespecified variables included in the model and outcome not detected by regression, and to further explore relationships where detected, these prespecified variables will be further investigated in an exploratory analysis examining the individual categories (quintiles in the case of continuous variables).The potential for bias due to non-participation in the IPD will be investigated by comparing aggregate data from eligible trials with and without IPD. Notwithstanding this and the impact of the inclusion criteria , publication bias for the primary outcome will be explored using Eggar's methods.It is hoped that individual patient data analysis will allow a greater understanding of observed between trial heterogeneity and lead to the identification of the characteristics of both the intervention and the individuals most likely to benefit from self-monitoring of BP. This will enhance understanding of self-monitoring of BP and enable better targeted and more effective use of this intervention.


Continuous or episodic allergen exposure is a major risk factor of frequent symptoms and exacerbations for patients with allergic asthma. It has been shown that temperature-controlled laminar airflow (TLA) significantly reduced allergen exposure and airway inflammation and improved quality of life of patients with poorly controlled allergic asthma.The objective was to evaluate the effects of nighttime TLA when used during real-life conditions for 12 consecutive months in addition to the patients’ regular medication.This multicenter, pre- and postretrospective observational study included patients with inadequately controlled moderate-to-severe allergic asthma who received add-on treatment with TLA for 12 consecutive months. Data on medication use, asthma control, asthma symptoms, lung function, use of hospital resources, and exacerbations were collected after 4 and 12 months and compared with corresponding data collected retrospectively from medical records during the year prior to inclusion in the study.p<0.0001), and the ratio of asthma-related emergency room visits or hospitalizations diminished from 72.4 to 23.3% (p=0.001) or from 44.8 to 20.0% (p<0.05), respectively, after 12 months of TLA use. The Asthma Control Test index increased from 14.1 to 18.5 (p<0.0001). After 4 months of TLA use, clear improvements can be shown for most variables in line with the data collected after 12 months.Data from 30 patients  completing 4 months and 27 patients completing 12 months of TLA use are presented. The mean number of exacerbations was reduced from 3.6 to 1.3 (The addition of TLA to the patients’ regular medication significantly reduced exacerbations, asthma symptoms, and the utilization of hospital resources. The data support that TLA may be an important new non-pharmacological approach in the management of poorly controlled allergic asthma. Asthma is a chronic inflammatory disease associated with genetic predisposition and increased responsiveness to multiple triggers inducing and maintaining airway inflammation . In alleAccordingly, reduction of allergen exposure is recommended to reduce asthma symptoms in addition to appropriate antiinflammatory medications –6. PatieWith this approach, asthma control can be attained and maintained for the majority of patients in a controlled trial setting, but this may be different in real-life practice –14. PoorThe patient group with unstable severe allergic asthma has a high unmet medical need and is at increased risk of hospitalization for exacerbations and for asthma death underlining the requirement for further means to gain control .Air filter devices have been tested to achieve a reduction in allergen exposure. Blinded studies have, however, failed to demonstrate significant benefit, which indicates that the reduction in allergen exposure achieved by these techniques was insufficient to impact airway inflammation and asthma symptoms , 22.The device Airsonett™  uses a temperature-controlled laminar airflow (TLA) of purified air directed to the breathing zone of a patient during sleep. The device, below referred to as TLA, distributes a filtered cooled laminar airflow, descending from an overhead position, which displaces aeroallergens from the breathing zone .The efficacy of the TLA device has previously been demonstrated in a randomized, controlled, parallel-group trial that evaluated the add-on use of the device or a placebo device in 312 patients with persistent atopic asthma and features of inadequate asthma control, according to Global Initiative for Asthma (GINA) 2006 . NocturnThe aim of this study was to investigate if the use of the TLA device during nighttime, as an add-on to prevailing regular asthma medication, would reduce airway inflammation and improve symptoms, including exacerbations, hospital admissions, emergency visits, and the use of systemic corticosteroids in patients with poorly controlled moderate-to-severe persistent allergic asthma. Of special interest was the evaluation of the frequency of asthma exacerbations and other consequences, for example, OCS use, hospital admissions or emergency room (ER) visits, due to improved disease management under the influence of TLA application.The study was approved by the Ethics Committee (der Med. Fakultät Bochum) on November 4, 2011 (Ref No. 4175–11). Local management (R&D) approval was obtained at each center.Potential eligible patients were identified at participating sites based on the below mentioned screening and eligibility criteria from a clinic database or diary. Informed patient consent was sought for study participation as well as research access to the medical records and, if needed, researcher contact with the general practitioner to complete the study dataset. For underage patients, written informed consent was also collected from their guardians.A non-randomized uncontrolled pre–post retrospective observational study was carried out to investigate the effect of 12 months’ TLA use during real-life conditions. The study was performed in 10 German centers specialized in pediatric or adult lung diseases with a special interest in severe and difficult-to-treat asthma. Patients with severe and difficult-to-control persistent asthma were followed according to a structured study protocol with clinical visits after 4 and 12 months while on nightly TLA use. The TLA device was installed in the home of the patients within 10 days of study inclusion.Prospectively collected data covering the 12 months of TLA use on asthma exacerbations and emergency care visits were compared with corresponding data collected retrospectively for the study baseline from medical records at the hospitals or clinics where the patients had been treated during the prestudy year.There was no prespecified hypothesis that the study was statistically powered to investigate. As the study involved a broad group of patients with poorly controlled persistent asthma, and the management of the patients during the study period was deemed by the individual status of the patient triggered by the same treatment goals during regular medical care, the handling of patients and clinical decisions were not restricted in any way, as normal in controlled clinical trials. The study, therefore, intentionally compared treatment effects in real-life circumstances.Specific screening criteria for potential study patients were applied at all participating centers Row 1 in . Study peligibility criteria were recruited (Patients with severe difficult-to-control asthma (Row 2 in Table) fulfilling the following ecruited : Physiciecruited , high leecruited , inadequecruited , during ecruited , writtenineligibility criteria were applied: Diagnosis of other obstructive or systemic lung diseases  at the time of inclusion, other lung diseases or congenital malformations in the airways, other significant chronic conditions, congenital or acquired heart disease with significant functional changes.The following Retrospective clinical data according to the study case report form (CRF), for the 12-month period preceding study inclusion and start of the period with the TLA device, were collected from paper or electronic hospital medical records available at the clinics where the patients had visited or been treated in the previous year.Data collected at study inclusion (baseline data) included patient demographics , presence of concomitant allergic diseases , concomitant allergy/asthma medications, number of perennial allergies, lung function parameters , classification of asthma control ; Table 2The Childhood Asthma Control Test™  was usedAt baseline, retrospective information from hospital medical records related to exacerbations during the 12 months prestudy period was collected including the number of exacerbations and need for medical intervention, for example, asthma-related ER visits, asthma-related hospital admissions, and exacerbations requiring intensive care.For classification of exacerbations, the ATS/ERS definition of moderate and severe exacerbations was used Row 6 in ; 30.After 4 months (16 weeks) and 12 months of TLA use, the data corresponding to that at study baseline were recorded. Data about exacerbations and need for hospital/medical resources during the past 4 or 8 months were collected at the study visits after 4 and 12 months, respectively.Data were collected in a paper CRF and entered into an Excel-based study database after study completion and analyzed according to a prespecified analysis plan.The primary objective of the study was to evaluate the intraindividual change in asthma control after 12 months of TLA use: 1) the number of exacerbations; 2) the need of asthma-related emergency care; 3) the need of asthma-related hospital admissions; 4) the need of asthma-related intensive care; 5) the use of OCS; 6) changes in asthma control according to ACT index and GINA classification.Lung function, use of relievers, ability to work (or go to school), symptoms of BHR, and frequencies of daily or nightly symptoms were documented as secondary outcome parameters.Patient demographics and other baseline characteristics were summarized using descriptive statistics, contingency tables for qualitative variables; and mean, standard deviation, median, minimum, and maximum for quantitative variables. The analysis used information for all patients with collected postuse data in accordance with an Intention-to-treat approach. No imputations of missing values were applied. Data collected after 4 months of TLA use, related to exacerbations and requirements of medical resources due to exacerbations, were compared with corresponding data collected at baseline. All statistical tests were performed on the observed differences between post-TLA and pre-TLA values. The changes in exacerbations and ACT score were analyzed using the Wilcoxon Signed Rank test. All qualitative variables were analyzed using McNemar's test.From 10 participating hospitals, patients were actively recruited at eight centers. A total of 43 patients were found to be eligible for participation and were screened. Thirty-two patients (74%) consented to study participation: 27 were classified with difficult-to-control asthma and 5 with treatment-resistant asthma. Two of these thirty-two patients never showed up for the follow-up visits after 4 and 12 months, and another three patients did not show up for the final visit after 12 months of TLA use. Data at 4 months were completed for 30 patients and at 12 months for 27 patients.Patient baseline characteristics are presented in The screening criteria for study participation required at least one episode of severe exacerbation during the previous 12 months; four patients did not fulfill this requirement and were excluded for statistical analysis for this parameter. One patient had no previous exacerbations at all and another three patients had had previous exacerbations but not during the past 12 months.p<0.001). The proportion of patients without any exacerbations increased from 13 to 33% (p<0.05) during the TLA period  to an average number of exacerbations of 1.3 for the whole period . The mean number of exacerbations during that period was 0.7 (p<0.0001).Within the first 4 months of TLA use, 60% of the participants were free of exacerbations (p=0.001). The proportion of patients requiring asthma-related inpatient hospitalization declined from 45 to 20% (p<0.05). No patient needed intensive care treatment after TLA was introduced as compared with 14% during the previous year, but this difference was statistically not significant  and 10% requiring inpatient hospitalization during that period (p<0.01).Data collected after the first 4-month treatment period verified a fast onset of the TLA effect, with only 14% of the participants requiring an ER visit (p=0.0503) but was highly significant (p<0.001) after 12 months TLA use  and after 12 months a score of 18.5 was recorded . However, the frequency of nighttime symptoms was significantly (p<0.05) lower after 4 months of TLA use; the difference approached statistical significance after 12 months (p=0.074).There was a trend for daytime symptoms to decline, but this was not significant (The proportion of patients reporting an asthma-related inability to work (or go to school) was lower but did not reach significance 43–22%, .The proportion of patients treated with oral steroids decreased during the study from 33 to 22% (NS). After 12 months, the number of patients requiring oral CS was reduced from 10 to 6 individuals .There were no significant changes in the use of inhaled corticosteroids (ICS) or other regular controller medications including the omalizumab dosing.p=0.062) , diminished during the 12-month TLA period and approached statistical significance (p=0.062) .p<0.01). Other values  showed numerical changes toward a normalization of lung function  and future risk (e.g. exacerbations and medication side effects) , 30. ThiThese findings demonstrate that the addition of TLA add-on to standard therapy may be an effective enhancement of the management of difficult-to-control allergic asthma, supporting previous results from randomized placebo-controlled efficacy trials .The study has several limitations. It was designed as a pre- and post-comparison of TLA use on the frequency of asthma exacerbations in patients with a verified medical history and documented frequent disease exacerbations requiring hospital resources, with patients serving as their own controls.The data quality of retrospective studies relies very much on the accuracy and completeness of the clinical records referred to. Given the nature of the study, incomplete data may have been obtained from the pre-TLA period, thus rather leading to an underestimation of the effects compared with the TLA period, when the study patients and physicians were aware of the study focus on exacerbations and asthma disease deteriorations. Therefore, this study's reported reduction of the exacerbation rates and hospital resource utilizations after the TLA introduction is likely to underestimate the true differences.Without a control group, any spontaneous improvements in asthma morbidity during the 12-month study period (TLA use) may have been missed. In addition, although we took care to select only patients with good treatment adherence, improved adherence to previous treatment during the observation period explaining part of the improvement cannot be excluded. However, we believe that this is unlikely since eligible patients had had troublesome asthma with considerable disease burden for several years, making previous non-adherence to treatment unlikely to be of major relevance.There were some exacerbation-related parameters that did not reach formal statistical significance, nevertheless these parameters all pointed into the same direction, that is, TLA improved the asthma control status in these severely ill asthmatics. The lack of statistical significance may be attributed to the heterogeneity of the patients included and the low number of events observed.The mode of action of TLA is to reduce the allergen exposure during sleep, which is the most likely mechanism behind the effects observed in this study. However, it should be noted that TLA also reduces the exposure to particles in the inhaled air, thus contributing to a general reduction of airway irritants . This maThe effect of TLA on concomitant allergic rhinitis and/or eczema was not recorded in the study. As there are some remarkable anecdotal reports (outside this study) about effects of TLA use in asthmatic patients with eczema and rhinitis comorbidities, further studies are warranted and are now underway to investigate the effect of TLA on both these conditions.The overall management of patients during the TLA intervention period did not change compared with the pre-TLA period. The actual nursing care during the TLA period was not restricted in any way, as is normally the case in controlled clinical trials. Consequently, the present study can be viewed as reflecting real-life circumstances and assessing symptom-related meaningful data.In conclusion, this open study assessing the effect of 12 months of TLA as add-on to pharmacological management in patients with uncontrolled moderate-to-severe allergic asthma showed a significant reduction of exacerbations and use of resources. Improvements in both subjective and objective asthma control measures confirmed the potential value of TLA in the management of patients with difficult-to-treat allergic asthma. This is even more relevant, as these severely affected patients were already treated with high doses of available medications including systemic corticosteroids. The use of TLA is not associated with any pharmacological side effects and is safe to use. Furthermore, the reduction in asthma-related hospital admissions and emergency resource use has important socioeconomic advantages. Further studies are warranted to confirm whether reductions in daily OCS use can be achieved and sustained. Finally, careful investigations should be carried out to identify those patients who will benefit most from TLA as a novel tool in the management of difficult allergic asthma.


Syncope is defined as a transient loss of consciousness and postural tone, characterized by rapid onset, short duration, and spontaneous recovery, and the process of syncope progression is here described with two types of sympathetic change. Simultaneous recordings of microneurographically-recorded muscle sympathetic nerve activity (MSNA) and continuous and noninvasive blood pressure measurement has disclosed what is going on during the course of syncope progression. For vasovagal or neurally mediated syncope, three stages are identified in the course of syncope onset, oscillation, imbalance, and catastrophe phases. Vasovagal syncope is characterized by sympathoexcitation, followed by vagal overcoming via the Bezold-Jarisch reflex. Orthostatic syncope is caused by response failure or a lack of sympathetic nerve activity to the orthostatic challenge, followed by fluid shift and subsequent low cerebral perfusion. Four causes are considered for the compensatory failure that triggers orthostatic syncope: hypovolemia, increased pooling in the lower body, failure to activate sympathetic activity, and failure of vasoconstriction against sympathetic vasoconstrictive stimulation. Many pathophysiological conditions have been described from the perspectives of (1) exaggerated sympathoexcitation and (2) failure to activate the sympathetic nerve. We conclude that the sympathetic nervous system can control cardiovascular function, and its failure results in syncope; however, responses of the system obtained by microneurographically-recorded MSNA would determine the pathophysiology of the onset and progression of syncope, explaining the treatment effect that could be achieved by the analysis of this mechanism. Syncope is defined as a transient loss of consciousness and postural tone, characterized by rapid onset, short duration, and spontaneous recovery, due to global cerebral hypoperfusion that most often results from hypotension. The accurate definition does not include the unconsciousness not caused by cerebral hypoperfusion, for example, epileptic seizures, concussion, and cerebrovascular accidents, which are persistent structural impairments, and persistent states of unconsciousness, for example, coma and cerebrovascular diseases Ross, .The pronunciation of “syncope” can differ from person to person; however, [síηkəpi] seems to be generally accepted, meaning “strike” or “cut-off” in ancient Greek.The human autonomic nervous system regulates the systemic arterial pressure to maintain constant cerebral perfusion under conditions of uneven fluid shift caused by postural change. Syncope is the state of failure of this regulating function.Many forms of syncope are preceded by a prodromal state that often includes dizziness and loss of vision, loss of hearing, loss of pain and feeling, nausea and abdominal discomfort, weakness, cold sweating, a feeling of hotness, palpitations and other phenomena, which are often called “presyncope” , where inversion of positive and negative signs is executed. The CVLM then transmits GABAergic (using γ-amino butyric acid as a neurotransmitter) neurons to the rostral ventrolateral medulla (RVLM). The topographical regional differentiation has been established Dampney, .The RVLM neurons are considered to be premotor neurons for the preganglionic efferent neurons whose cell bodies are situated in the intermediolateral nucleus (IML), with synapses to the preganglionic B-fiber neurons, and which exit from the spinal cord as white rami Netter, .On the other hand, input from NTS to the nucleus ambiguus and the dorsal nucleus of the vagus modulates the activity of the vagal nerve, innervating the heart and presphincters of the resistant vessels, and causing decrease in heart rate and cardiac contractility Patten, .in situ, which is the only baromodulatory sympathetic nerve activity directly recordable in humans  can be recorded microneurographically from human peripheral nerves s Figure . The tecs Figure .These pathways provide a negative feedback mechanism to suppress the sympathetic nerve activity while the vagus nerve activity is activated when blood pressure rises, and facilitate the sympathetic nerve activity and suppress the vagus nerve activity when blood pressure drops.How is the autonomic nervous system involved in the onset of syncope? It is primarily responsible for sympathetic responses toward environmental challenges. The most frequent challenge triggering syncope might be a postural change Figure . SyncopeIn the following sections, syncope from the perspectives of the autonomic nervous system is described, based on the premise that no structural or conduction disorder is present in the heart.The concept of vasovagal syncope was first proposed by Lewis in 1932, with primary symptoms of hypotension and bradycardia. Vasovagal syncope is triggered by an exaggerated sympathetic response to a situation; in other words, sympathoexcitation precedes the onset.The Bezold-Jarisch reflex plays an important role in the onset of this type of syncope. This reflex is generated by the cerebral hypoperfusion due to vagal-activation-mediated sympathosuppression for the protection of myocardium  fatigue, dehydration, and hypovolemia due to hemorrhage, followed by reduced venous return, (2) blood shift and pooling in the lower body, (3) hypersensitivity of the stretch receptors in the left ventricular wall, and (4) fear, emotional stress, and reaction to pain  and blood pressure display an oscillation pattern with the levels been well maintained. The time lag from MSNA discharge to blood pressure rise by the constriction of arterioles is approximately 4–5 s, while the time lag from the blood pressure rise to the vasodilatation by the suppression of sympathetic nerve activity is approximately 1 s from the descending pathway in the medulla oblongata to the peripheral vasodilating sphincter muscles via the synapse in the sympathetic chain to the postganglionic C-fiber; the time delay from the baroreceptor to the recording site of microneurography. The sympathetic discharge induces a blood pressure rise. This double feedback mechanism oscillates to maintain the blood pressure. In stage I, blood pressure wave and heart rate oscillate with a frequency of 0.1 Hz (10 s period), and the low frequency component (LF) of heart rate variability is enhanced. This phase includes mutual increases in both sympathetic and vagal activities.Stage II: imbalance phase Iwase, At this stage, venous return is reduced due to the failure to compensate for the enhanced venous pooling, which makes blood pressure maintenance difficult. The tidal volume is raised to increase the venous return. Failure of the double feedback mechanism arises with the enhanced power of the high frequency component (HF) of the blood pressure wave and heart rate variability. The falling blood pressure due to decreased stroke volume cannot be compensated for by only the peripheral vasoconstriction, inducing an extremely elevated heart rate. This tachycardia compensates for the reduced stroke volume, which could not be compensated for by decreased venous return or circulatory blood volume. In this state, cardiac echography sometimes reveals parallel movement of the interventricular septum and the left ventricular wall, which is called “paradoxical movement.” It is estimated that this state involves the sympathetic nerve activity being overwhelmed by the parasympathetic nerve activity, and the reciprocal relationship between the diastolic blood pressure and MSNA, denoting the baroreflex function, disappears late in this phase.Stage III: catastrophe phase Iwase, In spite of the effort to maintain the blood pressure by an increased heart rate, the stage transitions to stage III, when a sudden heart rate drop with the cessation of MSNA is observed, resulting in an immediate fall in blood pressure. Some patients experience cardiac arrest simultaneously with cold sweat, nausea, blackout, and loss of consciousness. Dominant activation of parasympathetic nerve activity occurs concomitantly with sympathosuppression. In “neurally mediated syncope,” this stage corresponds to the classification of cardiosuppressive, vasosuppresive, or mixed types, which are based on whether the suppressive drive is dominant over cardiac or vasomotor sympathetic drives or both.Therefore, sympathoactivation is observed, followed by sudden tachycardia, which triggers the onset of vasovagal syncope or neurally mediated syncope.The orthostatic hypotension or orthostatic syncope, or orthostatic intolerance associated with postural change is caused by the response failure or lack of sympathetic nerve activity to an orthostatic challenge. A change in posture from a supine to an upright position in humans induces a fluid shift of 300–800 mL from the thoracic cavity to the lower body, including abdominal cavity or legs, resulting in a reduction in venous return. This causes a stroke volume decrease, which in turn activates the sympathetic nervous system via the arterial baroreflex and cardiopulmonary reflex. This sympathoactivation induces increases in heart rate, cardiac contractility, and peripheral resistance, while arterial blood pressure is maintained and cerebral blood flow is maintained constant.In the case of activation failure, hypotension develops just after the postural change, sometimes progressing to fainting or syncope. The essence of orthostatic hypotension is failure of the compensation of the fluid shift that follows postural change. The largest difference from the neurally mediated syncope or vasovagal syncope is the latency of syncope onset after the orthostatic challenge. Usually, neurally mediated syncope or vasovagal syncope is induced when the individuals maintain an upright position for a comparatively long duration, possibly >10 min, whereas orthostatic hypotension develops in a short period. In tilt studies on 66 subjects, the onset latency was reported to be >1 min for 58 and >2 min for the remaining 8 individuals  hypovolemia, (2) increased pooling in the lower body, (3) failure to activate the sympathetic activity, and (4) failure of vasoconstriction upon sympathetic vasoconstrictive stimulation.Hypovolemia. Hypovolemia is the most prevalent cause of orthostatic hypotension, having associations with a hot environment, dehydration, hemorrhage, diarrhea, Addison's disease, and administration of diuretics. Hypovolemia results in a fluid shift to the lower body, causing insufficient venous return, stroke volume, and cardiac output, which lowers cerebral perfusion and induces syncope. A large fluid shift increases the heart rate, but usually insufficiently. If the increase is exaggerated, this might be a cause of neurally mediated or vasovagal syncope. In this case, the blood pressure might be maintained for several minutes, while gradual blood pressure decrease might be a cause. Here, the difference between neurally mediated or vasovagal syncope and orthostatic hypotension might be reduced responsiveness of the sympathetic nerve activity to fluid shift.Increased pooling in the lower body. This occurs due to (3) or (4) below, or due to the increased pooling in the lower body in pathological conditions including vascular disease that reduces the elasticity of the vessels, as seen in varices or pregnancy. The mechanism of development is the same as in (1).Failure to activate the sympathetic activity. Any disorder that impairs the baroreflex function is included in this category, including carotid deafferentation, carotid sinus neuropathy, primary autonomic failure , pure autonomic failure, Parkinson's disease with autonomic failure, and acute pandysautonomia. In addition to the primary autonomic failures, secondary ones include diabetic neuropathy, amyloid neuropathy, chronic renal failure, alcoholic neuropathy, spinal cord injury, brain tumors, and postoperative symptoms of lumbar sympathectomy for the treatment of Buerger's disease or Raynaud's syndrome all have an impaired efferent sympathetic pathway, which induces marked pooling of the body fluid , calcium antagonists (nifedipine), prostaglandin E1 (limaprost), or nitroglycerin. We previously reported that although the microneurographically recorded sympathetic nerve activity is not altered, the effectiveness of the sympathetic activity on blood flow reduction is attenuated , and fluid shift measurements by the bioimpedance method. Several investigations related to syncope with polygraphic recording have been reported by the recording of microneurographically recorded MSNA, among which Kamiya et al. reported the disappearance of 10 s oscillation in MSNA and blood pressure in tilt-induced syncope , Ichinosthreo-DOPS , a precursor of noradrenaline, ameliorated the orthostatic intolerance and induced MSNA discharge from the tibial nerve , and reported that although MSNA appeared not to be discharged from the tibial nerve, administration of L-Thus, these changes recorded by polygraphy during the fluid shift maneuver provided measures for diagnosing orthostatic hypotension or vasovagal syncope Figure . By the The sympathetic nervous system can control the cardiovascular function, and its failure results in syncope; however, responses of the system by microneurographically recorded MSNA would determine the pathophysiology of the onset and progression of syncope. An effective treatment could be achieved by the analysis of this mechanism.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Patients with chronic kidney disease (CKD) have poor health-related quality of life (HRQoL). The association of CKD-related complications such as anemia and mineral and bone disorders (MBD) with HRQoL in pre-dialysis patients is not well-studied. As such, this study aimed to determine the association of anemia and MBD with HRQoL in pre-dialysis patients.This was a cross-sectional study involving 311 adult pre-dialysis patients with stage 3–5 CKD from an acute-care hospital in Singapore. Patients’ HRQoL were assessed using Kidney Disease Quality of Life Short Form (KDQOL-SF™) and EuroQol 5 Dimensions–3 levels (EQ5D-3L). HRQoL between patients with and without anemia or MBD were compared by separate hierarchical multiple linear regression analyses using various HRQoL scales as dependent variables, adjusted for sociodemographic, clinical and psychosocial variables.p = 0.010; −3.0 (1.28), p = 0.018; and −4.2 (1.40), p = 0.003, respectively]. However, significance was lost after adjustments for sociodemographic variables. Patients with MBD had poorer HRQoL with respect to burden of kidney disease, WS, PF and general health . Although these remained significant after adjusting for sociodemographic variables, significance was lost after adjusting for clinical variables, particularly pill burden. This is of clinical importance due to the high pill burden of CKD patients, especially from medications for the management of multiple comorbidities such as cardiovascular and mineral and bone diseases.After adjusting for MBD, anemia was associated with lower HRQoL scores on work status (WS), physical functioning (PF) and role physical [β (SE): −10.9 (4.18), Neither anemia nor MBD was associated with HRQoL in our pre-dialysis patients. Instead, higher total daily pill burden was associated with worse HRQoL. Medication reconciliation should therefore be routinely performed by clinicians and pharmacists to reduce total daily pill burden where possible. Chronic kidney disease (CKD) is a serious public health problem affecting 12.8 % of Singapore’s population , and more likely to be Malay   Table . They alThe self-reported HRQoL is presented in Table p = 0.002], SF-36 PF  and RP . In bivariate analyses, after adjusting for MBD, patients with anemia persisted to have significantly lower work status , SF-36 PF  scores. These scores were no longer significantly different between patients with and without anemia after adjusting for sociodemographic variables.In univariate analyses, patients with anemia reported significantly lower HRQoL scores on the work status item, , work status , SF-36 PF [beta (SE): −3.0 (1.22) p = 0.014] and GH . After adjusting for anemia, the association between MBD and burden of kidney disease , as well as SF-36 GH  remained statistically significant. These associations remained statistically significant after adjusting for sociodemographic variables but were no longer significant after adjusting for sociodemographic and clinical variables. In fact, statistical significance was lost simply by adjusting for pill burden. Results of these analyses are shown in Table In univariate analyses, those with MBD reported significantly lower scores on burden of kidney disease  levels have been associated with poor HRQoL , 13, 47.Second, this is one of very few studies that evaluated the impact of anemia on HRQoL in pre-dialysis patients . In a stWe recognized that this study is not without its limitations. First, although our study included a wide spectrum of relevant variables in our regression analyses, other variables associated with impaired physical and mental HRQoL in pre-dialysis patients such as poor nutritional status, depression and inflammation were not captured , 54. As Our study has shown that anemia is not associated with HRQoL in pre-dialysis patients. While MBD as a whole is also not significantly associated with HRQoL, total daily pill burden in pre-dialysis patients with MBD is associated with HRQoL. This is of clinical importance due to the recognized high pill burden of CKD patients, especially from medications prescribed for the management of hyperphosphatemia, secondary hyperparathyroidism and comorbidities such as cardiovascular diseases. Clinicians and pharmacists should review patients’ medication lists regularly and perform medication reconciliation routinely to reduce their total daily pill burden, where possible. Future research is also needed to examine effective therapeutic options for MBD that does not compromise HRQoL due to excessive pill burden.Beta, Beta coefficient; BP, Bodily pain; Ca, Calcium; CKD, Chronic kidney disease; EQ5D-3L, EuroQol 5 Dimensions–3 levels; ESA, erythropoiesis-stimulating agent; FFM, Family functioning measure; GH, General health; Hgb, Hemoglobin; HRQoL, Health-related quality of life; iPTH, intact-parathyroid hormone; KDIGO, Kidney Disease: Improving Global Outcomes; KDOQI, Kidney Disease Quality Outcomes Initiative; KDQOL-SF™, Kidney Disease Quality of Life Short Form; MBD, Mineral and bone disorder; MCID, Minimally clinically important difference; MCS, Mental component summary; MDRD, Modification of Diet in Renal Diseases; MH, Mental health; NUH, National University Hospital; P, Phosphorus; PCS, Physical component summary; PF, Physical functioning; RE, Role-emotional; RP, Role physical; SCS, Cocial component summary; SD, standard deviation; SE, standard error; SF, Social functioning; U.S., United States; VT, Vitality; WS, Work status


KI channel protein phosphorylation and the KI current activity that in turn increased the cardiomyocyte APD and QTc interval in vitro and in the computer ORd model. These findings suggest that IS may play a role in the development of arrhythmogenesis in CKD patients.Total mortality and sudden cardiac death is highly prevalent in patients with chronic kidney disease (CKD). In CKD patients, the protein-bound uremic retention solute indoxyl sulfate (IS) is independently associated with cardiovascular disease. However, the underlying mechanisms of this association have yet to be elucidated. The relationship between IS and cardiac electrocardiographic parameters was investigated in a prospective observational study among early CKD patients. IS arrhythmogenic effect was evaluated by in vitro cardiomyocyte electrophysiological study and mathematical computer simulation. In a cohort of 100 early CKD patients, patients with corrected QT (QTc) prolongation had higher IS levels. Furthermore, serum IS level was independently associated with prolonged QTc interval. In vitro, the delay rectifier potassium current (IK) was found to be significantly decreased after the treatment of IS in a dose-dependent manner. The modulation of IS to the IK was through the regulation of the major potassium ion channel protein Kv 2.1 phosphorylation. In a computer simulation, the decrease of IK by IS could prolong the action potential duration (APD) and induce early afterdepolarization, which is known to be a trigger mechanism of lethal ventricular arrhythmias. In conclusion, serum IS level is independently associated with the prolonged QTc interval in early CKD patients. IS down-regulated  The importance of cardiovascular diseases (CVD) and cardiac arrhythmias in chronic kidney disease (CKD) is currently well established. Abnormal corrected QT (QTc) prolongation on the electrocardiogram, which is an independent risk factor for sudden cardiac death (SCD), is frequently found in patients with CKD and end-stage renal disease (ESRD) ,2. HowevIK) plays an important role in the repolarization of cardiac action potentials and is one of the major currents that determines the action potentials duration and QT interval [The delayed rectifier potassium current  had been calculated and followed up according to the extended Modification of Diet in Renal Disease Study formula 3–6 months before the study . WrittenPeripheral blood samples were taken after fasting for 8 hours overnight and before the examination. Complete blood counts and serum creatinine, sodium, potassium, calcium, uric acid, albumin, glucose and lipid profiles  were determined as our previous reports ,18.To determine the blood total IS, A UPLC assay was used as our previously reported ,17,18. ITwelve-lead ECGs were collected at the baseline examination by standardized protocol. Standard interval , amplitudes  were analyzed by standard protocol as described elsewhere . The QT p-cresyl sulfate was synthesized as a potassium salt, cells exposed to culture medium supplemented with equimolar concentrations of potassium chloride were used as controls. We found that the addition of 1.0 mmol/L of potassium chloride did not alter the number of EMPs compared with growth medium alone [Embryonic rat heart-derived cardiac H9c2 cells  were cultured in DMEM supplemented with 10% fetal bovine serum under an atmosphere of 95% air 5% CO2 at 37°C. Experiments were carried out using mononucleated myoblasts culture for 2–5 days . All culum alone .The protein level of Kv2.1 and phosphorylated Kv2.1 in H9c2 cells was analyzed by Western blot ,27. In bThe whole-cell potassium outward currents were recorded using an Axopatch 700A amplifier . The details of the methods has been described in previous reports ,28,29. B+, K+ and Ca2+.The latest mathematical model of the O'Hara-Rudy dynamic human ventricular model (ORd model) was used in our experiment . CardiomIK is derived from previously published K channel models [IK in H9c2 cells with and without IS treatment was digitized and formulated into a new Markov model computer equation and inserted into the ORd model to evaluate the IS effect on human cardiomyocyte action potential.A Markov model for l models . The curA pseudo-ECG was constructed and simulated by the transmural wedge model . The numData normality was analyzed using the Kolmogorov-Smirnov test. Continuous, normally distributed variables are presented as mean ± SD, and non-normally distributed variables as median (interquartile range). Statistical differences in variables were compared using the Wilcoxon rank-sum test. Categorical variables were recorded as frequencies and/or percentages, and inter-group comparisons were analyzed with the Fisher’s exact test. The general linear modeling function analysis was used to control for potential confounders other than age and sex. Simple linear regression analysis was used to examine the association and independence between serum IS and the values of other parameters. Using multiple logistic regression, variables were assessed for independent associations with the prolonged QTc interval. Multivariate adjusted ORs are presented with 95% confidence interval (CI). All the tests were two-tailed, and a p value of < 0.05 was considered statistically significant. All of the statistical analyses were performed using SAS statistical software, version 8.2 .2  and pseudo ECG QT interval Click here for additional data file.


Chronic intermittent hypoxia, platelet activation and inflammation all play roles in the pathogenesis of obstructive sleep apnea syndrome (OSAS), which may increase the risk of cardiovascular disease (CVD). The aim of this study was to evaluate the relationship of the platelet-to-lymphocyte ratio (PLR) as a new biomarker showing systemic inflammation and platelet distribution width (PDW) as an indicator of platelet activation to the severity of OSAS.A total of 290 patients suspected with OSAS who underwent a full night of polysomnography were included. The patients were placed into 4 separate groups according to their apnea-hypopnea index (AHI) scores; the control group (AHI <5), mild OSAS group (AHI 5–15), moderate OSAS group (AHI 16–30), and severe OSAS group (AHI >30). CVD risk was defined by the presence of hypertension, diabetes mellitus, current smoking, and dyslipidemia.r = 0.227 for PDW, all p-values < 0.001) and the Epworth sleepiness scale . Multivariate regression analysis revealed that AHI ≥9.2  = 1.67-15.2, p = 0.004) and PLR ≥159  were independently associated with the presence of hypertension.Higher AHI groups were significantly correlated with increasing age, body mass index, systolic blood pressure and male sex. PLR and PDW were also significantly associated with AHI (r = 0.417 for PLR and PLR and PDW are associated with OSAS severity. PLR may also be useful as a systemic biomarker for the concurrent hypertension in OSAS patients. Obstructive sleep apnea (OSA) induces hypoxia and hypercapnia, which adversely affect the myocardial oxygen supply. These changes ultimately contribute to the development of altered metabolic, immune, and inflammatory systemic responses . SeveralIncreased platelet activation plays a major role in the initiation and progression of atherosclerosis . Recent This is a retrospective cohort study performed at two centers. A total of 290 patients who had undergone polysomnography between January 2010 and December 2014 were evaluated. Patients were considered for inclusion if they were between 18 and 80 years old, had normal renal function and regular menstruation (with regard to the women included). Patients were excluded if any of the following criteria applied: systemic disease such as liver disease; neurologic disorders or malignancy; secondary hypertension; respiratory infection and failure; critical illness with poor functional status; refractory arrhythmia; history of heart failure; history of acute coronary syndrome, myocardial infarction and/or any revascularization procedure. Demographic characteristics including age, sex, height, weight, current medications, smoking history and other diseases were recorded at first visit. Patients were assessed for any CVD risk factors including the presence or absence of medically diagnosed hypertension, diabetes mellitus, dyslipidemia, and current smoking status. Blood pressure (BP) was measured with using a standard mercury manometer. Hypertension was defined as systolic BP (SBP) ≥140 mmHg, diastolic BP (DBP) ≥90 mmHg and/or current use of antihypertensive drugs. Body mass index (BMI) was calculated as the ratio of dry weight in kilograms to height in meters squared. This study was approved by the Institutional Review Board.The full night polysomnography (PSG) studies used for OSAS diagnosis were retrospectively reviewed. Full night PSG  examination was performed using a device equipped with a snoring sensor, respiratory effort sensors, pressure sensor, body position center, thermister, electroencephalography (EEG), electrocardiogram (ECG), pulse oximeter with oxygen saturation, lower extremity electromyography and chest excursion. The value index of PSG testing included AHI scores, percentage of sleep efficacy, total sleep time, baseline/lowest oxygen saturation, and the Epworth sleepiness scale (ESS). The ESS was evaluated before PSG using a survey. Apnea was defined as a standstill in the airflow for more than 10 s. Hypopnea was defined as ≥30 % reduction in airway flow for more than 10 s followed by a decrease of approximately 4 % in the patient’s oxygen saturation . AHI wasThe biochemical parameters analyzed included total cholesterol, triglyceride, fasting glucose, erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein (hs-CRP), and complete blood cell count. The PLR was calculated by dividing the lymphocyte from the platelet.U test was used for continuous variables and the chi-square test was used for categorical data. The Kolmogorov-Smirnov test was used to test the data’s normality. Parameter differences among the three groups were evaluated using a one-way analysis of variance (ANOVA) or the Kruskal–Wallis test for normally or non-normally distributed variables, respectively. The Tukey test was used for multiple comparisons. Pearson correlation coefficients were used to determine relationships between variables. Linear association analysis was used to verify the correlations between variables. Receiver operator characteristic (ROC) curve analysis was used to estimate the cutoff values for AHI and PLR in the prediction of hypertension. Multivariate logistic regression models were built to determine which variables are independently associated with concurrent hypertension. Two-tailed p-values < 0.05 were considered statistically significant.Statistical analyses were performed using the commercially available computer program SPSS 18.0 for Windows . Data are presented as means ± standard deviations for continuous variables and their percentages (%) for categorical data. The Mann - Whitney p-values < 0.05, Fig. p = 0.001, Fig. p = 0.003). Table p-values <0.05).There was a total 290 patients including 193 men (66.6 %) and 97 women (33.4 %) included in this study. The mean age was 48.6 ± 13.4 years (range: 18–78). There were 61 control patients, 67 mild OSAS, 61 moderate OSAS, and 101 severe OSAS patients. Table r = 0.417, p <0.001, Fig. 2 saturation values , ESS  and hs-CRP . In addition, PDW was significantly correlated with AHI  and ESS . However, red blood cell count (RBC) showed no significant correlation with AHI . Multivariate logistic regression analysis showed that PLR  and PDW  were independently associated with AHI after adjustment of the presence of hypertension, diabetes mellitus, dyslipidemia, obesity defined as BMI ≥ 25 kg/m2 and current smoking status.Then, we analyzed the correlations between inflammatory markers and the clinical OSAS factors. PLR was significantly associated with AHI (p < 0.001) and PLR ≥159 . Multivariate logistic regression analysis showed that AHI ≥9.2  and PLR ≥159  were independently associated with the concurrent hypertension in OSAS after adjusting for age, male gender, and BMI  and systemic inflammation (PLR) were both found to be significantly associated with OSAS severity (reflected by AHI). In addition, we have demonstrated that PLR may be a systemic biomarker that is independently associated with concurrent hypertension in OSAS patients. OSAS is a chronic disease that is frequently associated with various comorbidities including cognitive impairment, CVD, pulmonary disease, endocrine dysfunction, and neuropsychiatric problems –20. The The PLR combines the predictive risk of platelet and lymphocyte counts into a new prognostic marker of inflammation for many types of cardiovascular disease including hypertension, coronary artery disease, occlusive peripheral arterial disease , 12, andAnother interesting finding from this study is that OSAS patients with concurrent hypertension had significantly higher PLR values than did those without hypertension. The hypertension that occurs with OSAS may be multifactorial in origin. Systemic inflammation likely plays a major role in the development of hypertension in OSAS. A previous study showed that OSAS patients with hypertension had higher levels of inflammation and insulin resistance than do those without hypertension . Since sThis study has several limitations. Since this was a retrospective cohort study, the blood sampling and test parameters were not performed with identical methods. Any variability may have influenced the value of the parameter. In addition, PLR and PDW were based on single measurements. It would be important to determine whether PLR changes over time, and if it is a consistent predictor of OSAS severity. Our study was also conducted with a relatively small sample of patients that was likely insufficient to demonstrate cardiovascular outcomes. In order to achieve more statistical power and substantiate our findings, larger randomized controlled trials are necessary.In conclusion, this study demonstrates evidence of inflammation and platelet activation in OSAS. Therefore, PLR and PDW may be relevant inflammatory markers of OSAS severity. Furthermore, PLR may be a useful inflammatory biomarker associated with concurrent hypertension in OSAS. Further, larger studies using PLR and PDW are needed to assess the effectiveness of continuous positive airway pressure therapy on OSAS.


Medicinal plants have served as valuable starting materials for drug development in both developing and developed countries. Today, more than 80% of the people living in Africa were depended on medicinal plants based medicines to satisfy their healthcare needs. The main goal of the present study was to collect and document information on herbal remedies traditionally used for the treatment of diabetes and/or hypertension in Cameroon. To reach this objective, data were collected from 328 patients who have been diagnosed at least once by a physician as diabetics and/or hypertension patients. One hundred and eighty two (182) among them took for a period of 10 days different varieties of medicinal plants which were prepared in form of decoction, maceration and infusion and administered orally twice or three times daily.As result, 70% of patients who used plants were relieved at the end of the treatment. Thirty-three plants have been recorded and documented for the treatment of diabetes and/or hypertension. The results of this study can stimulate a sustainable development by providing the basis for drugs discovery and by documenting biodiversity for long time exploitation. Hypertension affects approximately 70% of patients with type 2 diabetes, 30% of patients with type 1 diabetes and it is approximately twice as common in persons with diabetes as in non-diabetics . AccordiPatients admitted in this study have presented a medical book or a bulletin of medical exam that certifies their diabetic and/or hypertensive state at the moment of their selection. During the clinical following up, they have used the familiar blood pressure monitor and/or the familiar glycemic monitor to control daily blood pressure or fasting blood sugar concentrationTo reach our objective, we selected for this study 182 patients upon 328 who have been diagnosed at least once in medical centers and who took different varieties of herbal remedies and accept the clinical following up for a period of 10 days. They were distributed in three groups: confirmed diabetics, confirmed hypertensive patients and confirmed diabetics with hypertension patients.Research of minimal efficient therapeutic dosage of each plant used by followed up patients and minimal duration of treatmentOnly the more efficient dosage for a given plant prepared with a minimal quantity of plant material for a minimal time of treatment was selected. The daily fasten glycemic and/or the blood pressure of each patient in treatment were measured until the normal fasting glycaemia (0.66 to 1.1 g/l) or the normal blood pressure (110 to 130 mmhg for systolic and 70 to 90 mmhg for diastolic).Data were collected using an ethnobotanical data form and from 182 upon 328 patients drawn in 28 tribes in Cameroon. All plants recorded here were described in detail with the precision of the quantity of plant material, volume of water, time of ebullition, maceration or infusion, quality of preparation used per dosage, the number uses per day and duration of treatment .One hundred and eighty two (182) confirmed patients  used familiar herbal remedies. Familiar herbal remedies have regulated the hyperglycemia and/or the high blood pressure for 129/182 patients (70.87%). Oral use of herbal remedies has relieved the hyperglycemia of 80% of patients of NIDD, of 69.44% of patients of IDD on the one hand, the high blood pressure of 46.15% of patients of essential hypertension and 65.07% of patients of secondary hypertension on the other hand. The analysis of the different glycemic values and blood pressure in A total of 86 abnormal blood pressure values  upon 152 have been regulated, representing 56,57%. However 22 of such values have persisted after the treatment, representing 14.47%. At last 33 diastolic normal values (21.71%) remained constant until the end of the treatment. At last a normal systolic value that represents 0.65% remained constant until the end of the treatment. For the two diseases 64.17% of glycemic values and blood pressure values have been regulated.These increased percentages constitute an element that sustains the use of herbal remedies in the treatment of the two pathologies. However because of the disparity observed in the results of treatment, it is necessary to precise that the use of plants must be done under a control of a physician. Stop the treatment, after a time to determine from that the glycaemia and/or the blood pressure become normal. This precision must avoid the excessive use of herbal remedies and the danger of hypoglycemia and hypotension.Thirty-three plants were used by the 182 followed up patients. The minimal efficient dosage of each of these plants was taken in consideration. It is expressed sometimes in function of patients' weight and is subsequently described in details in Solanum melongena in the form of a decoction called ‘medip-me-zon’ in Boulou tribe, the soup with garden eggs of fufu called ‘ashu’ and ‘abalah ‘respectively in North West and West regions and the soup of fufu corn with hypoglycemic Corchorus olitorius called ‘lalo’ in Fulfulbe and Kenekene in Eton and the lack of physical exercises can explain the increase prevalence of the diabetes and hypertension in towns.The abandon of several foods in benefit of sweet coffee and milk by the urban populations including hypoglycemic garden eggs The high percentage of regulated or relieved patients  depends on many factors including the aggravation of the diseases by the development of complications, the causes of diseases and the mechanisms of the herbal remedies including insulin-secretion and peripheral action. Most of the unrelieved patients have developed the disease for a long time.It is the pancreatic action that is possible if β- cells still available . In the It is the extrapancreatic action (as injected insulin) . The TabThe two mechanisms present by the plants* of Phyllanthus niruri is an inhibitor of conversion enzyme (ICE). These compounds are hypotensive and they interfere with the liberation of angiotensin. The Heart Outcomes Prevention Evaluation study showed that inhibition of angiotensin-converting enzyme in patients with type 2 diabetes reduces the risk of vascular complications [ications . TherefoPhyllanthus amarus (5-80 mg/kg) to anesthetized male rabbits produced a significant fall in mean diastolic, systolic, and mean arterial pressures in a graded dose-response manner. The dose of 5 mg/kg produced the least hypotensive effect, causing a fall in mean diastolic, systolic, and mean arterial pressure of 13.3 ± 3.1, 19.7 ± 5.4, and 14.3 ± 3.4 mmHg, respectively, whereas the dose of 80 mg/kg produced the greatest fall in mean diastolic, systolic, and mean arterial pressure of 49.7 ± 7.9, 45.5 ± 9.5, and 48.00 ± 6.5 mmHg, respectively. The extract produced greater depressant effect on the diastolic blood pressure than the systolic blood pressure.Amaechina and Omogbai  reportedRauvolfia vomitoria reacts like a central antihypertensive product; as vasodilator of coronary vessels and as a regulator of cardiac rhythm in patients suffering of tachycardia. Allium cepa is a diuretic; it treats some hypertensive patients by facilitating the blood circulation and prevents thrombosis, responsible of some secondary hypertensions. This favorable effect can be partially explained by the physio-pathological mechanisms conceivable in African population like hypervolemia , the sensibility in salt, the excessive consumption of salt and the climate conditions. In anesthetized rats, the crude extract of the leaves of Moringa oleifera caused a fall in systolic, diastolic, and mean blood pressure in a dose-dependent manner. It was also established that thiocarbamate and isothiocyanate fractions of this crude extract were responsible for the antihypertensive activity. Sacks, et al. and Mojiminiyi et al. [Hibiscus sabdariffa. The antihypertensive effects of the crude extract have been attributed to mediation through acetylcholine and histamine like dependent mechanism through direct vasorelaxant effects [Some plants 1 in i et al. ,11 repor effects . Earlier effects . The chr effects .Clinical trials of the plant extract in human being show trustworthy evidence of antihypertensive effects. A standardized doses of 9.6 mg per day given to 39 patients, 50 mg per day given to the same number of patients don't show significant difference relative to hypotensive effects, antihypertensive effectiveness and tolerability .In Cameroon, the persisted economic crisis, the insulin-resistance, the resistance of some hypertensions to antihypertensive products and certain germs to synthetic antibiotics has reinforced the recourse to traditional medicine in both urban and rural populations.Momordica charantia, Sclerocarya birrea and Ceiba pentandra have revealed two interesting mechanisms of action: pancreatic and extra-pancreatic in the treatment of diabetes. Phyllanthus niruri is an inhibitor action for the production aldosterone responsible of certain severe hypertensions [The clinical follow up of diabetics and/or hypertensive patients in treatment with familiar herbal remedies led to the identification of 33 hypoglycemic and/or antihypertensive plants. In general the oral use of these 33 plants have reduced the hyperglycemia of 80% of NID patients, 69.4% of IDD patients on the one hand; the high blood pressure of 46.1% of patients of essential hypertension and 65.1% of patients of secondary hypertension on the other hand. For the two diseases 172 glycemic and tension values upon 268 were regulated representing 64.17% . Some plThe knowledge of bioactive plants can contribute to the better treatment of patients and the improvement of the quality of socio-sanitary allowance administrated to them . But man


This difference was still present after adjustment for age, gender, mean arterial blood pressure (MAP), heart rate and diabetes mellitus (p = 0.001), and was shown by subgroup analysis to apply to the 40-59 years age group (p = 0.004) and 60+ years age group (p = 0.01), but not to younger age groups (p = 0.99). Except for a shorter aortic reflexion time (p = 0.02), indirect indicators of arterial stiffness did not differ between patients and volunteers. Relative to volunteers (20 %), more Pompe patients had a history of hypertension , and the MAP was higher than in volunteers . This study shows that patients with non-classic Pompe disease have increased aortic stiffness and blood pressure. Whether this is due to glycogen accumulation requires further investigation. To reduce the potential risk of cardiovascular diseases, we recommend that blood pressure and other common cardiovascular risk factors are monitored regularly.Vascular abnormalities and glycogen accumulation in vascular smooth muscle fibres have been described in Pompe disease. Using carotid-femoral pulse wave velocity (cfPWV), the gold standard methodology for determining aortic stiffness, we studied whether aortic stiffness is increased in patients with Pompe disease. Eighty-four adult Pompe patients and 179 age- and gender-matched volunteers participated in this cross-sectional case-controlled study. Intima media thickness and the distensibility of the right common carotid artery were measured using a Duplex scanner. Aortic augmentation index, central pulse pressure, aortic reflexion time and cfPWV were assessed using the SphygmoCor® system. CfPWV was higher in patients than in volunteers (8.8 versus 7.4 m/s,  Pompe disease  is an inheritable lysosomal storage disorder caused by a deficiency of acid α-glucosidase that leads to glycogen accumulation in various body tissues, predominantly skeletal, cardiac and smooth muscle , when the patient was in supine position after 5 min of rest in a quiet and heat-controlled room. Hypertension was defined as a systolic blood pressure (SBP) > 140 mmHg and/or diastolic blood pressure (DBP) > 90 mmHg . Body mass index (BMI), which was calculated as body weight divided by height squared, was expressed as kg/m® device  according to previously described procedures   according to previously described procedures . Because cfPWV, PPc, AIx, ATr, distensibility and IMT were not normally distributed, the Mann–Whitney test was used to compare these outcomes between the total groups of patients and volunteers.Linear regression analyses were used to study cfPWV separately. First, univariate regression analyses were performed. Next, the regression coefficients with a p-value less than 0.05 or variables that were considered clinically relevant were analysed in a multivariate regression model using bootstrap estimation. The final multivariate model contained age, gender, MAP, heart rate and diabetes mellitus.We also performed a stratified analysis between patients and volunteers in three age groups: 20-39, 40-59 and 60+. To determine whether cfPWV was influenced by disease duration, treatment with ERT, and wheelchair or ventilator dependency, we also analysed cfPWV in separate multivariate regression models using bootstrap estimation. The final model for these analyses included four variables: age, gender, MAP and heart rate. The data were analysed using SPSS 20. A p-value of less than 0.05 was considered statistically significant.Table p = 0.005, Table p < 0.001). Thirty-nine per cent of the patients met the criteria for hypertension (SBP > 140 mmHg and/or DBP > 90 mmHg), versus 20 % of the volunteers (p = 0.001). At group level, patients with Pompe disease had a higher heart rate (75 beats per minute (bpm) (IQR 68-83)) than the volunteers (65 bpm (IQR 59-71), p < 0.001).In the past, more patients with Pompe disease than volunteers had been diagnosed with hypertension (p = 0.30).There were no differences in the occurrence of comorbidities such as diabetes mellitus or hypercholesterolemia. Seven patients with Pompe disease had a medical history of cardiovascular disease: four of them  had had a transient ischemic attack between the ages of 48 and 62 years); two male patients had developed atrial fibrillation at the ages of 37 and 64 years; and one female patient had had a myocardial infarction at the age of 74 years. Nine volunteers had a medical history of cardiovascular disease. This was not statistically different from the seven Pompe patients (p < 0.001). This difference was still present after adjustment for age, gender, MAP, heart rate and diabetes mellitus (p = 0.001). Subgroup analysis showed that while it occurred in the 40-59 years age group  and the 60+ years , it did not occur in the 20-39 years age group .As shown in Table n = 35) and those whose disease duration was longer than 15 years (n = 44) . Neither did it differ between patients treated with ERT (n = 64) and treatment-naïve patients (n = 15) . Similarly, cfPWV did not differ between wheelchair-dependent patients (n = 12) and ambulant patients (n = 62) , or between ventilator-dependent patients (n = 18) and non-ventilated patients (n = 56) .CfPWV did not differ between Pompe patients whose disease duration was shorter than 15 years (p < 0.001). Subgroup analysis showed that the distensibility was lower in patients with Pompe disease aged between 20 and 39 years than in volunteers (p = 0.03), but not in the other age-related subgroups.Table Figure We found that patients with the non-classic form of Pompe disease have increased aortic stiffness and blood pressure. These findings indicate clinical relevant involvement of the cardiovascular musculature in this group of Pompe patients.Glycogen accumulation in smooth muscle fibres and in the endothelial layer of arteries has been shown in morphological studies and autopsy reports of patients with Pompe disease . In Fabry disease, storage of glycosphingolipids takes place in vascular endothelial and smooth muscle cells, and in MPS I, accumulation of glycosaminoglycans in the connective tissue of the aortic wall impairs the formation of elastin and leads to changes in collagen formation (Nemes et al To the best of our knowledge, this is the first study to show that arterial blood pressure is increased in patients with Pompe disease. It is reasonable to assume that any structural changes in the blood vessels caused by the increased aortic stiffness would lead to higher blood pressure. Increased aortic stiffness and hypertension are both independent risk factors for cardiovascular disease and mortality (Mattace-Raso et al Although we expected Pompe disease to have a similar effect on the vascular structure of all arteries, and thereby to increase cfPWV and reduce distensibility, we found changes in carotid distensibility only in patients aged between 20 and 39 years. In those with high blood pressure and diabetes it has been reported that the aorta stiffened more than the carotid artery with age and with other cardiovascular risk factors such as increased body mass index and heart rate (Paini et al A strength of our study is that we used cfPWV, which is currently the gold standard for measuring aortic stiffness directly and non-invasively in a relatively large group of Pompe patients. A previous study that found increased aortic stiffness in a small group of patients with Pompe disease used transthoracic echocardiography, an indirect way of measuring aortic stiffness (Nemes et al Our study has some limitations. First, due to physical or temporary technical problems, measurements of aortic stiffness were not available for all subjects. However, as most of the patient data that were missing in the group of Pompe patients were those for the elderly and more severely affected patients, this would probably have led to an underestimation of the real difference in aortic stiffness between Pompe patients and healthy volunteers. Second, as this was a cross-sectional study, we do not know about the progression of aortic stiffness over time, or about the effects of ERT on aortic stiffness. Additionally, rather than measuring glucose or cholesterol in blood samples, we used a questionnaire to establish whether patients had a history of hypercholesterolemia or diabetes mellitus.In conclusion, patients with non-classic Pompe disease have increased aortic stiffness and blood pressure. To reduce the potential risk of cardiovascular diseases, we recommend that blood pressure and other common cardiovascular risk factors are monitored closely. Prospective studies should investigate whether ERT reduces aortic stiffness, or whether early treatment even prevents it.


Background. Chronic kidney disease (CKD) is a covert disease. Accurate prediction of CKD progression over time is necessary for reducing its costs and mortality rates. The present study proposes an adaptive neurofuzzy inference system (ANFIS) for predicting the renal failure timeframe of CKD based on real clinical data. Methods. This study used 10-year clinical records of newly diagnosed CKD patients. The threshold value of 15 cc/kg/min/1.73 m2 of glomerular filtration rate (GFR) was used as the marker of renal failure. A Takagi-Sugeno type ANFIS model was used to predict GFR values. Variables of age, sex, weight, underlying diseases, diastolic blood pressure, creatinine, calcium, phosphorus, uric acid, and GFR were initially selected for the predicting model. Results. Weight, diastolic blood pressure, diabetes mellitus as underlying disease, and current GFRt). Conclusions. Despite the high uncertainties of human body and dynamic nature of CKD progression, our model can accurately predict the GFR variations at long future periods. Chronic kidney disease (CKD) is a growing health problem worldwide  . The worIn recent years, early diagnosis of the disease, especially determining the appropriate time to apply medical treatments for CKD has received great attention among clinicians and researchers –11. ReseIn recent years, fuzzy intelligent methods, especially fuzzy expert systems, have been increasingly used to predict different diseases. It seems that employing this method along with the clinical tools for diagnosis of different diseases and conditions may drastically reduce diagnostic errors. Fuzzy expert technique is more accurate than machine learning techniques.fi), while error back propagation algorithm is used to update fundamental factors of the system [Adaptive neurofuzzy inference system (ANFIS) is a learning based system based on the neural networks concepts. The ANFIS network used in the present study is based on the model proposed by Jang et al. . This ise system , 20.2, renal replacement therapy (RRT) including dialysis or transplant is necessary for the patient survival. If GFR variation is predicted in a CKD patient, we can appropriately predict the time to reach GFR threshold value of 15 cc/kg/min/1.73 m2. In other words, the time for renal replacement therapy is predicted. In this study, speed of GFR decrease in CKD patients has been predicted based on the follow-up of the CKD patients during the study. To our knowledge, there has not been any efficient method proposed for predicting the timeframe of CKD worsening in individual cases [If we can model and predict the renal function worsening, we can effectively manage this disorder. In this regard, an appropriate parameter should be considered as the marker of disease worsening. The GFR is the only reliable parameter of the renal function and progression of CKD . The Cocal cases . Further2 for more than 3 months. The datasets were built using the clinical and laboratory data of different parameters. All the procedures of the study were approved by the ethics committee of Tehran University of Medical Sciences that completely coincide with the Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects. The written consent form was obtained from each patient to participate in the study.All the data of the present study were the clinical records of a cohort study of newly diagnosed CKD patients who were serially admitted to the Clinic of Nephrology, Imam Khomeini Hospital , during October 2002–October 2011. The inclusion criteria for CKD definition included small sized kidney in ultrasound images or GFR less than 60 cc/kg/min/1.73 mThe patients were divided into two groups according to the pattern of their adherence to follow-up schedule in the clinic. A total of 465 CKD patients were enrolled in the study. The test group consisted of 389 patients who continuously (at least every six months) were visited in the clinic. The control group consisted of 76 patients who did not regularly follow their visit schedule in the clinic, but their visits had lasted at least one year. The details of demographic data and clinical measurements of the patients are presented in 2, start of RRT, or patient death. All quantitative variables were used as continuous to have a better training of model. According to the nephrologists' opinions and the kidney function, ten variables were initially selected as influencing parameters on the GFR variations. These variables included age, sex, weight, underlying diseases, diastolic blood pressure (dbp), creatinine (Cr), calcium (Ca), phosphorus (P), uric acid, and GFR. They were considered as the inputs of the predicting model. Some of these variables did not necessarily show strong correlation with the output (GFRt+p). On the other hand, in ANFIS model, input number reduction increased the accuracy of prediction and better training of model. Therefore, only the more significant inputs were selected according to the level of their correlation with the output. Pearson correlation coefficients test was used to determine the most significant input variables to be introduced in the ANFIS model. The Pearson correlation coefficients test was used because of the continuous nature of the variables. t+p) at 6-month interval. Of the 10 inputs, only four inputs underlying disease, dbp, weight, and GFRt)( have an acceptable correlation with the output (GFRt+p). Therefore, just these four variables were selected for future processing and modeling. In the next step, the GFR values were predicted at 6-, 12-, and 18-month intervals using ANFIS network model. The real data recorded during a ten-year period were recorded at 6-month intervals. Therefore, the GFR values were predicted for three sequential 6-month intervals at 6-, 12-, and 18-month intervals. The GFRt+p) clustering technique to fuzzify variables. The membership functions are Gaussian.Genfis3 code in MATLAB was used to fuzzify input variables and to establish the rule base. Genfis3 uses fuzzy It is easy to establish a fuzzy rule base for ANFIS after fuzzifying variables using FCM clustering technique in Genfis3. The number of fuzzy rules is equal to the number of membership functions of input variables (11 functions). Thus, 11 fuzzy rules have been created in the rule base and used to estimate GFR values. Figures 2 in 154 patients (33.1%); 30–45 cc/kg/min/1.73 m2 in 215 (46.2%); and 15–30 cc/kg/min/1.73 m2 in 96 patients (20.7%).A total of 465 CKD patients were evaluated in the study, 277 of them were male. Diabetes mellitus was the underlying disease in 153 patients (33%). The GFR values ranged from 45 to 60 cc/kg/min/1.73 mAccording to the clinical dataset recorded from patients, fuzzy clustering of the four significant input variables is shown for the period of 6 months in Figures The rules in the rule base build a fuzzy inference system. After training, it was converted to a fuzzy inference system called ANFIS. ANFIS training was performed using MATLAB.t), Mean Absolute Error (MAE), and Normalized MSE (NMSE). Of them, the NMSE is preferred since it provides the normalized error ranged from 0 to 100 percent. The formulas for error criteria are expressed by  were selected. The accuracy of models was enhanced through eliminating other variables.p) should be selected so that is a tradeoff between time interval and the modeling error. The implementation of models and comparisons confirm that ANFIS provides highly reliable results for the all 6-, 12- and 18-month periods. Therefore, the ANFIS is considered as an acceptable model. The main reasons for preferring the ANFIS are as follows.The model provides the ability to model fuzzy variables. In this regard, the uncertainty can be appropriately modeled.The model is able to estimate and predict GFR, so that the error rate has been reduced to 4% in some cases.In addition to GFR prediction, the model produces a fuzzy database. The database shows the complex relationships between experimental inputs and GFR as simple linear models in different modeling environments. The transparency of GFR membership function in the ANFIS is the advantage of ANFIS compared to other models such as statistical model like regression or neural network like multilayer perceptron neural network.The present study was conducted in specific clinical situations (predicting the CKD progression) by integrated fuzzy modeling. This can be helpful in expediting medical applications. However, a question whether the numbers of time periods or lags considered for prediction affect modeling and error rate arises. It is noteworthy that a modeler always prefers to do forecasts for long periods, provided that the forecast error is not very high. Therefore, the time delay  to help physicians in making appropriate decisions about the time of renal replacement therapy. This system can take physiological parameters as input and predict the GFR values at future intervals. Using appropriate threshold value of GFR, nephrologists can effectively manage the CKD patients. To build such MDSS, it is necessary to complement the predicting model through evaluating the other possible influential parameters in kidney function.The results of modeling and forecasting by ANFIS networks show that the models have a reliable accuracy for all periods of 6, 12, and 18 months. Therefore, fuzzy model could be used to predict GFR with a high reliability. The main challenge in modeling the renal failure progression is the high uncertainties of the human body as the environment as well as high dynamicity of the disease. Statistical and machine learning based prediction models cannot effectively overcome these problems. However, the proposed model could significantly control these issues using neurofuzzy approach. Furthermore, our model can accurately predict the GFR values in long future period so that increasing the forecasting period to 12 and 18 months do not reduce the accuracy of the prediction model (4.88% NMAE). This model can be used in clinical practice.2 had faster decline of GFR (2.8 mL/min/1.73 m2) than those with baseline eGFR of <33 mL/min/1.73 m2 and a baseline serum phosphorus of >4.3 mg/dL in their retrospective study. Among patients without proteinuria, those younger than 67 years exhibited a significantly faster progression, which was even faster for the subgroup with diabetes. Among patients aged older than 67 years, females had more steady eGFR than men [One of the main concerns of clinicians has been the efficacy of CKD patients' supervision and regular follow-up on decreasing the speed of disease progression and prevention of its inevitable complications. Therefore, the use of efficient predicting model proposed in this study for decision support system in the field of kidney diseases as well as CKD management in a more quantitative manner may be an important strategy for reducing its burden. Using this model, it is possible to monitor the impact of each variable, routinely measured in CKD patients. Rucci et al. found that patients with proteinuria and a baseline estimated GFR (eGFR) of >33 mL/min/1.73 mthan men .Our results in comparison with the results of Tian et al.  on the sAn ANFIS based model was developed for modeling the renal failure progression and predicting the renal failure time. The model could accurately (>95%) predict the GFR for sequential 6-, 12-, and 18-month intervals. The main limitation of this study from the clinical point of view was that urine protein was not among the variables evaluated for the prediction of GFR in 6 to 18 months.