In the present study, the prognostic value of the VE/VCO2 slope was investigated in patients with CHF. A total of 258 subjects underwent symptom-limited cardiopulmonary exercise testing (CPET) and were divided into CHF  and control  groups. The cardiac-related events over a median 33.7-month follow-up period subsequent to the CPET were evaluated using receiver operating characteristic curve analysis. The VE/VCO2 slope was significantly different between the CHF and control groups (P<0.001). The area under the curve (AUC) for the VE/VCO2 slope in predicting cardiac-related mortalities in the patients with CHF was 0.670 (P<0.05), and the sensitivity and specificity of the VE/VCO2 slope were 0.667 and 0.620, respectively. The optimal threshold of the VE/VCO2 slope for predicting cardiac-related mortalities in patients with CHF was ≥39.3. The AUC for the VE/VCO2 slope in predicting cardiac-related hospitalizations in patients with CHF was 0.682 (P<0.05), and the sensitivity and specificity of the VE/VCO2 slope were 0.631 and 0.778, respectively. The optimal threshold of the VE/VCO2 slope for predicting cardiac-related hospitalizations in patients with CHF was ≥32.9. In conclusion, ventilatory efficiency decreases in patients with CHF. The VE/VCO2 slope is a strong predictor of cardiac-related mortalities in the patients with CHF analyzed.The minute ventilation/carbon dioxide production (VE/VCO Other indices, including peak oxygen consumption rate (VO2), anaerobic threshhold VO2 and the oxygen uptake efficiency slope, can be used to indicate the prognosis for cardiac-related events. Studies have shown that the VE/VCO2 slope exhibits a high prognostic value for cardiac-related events in patients with chronic heart failure (CHF)  , and theis >32.8 . The VE/2 slope in Chinese patients with CHF and to assess the prognostic value of the VE/VCO2 slope in this population.In China, the estimated prevalence of heart failure is 0.9%, and there are ~4 million patients with CHF. Furthermore, the number of patients is increasing annually . High mo2 and the LVEF was 0.38±0.09%. The cardiac function of the patients was classified according to the New York Heart Function Assessment (NYHA) as grades I–III   between August 2007 and May 2013. The inclusion criteria consisted of a diagnosis of heart failure  and evidI, n=56) . Among tIn addition to the CHF group, healthy volunteers were screened for inclusion in a control group. Volunteers were excluded if they had been diagnosed with a chronic illness or were receiving chronic medication; if they had any current health complaints, an abnormal physical examination (including a blood pressure of ≥140/90 mmHg) or abnormal results on the screening tests ; or if they were participating in regular exercise. A total of 129 healthy age-matched volunteers  met these criteria and were enrolled. The gender and body mass index (BMI) of the volunteers were also matched. Informed consent was obtained from all patients prior to recruitment in accordance with the protocol approved by the Ethics Committee of the Affiliated Tongji Hospital of Tongji University. The study was registered in the China Clinical Trial Registration Center (registration no. ChicTR-TRC-00000235).et al (3 - LVEDD3] + 0.6. The LVM was subsequently adjusted for body surface area (BSA) to obtain the LVM index (LVMI): LVMI (g/m2) = LVM/BSA.Echocardiography was performed on each subject using the GE Vivid™ 7 EchoPAC™ system  with a high-definition 3.2-MHz transducer. All data were measured by the same qualified physician. Standard M-mode and two-dimensional echocardiography, as well as Doppler blood flow measurements, were performed in accordance with the American Society of Echocardiography guidelines . Interveet al : LVM (g)2), VCO2 and VE. The anaerobic threshold was determined by the V slope  for assessments of cardiac-related mortality and hospitalization following the CPET via medical chart review. Any mortality or hospitalization that occurred as a result of cardiac dysfunction, as per the hospital discharge diagnosis, was regarded as an event. The most common causes of mortality noted were cardiac arrest, myocardial infarction and end-stage heart failure. The most common causes of hospitalization were decompensated heart failure and coronary artery disease.2 analysis were utilized to compare differences in the continuous and categorical variables, respectively. The NYHA grades were compared with a nonparametric rank-sum test. Receiver operating characteristic (ROC) and Cox regression analyses were employed to evaluate the predictive value of the VE/VCO2 slope for cardiac-related mortality and hospitalization. SPSS version 18.0  was used for the statistical analysis. A two-tailed P-value of <0.05 was considered to indicate a statistically significant difference.All continuous data are presented as the mean ± standard deviation. Categorical variables are reported as percentages. The Student’s t-test and χ2 was significantly lower in patients with CHF compared with controls (P<0.01). The VE/VCO2 slope was significantly higher for the patients with CHF as compared with that for the controls (P<0.01). The patients with CHF (n=129) were followed-up for a median period of 33.7 months , and 19 cardiac-related mortalities and 198 cardiac-related hospitalizations were recorded. The control group was followed up for a median period of 37.8 months  and no cardiac-related mortalities or hospitalizations were recorded.2 slope for cardiac-related mortalities and hospitalizations in patients with CHF. The area under the curve (AUC) of the VE/VCO2 slope for predicting cardiac-related mortalities was 0.670 (P<0.05), and the sensitivity and specificity were 0.667 and 0.620, respectively. The optimal threshold of the VE/VCO2 slope for predicting cardiac-related mortalities was ≥39.3 in the patients with CHF. The AUC of the VE/VCO2 slope for predicting cardiac-related hospitalizations was 0.682 (P<0.05), and the sensitivity and specificity were 0.631 and 0.778, respectively. The optimal threshold of the VE/VCO2 slope for predicting cardiac-related hospitalizations was ≥32.9 in the patients with CHF   . The sur2 and the VE/VCO2 slope during exercise are traditionally considered to be the major indices influencing the functional impairment and prognostic value. Exercise capacity, as reflected by peak VO2, has been consistently shown to be one of the most powerful prognostic markers in patients with CHF   . Furtherna et al , which una et al  indicate2 slope is a valuable prognostic indicator in Chinese patients with CHF.In conclusion, the present results indicate that ventilatory efficiency decreases in Chinese patients with CHF and support the proposal that the VE/VCO


Augmentation index, a marker of central wave reflection, is influenced by age, sex, height, blood pressure, heart rate, and arterial stiffness. However, the detailed haemodynamic determinants of augmentation index, and their relations, remain uncertain. We examined the association of augmentation index with vascular resistance and other haemodynamic and non-haemodynamic factors.Background information, laboratory values, and haemodynamics of 488 subjects  without antihypertensive medication were obtained. Indices of central wave reflection, systemic vascular resistance, cardiac function, and pulse wave velocity were measured using continuous radial pulse wave analysis and whole-body impedance cardiography.P < 0.001 for all), stroke volume  (P = 0.001 for both) and heart rate  (P = 0.049 and P = 0.036). When age, height, weight, smoking habits, and laboratory values were included in the regression model, the most significant explanatory variables for augmentation index in males and females, respectively, were age  and systemic vascular resistance  . In the final regression model, pulse wave velocity was not a significant explanatory variable for augmentation index, probably due to the high correlation of this variable with age (Spearman’s correlation ≥0.617).In a regression model including only haemodynamic variables, augmentation index in males and female subjects, respectively, was associated with systemic vascular resistance , pulse wave velocity   contains supplementary material, which is available to authorized users. Reflected pressure waves from the peripheral circulation, originating from the arterial branches and resistance arteries, augment central blood pressure (BP) at the aortic root level . AugmentDespite intensive research in the field of central wave reflection, the detailed determinants of AIx are still under debate. Naturally, there is a strong correlation between AIx and BP. AIx has shown to be higher among females when compared with males, and there is an inverse correlation between AIx and height , 10. ThiSince central wave reflection is influenced by arterial compliance, AIx is often referred to as a marker of arterial stiffness –19. HoweSystemic vascular resistance (SVR) is of foremost importance in defining BP and haemodynamics, but this variable is hardly ever determined in clinical practice and seldom even in research settings . Since tTaken together, there are still several unanswered questions regarding the determinants of AIx. In this study, we compared the role of SVR versus PWV as haemodynamic determinants of AIx by parallel measurements of these variables in 488 subjects.Subjects to this study on haemodynamics were recruited from the University of Tampere, Tampere University Hospital, occupational health care providers, and by the use of two newspaper announcements . Also, people enrolling in a long-distance running program for beginners at Varala Sports Institute were informed about the study. The responding subjects from all of the above sources were recruited. Both normotensive and hypertensive individuals were allowed to participate. Before acceptance to the present study, lifestyle habits, medical history, and family history for cardiovascular disease were documented. Exercise habits were recorded as the number of self-reported ≥30 min exercise sessions per week that caused shortness of breath or sweating. A medical examination by a physician, and routine laboratory analyses of hypertension were performed . By the Blood samples were obtained after approximately 12 h of fasting. A standard 12-lead electrocardiogram was recorded, and Cornell ECG voltage product was calculated. Plasma sodium, potassium, calcium, glucose, creatinine, cystatin-C, triglyceride, and total, high-density and low-density lipoprotein  cholesterol concentrations were determined by using Cobas Integra 700/800 or Cobas6000, module c501 . Blood cell count was analysed by ADVIA 120 or 2120 . Since creatinine values were within normal range, glomerular filtration rate was estimated using the Rule formula .Haemodynamics were recorded in a research laboratory by trained nurses. Study subjects were instructed to avoid caffeine containing products, smoking and heavy meals for at least 4 h prior to the investigation, whereas alcohol and heavy exercise were to be avoided for at least 24 h. Impedance cardiography electrodes were placed on body surface, tonometric sensor for pulse wave analysis on the radial pulsation to the left wrist, and an oscillometric brachial cuff for BP calibration to the right upper arm. The left arm (abducted to 90°) with the tonometric sensor rested on the level of the heart in an arm support . Cardiac output, stroke volume and SVR were indexed to body surface area .A whole-body impedance cardiography device  were used as explanatory variables for AIx , presented as mean ± SD, and n = 488; 239 men and 249 women) are summarized in Table n = 101), asthma (n = 25), hypothyroidism , migraine (n = 15), gout (n = 14), osteoarthritis (n = 11), gastro-oesophageal reflux (n = 9), depression (n = 8), panic disorder (n = 5), and coeliac disease (n = 4). The majority of the subjects (n = 309/488) were completely without medications . Although 101 subjects reported a history of dyslipidaemia, only 11 were using lipid-lowering medication.The features of the study population , whereas PWV (p < 0.001) and SVRI (p = 0.001) were higher in males. Apart from CI, all haemodynamic variables showed significant differences between the sexes   Fig. . A Spear33) Fig. .Fig. 3AsP < 0.001 for both), PWV (P < 0.001 for both), SVI (P = 0.001 for both) and HR  were significant explanatory variables for AIx. The contributions of the beta values of the variables  showed overlapping confidence intervals in this model. The overall R2 of the model was 0.381 in males and 0.317 in females . In female subjects, age, SVR, height, stroke volume and smoking were the explanatory variables for AIx (R2 = 0.621). Of note, PWV was no more a significant explanatory variable for AIx in this model, probably due to the high correlation of this variable with age , asthma (n = 10), gastro-oesophageal reflux (n = 3), hypothyroidism (n = 3) and osteoarthritis (n = 2). Thirteen subjects were on BP-lowering medication. The mean carotid-femoral PWV measured using applanation tonometry was 7.63 m/s, whereas the mean aortic-popliteal PWV using impedance cardiography was 7.64 m/s. The bias (PWV(impedance cardiography) – PWV(applanation tonometry)) and precision (SD of differences) between these two methods were 0.02 and 1.06 m/s, respectively, and the correlation between these two methods was very good , AIx was significantly associated with peripheral vascular resistance in addition to PWV. As stiffening of the arteries results in earlier wave reflection and augmentation of central systolic pressure, AIx has often been labelled as a direct marker of arterial stiffness [In the present study comprising a relatively large population , and between age and PWV (r = 0.572-0.626), but the association between AIx and PWV was less marked (r = 0.361-0.376). Thus, age-related changes in AIx cannot be entirely explained by increased arterial stiffness, at least when stiffness is evaluated by measurement of PWV. The present haemodynamic measurements were continuous and data capture lasted for 3 min, and the statistical analyses of each variable in individual subjects were based on the mean of approximately 180–190 cardiac cycles. Many previous studies utilizing pulse wave analysis have obtained haemodynamic values with a pen-like tonometric sensor from 10 consecutive heart beats [Although the present results indicate that SVRI is significantly associated with AIx, they show no causalities, and a reverse connection could also be possible. Increased pulsatile pressure has been suggested to damage the peripheral vasculature causing vascular remodelling with a subsequent increase in arterial resistance . We founrt beats , which irt beats . Our preWe found that AIx was significantly determined by both SVRI and PWV. However, SVR was a more significant determinant in a model, where demographic, metabolic and haemodynamic factors were comprehensively considered. The present results add up to the data showing that AIx is a marker of central wave reflections, the magnitude of which is influenced by arterial stiffness.AIx, augmentation index; BP, blood pressure; HDL, high-density lipoprotein; HR, heart rate; LDL, low-density lipoprotein; PWV, pulse wave velocity; SVI, stroke volume index; SVR, systemic vascular resistance; SVRI, systemic vascular resistance index


This study aimed to investigate renal outcomes and their predictors in biopsy-proven hypertensive nephrosclerosis (HN) patients and to compare clinico-pathological characteristics and prognoses between benign nephrosclerosis (BN) and malignant nephrosclerosis (MN) patients.Data for biopsy-proven HN patients were retrospectively analyzed. Renal survival rates and relationships between clinico-pathological characteristics and outcomes were assessed.2, and 0.80 g/24 h, respectively. BN and MN were found by renal biopsy in 55.2 % and 44.8 % of patients, respectively. At biopsy, MN patients were younger, and had higher median Scr and proteinuria levels, higher incidences of anemia, hypertensive heart disease and hypertensive retinopathy, and worse renal outcomes than BN patients. During a median follow-up period of 3.0 years, 36 patients (18.6 %) reached end-stage renal disease (ESRD), and the 5- and 10-year cumulative renal survival rates for HN patients were 84.5 % and 48.9 %, respectively. A decreased baseline eGFR, an increased baseline proteinuria level, anemia, increased percentage of global glomerulosclerosis and tubular atrophy and interstitial fibrosis (TAIF) were independent predictors of future ESRD.A total of 194 patients were enrolled; the mean age at biopsy was 43.8 years, and male gender predominated (82.5 %). The median duration of hypertension was 5.0 years, and the mean systolic and diastolic blood pressures were 195 ± 37 and 126 ± 26 mmHg, respectively. The median serum creatinine (Scr) level, estimated glomerular filtration rate (eGFR), and proteinuria level were 1.61 mg/dl, 49.6 ml/min/1.73 mThe clinico-pathological characteristics and prognoses were significantly different between the MN and BN patients. The renal outcomes of HN patients were independently associated with the baseline eGFR and proteinuria level, anemia, percentage of global glomerulosclerosis and TAIF.The online version of this article (doi:10.1186/s12882-016-0254-2) contains supplementary material, which is available to authorized users. Hypertension is a worldwide public health challenge due to its high prevalence, occurring in up to 26 % of the adult population , and theUsually, a diagnosis of HN is assigned based on clinical manifestations. Most studies of HN have focused on the clinical predictors of renal disease progression, including race , 5, blooWe analyzed data from adult Chinese patients with biopsy-proven HN to investigate the clinico-pathological characteristics and to evaluate the long-term renal survival rates and related risk factors for progression to ESRD. In addition, the clinico-pathological characteristics and prognoses between patients with BN and MN were compared.The clinical and renal histopathological data of patients with biopsy-proven HN in Jinling Hospital, Nanjing, from January 2003 to June 2013 were retrospectively reviewed. During the study period, the total number of native kidney biopsies was 31594, from which 411 patients (1.3 %) with a diagnosis of HN were identified. The inclusion criteria were as follows: (1) evidence of hypertension before the detection of proteinuria, hematuria and/or impaired renal function; (2) evidence of HN on renal histology; (3) the lack of any clinical, immunological or histological evidence of other glomerular disease or systemic disorder, such as glomerulonephritis or diabetic nephropathy, and the lack of any defined cause of thrombotic microangiopathy such as hemolytic uremic syndrome or thrombotic thrombocytopenic purpura; (4) an age of between 18 and 65 years; (5) a follow-up period of ≥1.0 year or reaching ESRD within 1 year; and (6) the availability of adequate biopsies (≥8 glomeruli). A total of 194 patients were included in this study.Indications for renal biopsies included proteinuria (>0.4 g/24 h), hematuria  and/or impaired renal function. Renal biopsies were performed after adequate blood pressure control was achieved.9/L), 24-h urinary protein excretion, microscopic hematuria, hypertensive heart disease, cerebrovascular disease, and retinopathy (using the Keith-Wagener-Barker criteria). The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Mean arterial pressure (MAP) was defined as the diastolic pressure plus one third of the pulse pressure. For each patient, the highest blood pressure before biopsy and the time-average blood pressure during follow-up, which was defined as the ratio of the area under the curve of MAP during follow-up to the duration of the follow-up  and compared using the Mann–Whitney-Wilcoxon test. Categorical variables were expressed as the number of positive cases (percentages) and compared using the Pearson χ2 test. The reproducibility of the pathology variables was evaluated using intraclass correlation coefficients (ICCs). Correlations between the pathology variables were analyzed using the Spearman test. The renal survival rates were estimated using the Kaplan-Meier method, and the log-rank test was used to assess the significance of differences in the Kaplan-Meier survival curves. The Cox proportional hazard model was used to explore the influences of the variables on the occurrence of ESRD. The pathological variables of poor reproducibility (ICC <0.40) were excluded from the model. The variables which were found to be significant (P < 0.05) by univariate analysis were included in the multivariate model using backward stepwise method. The assumption of Cox proportional hazards model were assessed using Schoenfeld residuals plots. All P values were two-tailed, and a P < 0.05 was considered statistically significant. All analyses were performed using SPSS 18.0 software for Windows  and R software (version 3.2.1).Normally distributed variables were expressed as the mean ± SD and compared using Student’s 2 , and the median proteinuria level was 0.80 g/24 h . During a median follow-up period of 3.0 years , 36 patients (18.6 %) developed ESRD . The mean age at the time of biopsy was 43.8 ± 4.1 years. The median duration of hypertension was 5.0 years . The mean SBP and DBP were 195 ± 37 and 126 ± 26 mmHg, respectively. The median Scr level was 1.61 mg/dl , the median eGFR was 49.6 ml/min/1.73 mMN was found in 87 patients (44.8 %), and BN was found in 107 (55.2 %). The comparisons of the clinical features between the BN and MN groups are presented in Table The patients with MN exhibited more severe renal injuries, as indicated by higher median Scr, mean serum uric acid and median proteinuria levels, and a higher incidence of anemia, compared with those with BN.P < 0.001) . The percentage of ischemic glomeruli was significantly higher in the MN group than in the BN group, but the percentage of global glomerulosclerosis did not differ between two groups. The percentage of TAIF was significantly greater in the MN group than in the BN group  and arterial (37 cases) involvement. Acute MN lesions were observed in 37.9 % of the patients in the MN group with arteriolar (33 cases) and arterial (1 case) involvement. Twenty-eight patients presented with both chronic and acute MN lesions. Only one case showed glomerular fibrinoid necrosis.Reproducibility was assessed statistically using ICCs, which are summarized in Table Correlations between the pathology variables are shown in Additional file P < 0.001; 33.3 % vs. 13.3 %, P = 0.004, respectively). Based on the vessel size, the involvement of both arterioles and arteries in chronic MN lesions and the involvement of arterioles in acute MN lesions were associated with ESRD.Table 2 increase, P < 0.001], baseline proteinuria , anemia , hyperuricemia , the percentage of global glomerulosclerosis , percentage of segmental glomerulosclerosis , percentage of TAIF , and the presence of MN  were associated with renal outcome , baseline proteinuria , anemia , percentage of global glomerulosclerosis  and percentage of TAIF  were independent predictors of renal outcome , 0.42, 95 % confidence interval (CI), 0.32-0.56 per 10 ml/min/1.73 mThe incidence of hypertension significantly increased from 1991–2009 in China , and acc2 vs. 49.6 ml/min/1.73 m2). The different incidences of MN in biopsy-proven HN may be associated with variations in ethnicity and patient inclusion criteria.Hypertension is categorized as benign hypertension and malignant hypertension, and the renal damage caused by these types of hypertension is classified as BN and MN. MN was observed in 44.8 % of 194 patients with biopsy-proven HN in the present study, which was nearly identical to that reported by Caetano et al. (43 %)  and was In the present study, the MN group was younger, displayed higher SBP and DBP levels, had higher median Scr, mean uric acid and median proteinuria levels, and had higher incidences of hypertensive heart disease and retinopathy at baseline than the BN group. In Caetano’s series , the MN In the MN group, 5 patients had elevated LDH and 1 patient had thrombocytopenia at the time of biopsy. In previous retrospective studies of patients with malignant hypertension, 27-44 % of patients have presented with thrombotic microangiopathy , 31, 32.Two pathological patterns based on the vascular lesion, BN and MN, have been described as HN. MN is characterized by fibrinoid necrosis (acute stage) and myointimal cell proliferation, usually with an “onion-skinning” appearance (chronic stage). In the present study, the incidence of chronic-stage MN lesions was as high as 94.3 % in the MN group, whereas that of acute-stage MN lesions was low (37.9 % in the MN group). Furthermore, most patients with acute-stage MN lesions coexisted with chronic-stage MN lesions. These findings are similar to those of previous reports , 34. TheThe patients with MN presented with more severe histological lesions than those with BN. In agreement with previous studies , 30, theHN can lead to ESRD, as shown in Table The clinical parameters showed significant prognostic value for patients with HN. Our study confirmed the baseline eGFR and proteinuria level as independent prognostic factors for progression to ESRD –13, 40. r = 0.643). Thus, the presence of MN predicted the risk for progression to ESRD in univariate Cox analysis, but lost its prognostic value in multivariate Cox analysis.Some pathological parameters were identified to predict renal outcome. TAIF was one of the prognostic factors identified in the present study that has also been reported as a factor for other renal diseases . Global The limitations of this study must be recognized. The major limitation in this study is its retrospective nature. We cannot rule out the influence of selection bias because some patients, especially those only very mild cases, were unwilling to undergo renal biopsy when HN was diagnosed according to the clinical criteria. In addition, data on patient deaths were incomplete and the candidate factors associated with death were not assessed in this study.Our results indicated that patients with MN and BN exhibited significantly different clinico-pathological characteristics. The MN group presented with more severe renal involvement and higher incidences of hypertensive heart disease and retinopathy, received more antihypertensive medications, and had poorer renal outcomes than the BN group. A decreased baseline eGFR, an increased baseline proteinuria level, anemia, increased percentage of global glomerulosclerosis and TAIF were associated with unfavorable renal outcomes in the patients with biopsy-proven HN.The study was approved by the Ethics Committee of Jinling Hospital. No additional administrative permissions were necessary in order to access the clinical and renal histopathological data.All data underlying the findings are within the paper and the supporting information file .


The present article intends to provide an update of the article “Focus on prevention, diagnosis and treatment of hypertension in children and adolescents” published in 2013  in this journal. This revision is justified by the fact that during the last years there have been several new scientific contributions to the problem of hypertension in pediatric age and during adolescence. Nevertheless, for what regards some aspects of the previous article, the newly acquired information did not require substantial changes to what was already published, both from a cultural and from a clinical point of view. We felt, however, the necessity to rewrite and/or to extend other parts in the light of the most recent scientific publications. More specifically, we updated and extended the chapters on the diagnosis and management of hypertension in newborns and unweaned babies, on the use and interpretation of ambulatory blood pressure monitoring, and on the usefulness of and indications for physical activity. Furthermore, we added an entirely new section on the role that simple carbohydrates (fructose in particular) and uric acid may play in the pathogenesis of hypertension in pediatric age. A few years ago we published in this journal an article on prevention, diagnosis and treatment of hypertension in children. During the last years there have been several new scientific contributions to the problem of hypertension in pediatric age and during adolescence. For this reason we felt the necessity to rewrite and/or to extend some parts of the previous article in the light of the most recent scientific publications.th, 95th, and 99th percentile at 15 days of age according to gestational age [th percentile is important, because it distinguishes patients that need closer diagnostic examination and sometimes pharmacological therapy from those with borderline blood pressure values for whom an accurate follow-up may be sufficient. Regarding blood pressure progression with time in the infants, reference values for systolic and diastolic blood pressure during the first 12 months of life are reported in Fig. The incidence of hypertension in healthy newborn infants is considered so low that blood pressure measurement is not recommended among the procedures to be performed during the first days of life; instead, the incidence appears to be higher about 1-2 %) in newborns hospitalized in intensive care units. Reference values are based on surveys on a limited number of cases such as the American Task Force -2 % in n of 43 stonal age  . Instead, when it is necessary to resort to medical treatment it is advisable to use intravenous administration in all the emergency situations in which it is beneficial to allow quick dose changes according to the blood pressure response; oral administration is indicated in less urgent cases or as long-term treatment after having succeeded in controlling the hypertension by intravenous therapy. Among the different classes of antihypertensive drugs, ACE-inhibitors are the most frequently used in newborns, especially when renal diseases are present [A wide variety of drugs is being used in the treatment of hypertension in neonates, but the indications provided by literature are exclusively based on isolated surveys or on expert’s opinions and no controlled studies on efficacy an safety are available. For these reasons the use of antihypertensive agents in this age range is generally not approved by the regulatory authorities  and should be considered off-label. There is not even a unanimous consensus on which blood pressure values would benefit from treatment, as it is not well known what are the harmful effects of persistently high blood pressure levels at this age. In any case it is appropriate to consider pharmacological treatment when blood pressure repeatedly exceed the 99 present . However present  have rec present . Diureti present . Arterio present , 30. TabHypertension is the main cause of myocardial hypertrophy with consequent fibrosis and dilatation; in adults such conditions are associated with cardiac and non-cardiac morbidity and untimely mortality –33 AntihIn recent years it has been established that primary hypertension, besides being controlled by an important genetic component, is influenced by environmental stimuli according to the concept of programming; i.e. the process by which a stimulus or a lesion to an organism during a critical period of its development determines long-lasting or even permanent effects. While the duration of the stimulus is certainly important, the period in life in which it occurs is even more critical. If common stimuli affecting blood pressure such as stress, diet, drugs, are present during intrauterine life or during the first year of life, they may alter the programming and determine permanent changes in blood pressure . There ith percentile [th and 95th percentiles) according to gender and height and to gender and age. The authors emphasize the necessity to more precisely identify the relationship between different ABPM patterns and the presence of organ damage. The new document more clearly explains a number of crucial points for the correct performance of ABPM in children; Our aim is to summarize and comment these points.In 2008 the first recommendations were published for the use and interpretation of 24-h ambulatory blood pressure monitoring (ABPM) in children and adolescents . As specrcentile . A bloodrcentile . In shorrcentile . In thisSeveral studies reported a correlation between blood pressure values observed in pediatric age and the presence of organ damage in adulthood, and in particular the presence of left ventricular hypertrophy, carotid intima-media thickening and increase in arterial stiffness –64. ABPMData provided by ABPM consist of the mean of systolic and diastolic blood pressure values recorded during 24 h and, separately, during waking hours (daytime mean) and during sleep (nighttime mean). The recording of nighttime blood pressure allows the determination of the presence of the physiological fall in blood pressure during sleep (dipping), which should be at least 10 % of the diurnal blood pressure mean. The absence of a nighttime fall in blood pressure and the presence of isolated nocturnal hypertension have been shown to be important prognostic factors in several forms of secondary hypertension, especially those due to renal damage –76. Anotth percentile (transitory hypertensives) may be at increased risk of presenting left ventricular hypertrophy [The American recommendations suggest to perform ABPM in children with elevated office blood pressure values in whom an excess reactivity to the measurements (white coat hypertension) is suspected, in order to confirm such possible diagnosis. However, as initial organ damage may already be present in subjects with white coat hypertension –80 in thertrophy . For theChildren who present normal office, but elevated ABPM blood pressure values are defined as having masked hypertension. Some studies suggest that masked hypertension in children is associated with early organ damage and that it may be a precursor of sustained forms of hypertension , 83. Forth but below the 95th percentile and that was substituted in the most recent recommendations by the term “high-normal blood pressure”. In the present document prehypertension is defined  should not be taken into consideration and all data lying outside the following intervals should be discarded :Once the 24-h systo-diastolic blood pressure tracing has been obtained, the data should be interpreted using the appropriate pediatric nomograms Tables , 8 and 9In pediatric age ABPM should not be used “routinely”. This test, can be extreme usefulness if used by skilled operators and if justified by specific questions . The use of ABPM is particularly helpful in children aged more than 10 years. In younger children, who often do not tolerate the examination, ABPM should be used in targeted cases and bearing in mind that, in this age group, office blood pressure values are lower than those found with ABPM, and that this phenomenon tends to attenuate over the years. A future goal regarding ABPM in children will be to obtain more reference data for different age ranges and different ethnicities. It is also important to perform studies that assess the association between ambulatory blood pressure values and organ damage, not only by considering mean values, but also by examining anomalies regarding pressure load and the absence of physiological nocturnal dipping. Finally, it would be extremely useful to carry out prospective studies that could verify if normalization of 24-h blood pressure values is or is not accompanied by a regression of pre-existing organ damage.Physical activity, be it playful and recreational or structured in organized sports, represents a fundamental cornerstone in the prevention and treatment of hypertension in pediatric age. This consideration, even though shared by all pediatricians and supported by broad evidence, is generally taken for granted and only briefly mentioned in the recommendations of the scientific societies dedicated to this subject. On the contrary, in the present update we dedicate a section to physical activity that is adequate and moreover proportional to our conviction that it is a primary and irreplaceable instrument in the prevention and treatment of hypertension in view of the well-known effects physical activity has on the pathogenetic mechanisms of hypertension. Furthermore, we will shortly deal with the legal aspects of the certifications for sports practice and the (few) contraindications for physical activity to be taken into consideration in children and adolescents with hypertension.The prevention of primary hypertension in children and adolescents is based on an intervention strategy on modifiable risk factors. Among these, the ones with the greatest impact are: overweight, diet, salt intake, sedentary behavior, bad sleep quality and cigarette smoking . Physical exercise may exert a possible effect on: overweight, sodium balance and bad quality of sleep, thus acting indirectly on the metabolic mechanisms involved in the development and maintenance of pressure increase, such as deposition and distribution of the fat mass, insulin resistance, activation of the sympathetic nervous system, sodium homeostasis, renin-angiotensin system, regulation of vascular function.Obesity is the main risk factor for hypertension in children and adolescents. A recent meta-analysis analyzed the effects of childhood obesity prevention programs on hypertension . The mosOn the average sodium intake in children and adolescents exceeds the recommended quantities . Physicavice versa [Duration of sleep is inversely correlated to cardio-metabolic risk, obesity and levels of physical activity in children , 95. Chice versa . Also thce versa . The amoce versa .The benefits of physical activity for the treatment of hypertension have been well documented for what regards hypertensive adults, both with and without obesity , 99. On Several scientific studies confirm that the level of physical activity is inversely proportional to mortality from cardiovascular causes both in men and women. This consideration holds true for hypertensive subjects as well, in whom the absence of physical activity increase the risk of cardiovascular diseases. It is well known that blood pressure control during physical activity is a complex process, involving increase in stroke volume and heart rate, changes in the peripheral vascular resistances and altered sympathetic tone. All these adaptations, always depending on one another, are related both to the type of physical exercise and to its intensity and duration. They are also affected by gender, with more marked changes in males compared to females, but also by the proportion between lean mass and fat mass. Furthermore it is necessary to distinguish physical exercise in two main types: dynamic and isometric (or static). The first type of exercise causes an increase in cardiac output associated with rapid increases in heart rate and systolic blood pressure (with slight decrease in diastolic blood pressure), but also with significant reductions in peripheral vascular resistance. Recordings have been reported hat show systolic blood pressure values up to 250 mmHg during treadmill exercise stress test in young healthy males . The secIn Italy, unlike what happens in the United States, in order to engage in any non-agonistic sports activity a medical certification is requested, that involves civil and penal responsibilities of the certifying doctor and that is regulated by specific decrees, in particular by the most recent changes described in the so-called Balduzzi decree . For obtIn this section we will deal with the relationship between blood pressure, simple carbohydrates (fructose in particular) and uric acid in pediatric age. As the metabolisms of these compounds are strongly interconnected, it is not easy to distinguish the specific role of each of them. Furthermore, they are also associated with parameters that characterize the metabolic syndrome, such as hypertriglyceridemia, low levels of HDL-cholesterol, hyperinsulinemia, type 2 diabetes mellitus, fatty liver, in addition to their role in the development and progression of renal disease.For the sake of clarity each compound is taken into consideration separately.This term comprehends both the monosaccharides glucose and fructose and the disaccharide sucrose, all used in the food industry, in homemade preparations or directly by the consumer and which are also the sugars naturally contained in honey, syrups, juices or fruit concentrates. One molecule of glucose bound to one of fructose by a glycosidic linkage form one molecule of sucrose, the common table sugar. In 2000 the dietary consumption of simple carbohydrates in the Unites States was found to amount to 72.6 kg/person/year and it has been calculated that about 40 % of this total was accounted for by sweetened beverages . This coFructose is the sugar that can be found in fruit, but in the present-day diet, the amount of fructose actually deriving from fruit is quite modest. An important proportion of the intake of fructose derives from sucrose, while another major source of fructose is represented by high fructose corn syrup (HFCS). This is an industrially produced syrup derived from corn starch, introduced in the seventies, which contains 55-60 % of fructose and is obtained by isomerization of glucose. These syrups are frequently used in the food industry for the production of various prepackaged foods that do not necessarily have a sweet taste, like crackers or ketchup, but are actually mainly employed in the production of sweetened beverages. Finally, currently fructose is also being used in several sweeteners. A moderate fructose intake, especially when deriving from fruit consumption, is well tolerated. What does cause quite a lot of concern, even though not yet shared by the public opinion, is an excessive fructose load as the human body does not envisage any system to regulate its metabolism. Fructose can be internalized by all types of cells, but the mechanisms of intracellular transport of this carbohydrate are most efficient in the liver and kidneys, and so these two organs are mainly involved in its metabolism. Unlike what happens with glucose, the intracellular use of fructose does not depend on any control system that considers the energetic state of the cell. As a consequence, abundant amounts of fructose induce an uncontrolled cascade synthesis of fatty acids, whereas equivalent amounts of glucose would not cause such effects . FurtherUric acid is produced during the breakdown of the purine bases adenine and guanine. A diet containing food at high concentrations of these compounds can bring about an increase in uric acid level in the blood, especially in the presence of minor metabolic dysfunctions in specific subjects. However, one should not forget the role that excessive fructose intake can have in increasing uric acid (see previous paragraph). Uric acid can exert negative effects even at concentrations that are lower than the ones provoking precipitation of urate crystals in the joints. In children and adolescents it is advised to attentively examine also uric acid levels that are at the upper limit of the normal range. The relationship between uric acid levels and blood pressure values was hypothesized many years ago, but lately research in this field has become quite strong, producing numerous data deriving from both animal and human studies, some with interesting results in pediatric age . In expehttp://www.sinu.it/html/pag/tabelle_larn_2014_rev.asp) affirm that the consumption of simple carbohydrates should not exceed 15 % of the total caloric intake, whereas the World Health Organization (WHO) limits this quote to only 10 % and suggests that 5 % would be ideally preferred (http://www.who.int/mediacentre/news/releases/2015/sugar-guideline/en). A recent study in Italian children of 0–36 months of age showed that as early as at six months of age only one third of the children presented a carbohydrate intake that was lower than 15 % of the total calories, while from 9 months on almost all children had an intake that exceeded this value [From the foregoing the consequences in terms of both prevention and dietary treatment of hypertension in children are quite clear. The recommended quantities of food intake for the Italian population (is value . Food wi


P < 10−05). The top GWAS result, rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations . Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs  were associated with decreased risk. Three SNPs  were present in three genes: CMTR1, TRIM24 and MAGI2. The CMTR1 mRNA transcript was significantly differentially expressed in nasal lavage samples from asthmatics during acute exacerbations, suggesting potential involvement of this gene in the development of this phenotype. We show that genetic variability may contribute to asthma exacerbations in patients taking ICS. Furthermore, our studies implicate CMTR1 as a novel candidate gene with potential roles in the pathogenesis of asthma exacerbations.Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population‐based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case–control study design, the association of each SNP locus with the outcome of asthma exacerbations , was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta‐analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations ( Asthma, a complex disease characterized by airway hyper‐responsiveness, airway obstruction, inflammation and airway remodeling, confers substantial global financial burden and is a significant source of increasing morbidity and mortality worldwide β2‐agonists (LABAs), up to 30% of individuals who adhere to controller therapy still respond minimally or not at all, and experience persistent symptoms that can lead to the development of exacerbations ST13ADRB2P2X7FCER2IL13Clinical treatment of asthma exacerbations consumes significant healthcare resources, and patients who experience severe exacerbations have more ED and ICU visits, more frequent and longer hospitalizations related to their asthma, increased numbers of lost school and work days, more frequent unscheduled physician visits, diminished quality of life, and increased mortality risk Although promising, these results do not entirely explain the heterogeneity of asthma severity despite ICS treatment, indicating that additional genetic and environmental risk factors are involved. In light of these findings, we have hypothesized that novel genetic loci contribute to the development of asthma exacerbations. In this study, we performed a genome‐wide screen of two independent asthmatic populations taking ICS, in an effort to identify pharmacogenetic predictors for asthma exacerbations.http://pgpop.mc.vanderbilt.edu/labkey/project/PGPop/begin.view).Demographic information for the populations investigated in this study is provided in Table http://PheKB.org) that was rigorously developed and validated at each site by chart review of 50 randomly selected patients. Using this algorithm, we selected Caucasian patients with a principal ICD‐9 diagnosis of asthma (493.xx), who had at least two clinical encounters related to their asthma on two different days, and who had a prescription for an ICS . Patients had initiated ICS treatment prior to the exacerbation event. We excluded patients with confounding diseases such as cystic fibrosis, chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary embolism, lung cancer, immunodeficiency, bronchiectasis, congestive heart failure, and other diseases. We also obtained patient demographic information, including age at enrollment and gender, for use as covariates in regression models.Both study populations were identified with an electronic algorithm  or wheezing (786.07) during the admission. If a patient had both a hospitalization and ED visit during the same time period, we only counted the hospitalization. We specified exacerbations as a binary variable (coded 0 or 1), where a value of 1 was coded if there was a record of at least one reported hospitalization or ED visit related to asthma over the year preceding the study visit for sample collection, while a value of 0 corresponded to a null report of exacerbations.P values among controls below 10−04 (64 SNPs). Five patients were excluded from BioVU for high autosomal heterozygosity (FDR <1%). The average genotyping completion rate for each patient was 99% for BioVU and 100% for PMRP. Prior to running the PCA‐adjusted GWAS, non‐independent markers, that is, those in approximate linkage equilibrium based on pairwise genotypic correlation, were pruned out using a window of 50 SNPs, a step size of 5 SNPs and r2 threshold of 0.5, resulting in a final dataset that included 806 patients (369 patients from BioVU and 437 patients from PMRP) and 237,726 common, independent SNPs.Whole blood samples were obtained from patients at each study site, and genomic DNA was extracted from the buffy‐coat fraction of the blood samples using the QIAamp DNA blood mini kit  according to the manufacturer's protocol. Exome array genotyping and analysis of array data was performed using Illumina's Omni2.5 Exome BeadChip  system at the Riken Center for Genomic Medicine (Japan). The samples from BioVU and PMRP were analyzed separately from one another. The software packages PLINK v.1.07 χ2 test, and a Bonferroni‐corrected genome‐wide significance threshold for all markers was set at 2.1 × 10−07 . A suggestive genome‐wide P value threshold of 1 × 10−05 was applied for screening of markers in the discovery stage, while a nominal P value threshold of 0.05 in the replication population was used to validate SNPs from the discovery set. A meta‐analysis of fixed effects was performed on SNPs common to both populations, and P values from the two GWA studies were combined using a weighted Z test P < 10−05), with one‐sided P values <0.05 in PMRP and meeting a joint P < 0.05 threshold, while also possessing concordant directions of effect in both populations, were considered significant.The R software package GenABEL limmalimma, and the significance of any differentially expressed mRNA was then assessed for the paired samples (post‐exacerbation vs. during exacerbation) using Welch's two‐sample t test, implemented in Bioconductor.The expression of mRNA in nasal lavage samples from children with asthma during exacerbations, and 7–14 days following exacerbation, has been described by Bosco, et al.The study population Table  includedP values deviate from what is expected for a null distribution, suggesting that some may reflect true pharmacogenetic associations with asthma exacerbations in ICS users. The genomic inflation factor λ was 1.03, indicating that minimal population stratification is present. The Manhattan plot  was significantly associated with increased risk of exacerbations in both BioVU and PMRP (Tables 2 and 3).We first performed individual GWA analyses in each population, specifying BioVU as the discovery population, and then conducted a meta‐analysis of the results. The corresponding quantile–quantile (Q–Q) plot of the discovery analysis Fig. A demonstP values for six SNPs sharing the same direction of effect in both populations were suggestive of genome‐wide significance  were potentially involved in the pathogenesis of asthma exacerbations, we examined the relative expression levels of these genes in patients experiencing exacerbations CMTR1 alone was significantly differentially expressed in paired nasal lavage samples obtained from asthmatic children 1–2 weeks following an acute exacerbation versus during the exacerbation event . Neither TRIM24  nor MAGI2  demonstrated significant changes in mRNA expression by exacerbation status.To further investigate whether any of the genes listed in Table CMTR1 is associated with an increased risk of asthma exacerbations. Our study identified six novel SNPs associated with differential risk of asthma exacerbations. In particular, we found that our top GWAS result, rs2395672, was present among the top‐ranked discovery SNPs and also replicated in PMRP  of capped RNA transcripts CMTR1 expression, along with other interferon stimulated genes, was associated with T‐cell mediated immune responses in human peripheral blood mononuclear cells (PBMC) CMTR1 may play an important role in regulating genes involved in immune responses to viral infections. Respiratory viruses are major triggers of exacerbations, and major cause of morbidity and mortality in adults and children with asthma CMTR1 is associated with an increased risk of exacerbations in genome‐wide genotype data from two independent asthmatic populations . While rs2395672 was not predicted to be an eQTL, three of the SNPs listed in Table P < 0.0001; CEU population): rs279728 , rs2691529 (CCNJ) and rs9303988 . However, the roles of these genes in asthma are unknown. Further genetic and molecular studies are needed to elucidate the function of these SNPs and genes in asthma pathogenesis.In addition to Our study has multiple strengths, with potential benefits for asthma therapy. First, we identified genetic risk factors associated with persistent exacerbations in patients taking ICS, which represents a severe, understudied asthmatic phenotype related to therapeutic outcomes. Using genetic information to help identify patients who are more likely to experience persisting asthma exacerbations, despite treatment with ICS, has significant value. Using this information, clinicians can consider alternative controller medications, and pursue additional asthma management interventions, such as increased outpatient follow‐up visits for patients who are more likely to experience exacerbations while taking ICS. Secondly, we evaluated samples and patient medical records from well‐phenotyped populations from the Vanderbilt and Marshfield biobank resources. Studying a population of patients, rather than subjects in a clinical trial, increases the generalizability of our findings to other asthmatic populations. Furthermore, we demonstrate the applicability of mining EMR data for patient selection, development of clinical outcome measures, and for guiding large‐scale genomic studies. In addition, our sample size of 806 patients is one of the largest used to evaluate the pharmacogenetics of ICS response. We anticipate that these results will inform future meta‐analyses and serve as replication for studies with larger cohorts.CMTR1.Despite the strengths of our study, several limitations should be mentioned. Foremost, none of our SNPs achieved genome‐wide significance. Second, the effect size estimates for these associations are small, although this is a common result for many complex trait GWA studies. Third, we only evaluated Caucasians, limiting generalizability of our study to a diverse population, but this may also be considered a strength as we were able to limit population stratification and thereby improve the interpretability of our findings. Fourth, inclusion of additional demographic data  could also help to determine whether the genetic associations with exacerbations are independent of these conventional risk factors for asthma exacerbations. Finally, the expression data were derived from an independent data set and not directly from the DNA of the biobank patients, although this could also serve as an independent validation of the mechanistic relevance of CMTR1, a novel candidate gene with a potential role in the pathogenesis of asthma exacerbations.In conclusion, genetic variability appears to contribute to asthma exacerbations in patients taking ICS. Our studies implicate several new loci, including


This study aims at comparing the very short-term effects of conventional and noisy (variable) pressure support ventilation (PSV) in mechanically ventilated patients with acute hypoxemic respiratory failure.Thirteen mechanically ventilated patients with acute hypoxemic respiratory failure were enrolled in this monocentric, randomized crossover study. Patients were mechanically ventilated with conventional and noisy PSV, for one hour each, in random sequence. Pressure support was titrated to reach tidal volumes approximately 8 mL/kg in both modes. The level of positive end-expiratory pressure and fraction of inspired oxygen were kept unchanged in both modes. The coefficient of variation of pressure support during noisy PSV was set at 30%. Gas exchange, hemodynamics, lung functional parameters, distribution of ventilation by electrical impedance tomography, breathing patterns and patient-ventilator synchrony were analyzed.P <0.05) and was associated with a reduced number of asynchrony events compared to conventional PSV (5 (0 to 15)/30 min vs. 10 (1 to 37)/30 min, P <0.05).Noisy PSV was not associated with any adverse event, and was well tolerated by all patients. Gas exchange, hemodynamics, respiratory mechanics and spatial distribution of ventilation did not differ significantly between conventional and noisy PSV. Noisy PSV increased the variability of tidal volume (24.4 ± 7.8% vs. 13.7 ± 9.1%, In the very short term, noisy PSV proved safe and feasible in patients with acute hypoxemic respiratory failure. Compared to conventional PSV, noisy PSV increased the variability of tidal volumes, and was associated with improved patient-ventilator synchrony, at comparable levels of gas exchange.NCT00786292ClinicialTrials.gov,  However, mechanical ventilation y (VILI) . It has y (VILI) . Early iPressure support ventilation (PSV) is one of the most common modes of assisted spontaneous breathing . During Noisy PSV can increase the variability of the respiratory pattern even when it is intrinsically reduced, as often seen in critically ill patients ,14. Howe2/FIO2) between 150 and 300 mmHg; total duration of mechanical less than 14 days; mechanical ventilation with biphasic positive airway pressure ventilation with at least 20% of minute ventilation corresponding to spontaneous breathing, or assisted mechanical ventilation with pressure support ventilation, at time of inclusion. Patients were excluded from the study if at least one of the following criteria was present: i) body mass index > 35; ii) esophageal disease; iii) neuromuscular disease; iv) instable thorax; v) pneumothorax; brain injury/increased intracranial pressure; vi) brain tumor; vii) agitation; viii) increased need for vasopressors or hemodynamic drug support, defined as dopamine or dobutamine dosage > 5 μg/kg/min, noradrenaline > 2 μg/kg/min, or use of vasopressin or milrinone; ix) chronic pulmonary disease; x) acute coronary insufficiency; xi) participation in other clinical trials in the preceding four weeks.This monocenter, randomized crossover study was approved by the institutional ethics review board of the University Hospital Dresden, Germany (EK 276112007) and registered at ClinicialTrials.gov (NCT00786292). Thirteen patients from the anesthesiological and surgical intensive care units of the University Hospital Dresden who were diagnosed with acute hypoxemic respiratory failure were enrolled in this study. Written informed consent was obtained from patient’s legal representative. Patients were included in the study if all of the following criteria were fulfilled: a) age between 18 and 75 years; b) ratio of arterial partial pressure of oxygen and inspired oxygen fraction  acute change of mental status; 2) diaphoresis; 3) exacerbated movement of intercostal muscles; 4) dyspnea; 5) paradoxical abdominal breathing; 6) respiratory rate >30/min or <6/min; g) arterial pH <7.30; 7) heart rate increase >20% compared to baseline, or <50/min, or >110/min (absolute); 8) mean arterial pressure (MAP) increase >20% compared to baseline, or <70 mmHg, or >110 mmHg (absolute).After finishing the study protocol, patients were switched back to their initial ventilator and therapy was continued at the discretion of the treating physician.All patients were monitored with electrocardiography, pulse oxymetry and invasive arterial blood pressure measurement according to the current standard of the intensive care units. Additionally, an esophageal balloon catheter  and electrical impedance tomography  were used for study specific measurements in case of the absence of contraindications to these procedures. Epidemiological data, current therapy and diagnosis were reviewed and captured using the intensive care units’ electronic patient data management system .T) of approximately 8 ml/kg ideal body weight. We chose that level since it represents the upper limit of VT still compatible with protective ventilation. The level of positive end-expiratory pressure (PEEP) and fraction of inspired oxygen (FIO2) were kept unchanged according the current therapy. The flow trigger was set at 3 L/min and cycling-off criteria at 25% of peak inspiratory flow in all patients, for both conventional and noisy PSV.All patients were already on assisted spontaneous breathing prior to the start of the study, and laid in the supine and semirecumbent 45° position. A commercial intensive care ventilator  was used for both PSV and noisy PSV. To perform noisy PSV, the ventilator was remote controlled by an external computer using the Dräger MediBus protocol as previously described . During 2/FIO2; arterial partial pressure of carbon dioxide (PaCO2)) were measured by point of care blood gas analysis . Hemodynamic variables (heart rate (HR), MAP) were recorded from the hemodynamic monitoring system. Airway flow signals were continuously recorded from the mechanical ventilator at a sample frequency of 125 Hz using the MediBus interface to calculate VT by means of numerical integration of the flow signal over time. Airway ) and esophageal pressures were measured, digitized and recorded using previously described routines [L) was calculated as the difference between airway and esophageal pressure. Pressure time product (PTP) was calculated by numerical integration of esophageal pressure and inspiratory time. The coefficient of variation of VT (CV VT) was calculated as the ratio of the standard deviation and the mean of VT. Patient-ventilator asynchrony was assessed from respiratory signals and quantified as described elsewhere [Gas exchange variables  (factors: group and region) with Bonferroni adjustment. All tests were performed using GraphPad Prism . Statistical significance was accepted at P <0.05.Values are given as mean and SD unless stated otherwise. Differences between noisy and conventional PSV were tested using paired 2/FIO2, PaCO2) , lactate)  Figure A-C, as wT was significantly higher with noisy PSV, as compared to conventional PSV  was higher than during conventional PSV .Pressure support levels (Δ pressure) and airway pressures  as well as pressure time product (PTP) and minute ventilation did not differ significantly between groups Figure A-F. CV VV Figure A. DuringSV Table . AccordiNoisy PSV was associated with a decreased number of asynchrony events compared to conventional PSV Figure B.T, mean respiratory rate (RR) and mean ratio of inspiratory time to total time of the breathing cycle (Ti/Ttot) did not differ significantly between assisted ventilation modes  noisy PSV was not associated with adverse events; 2) gas exchange, hemodynamics, mean respiratory variables and regional distribution of ventilation did not differ significantly between conventional and noisy PSV; 3) noisy PSV was associated with significantly higher tidal volume variability than conventional PSV; 4) noisy PSV was associated with improved patient-ventilator synchrony compared to conventional PSV.To the best of our knowledge, this is the first clinical trial on noisy PSV in patients. Since this was a safety and feasibility study, we focused on patients with mild to moderate acute hypoxemic respiratory failure, who were already mechanically ventilated with conventional PSV and had no major comorbidities. Also, we performed noisy PSV for a very short period of time in order to minimize potential risks. It is worth noting that none of the patients disclosed any sign of discomfort associated with the application of noisy PSV. Accordingly, no major changes in hemodynamics were observed during noisy PSV, suggesting that the new mode of assisted mechanical ventilation was well tolerated. Furthermore, noisy PSV was well accepted by the nursing and medical personnel.The use of assisted mechanical ventilation in acute respiratory failure has been intensively debated in recent years. Papazian and colleagues  showed tIt is worth noting that the transpulmonary pressure, which is the driving force leading to re-opening of collapsed lung regions, can be higher during assisted than controlled mechanical ventilation, especially in gravitationally dependent lung regions . Since dT in mechanically ventilated patients, is beneficial. A growing body of laboratory evidence suggests that variable mechanical ventilation modes aiming at imitating physiological respiratory variability improve gas exchange and respiratory system mechanics, and reduce ventilator-associated lung injury [It is well known that intrinsic variability in many organ systems is decreased during disease and the aging process ,22. Howeg injury ,6,9. Intg injury . On the g injury . Even thg injury .T[T values were lower, while the highest VT values were higher than during conventional PSV is not unexpected. Although the highest VT values during noisy PSV is outside the protective range of 4 to 8 mL/kg, they occur only rarely, due to the Gaussian distribution of the pattern underlying the new mode of mechanical ventilation. Furthermore, experimental evidence has shown that variable ventilation with extreme VT as high as 16 mL/kg and as low as 1.6 mL/kg occurring once every 20 to 30 minutes is associated with decreased ventilator lung histologic damage compared to non-variable ventilation with constant VT of 6 mL/kg [T values more protective than during conventional PSV also occurred in our population.Since the level of pressure support largely determines VT, the fin 6 mL/kg . In addiDifferent modes of assisted mechanical ventilation may lead to increased variability of respiratory variables in the clinical practice, most notably proportional assist ventilation (PAV) and neurally adjusted ventilator assist (NAVA). However, in contrast to PAV and NAVA, noisy PSV is able to restore the breath-by-breath variability of the respiratory pattern independent of a patient’s intrinsic respiratory variability. Thus, noisy PSV may increase the variability of the breathing pattern even in patients with reduced intrinsic variability, for example due to sedation or impairment of the respiratory center. Furthermore, noisy PSV does not require closed-loop mechanisms, rendering it technically simpler to implement and easier to handle compared to PAV and NAVA. Also, noisy PSV does not require insertion of esophageal catheters, making it attractive for patients with a contraindication for such catheters, and is devoid of movement artifacts.2 did not differ significantly between conventional and noisy PSV. There are several possible explanations for the lack of improvement in gas exchange: 1) the time period under noisy PSV was relatively short; 2) our patients had less severe hypoxemic respiratory failure than previous models of ARDS; 3) the hypoxic pulmonary vasoconstriction was blunted. In experimental models of ARDS, redistribution of pulmonary blood flow toward better aerated lung tissue has been observed during noisy PSV [In experimental models of the ARDS, noisy PSV led to an important improvement in arterial oxygenation compared to PSV ,10,25. IThe distribution of regional ventilation in our patients did not differ significantly during PSV and noisy PSV. This finding is in agreement with previous laboratory data of our group showing that noisy PSV does not result in recruitment of dependent lung zones ,10. HoweEven though the total number of asynchrony events was relatively low during both modes of assisted mechanical ventilation, it is somewhat surprising that patient-ventilator synchrony was higher during noisy compared to conventional PSV. Improved synchrony has been well documented during assisted mechanical ventilation modes that apply pressure support proportionally to the inspiratory effort, like PAV and NAVA ,27. HoweT. Thus, possible individual needs may have been overlooked. However, such coefficient of variation has been shown to deliver the best compromise between gas exchange and lung mechanics in a model of ARDS [This study has several limitations. First, it was designed as a randomized crossover study aimed at testing the safety and feasibility, as well as physiological effects, of the newly developed ventilator mode noisy PSV. Therefore, we did not obtain long-term information or clinically relevant outcome variables. Second, since most of our patients were classified as moderate acute hypoxemic respiratory failure, the effects of noisy PSV in severe or mild as well as lung-healthy patients remain to be determined. Third, we investigated a selected population of patients, mainly in the postoperative period, and our results cannot be extrapolated to other situations. Fourth, we did not compare noisy PSV with other modes capable of increasing the variability of the breathing pattern, namely NAVA and PAV. Fifth, noisy PSV was performed with a coefficient of variation of 30% in pressure support in all patients, which resulted in a similar coefficient of variation in V of ARDS . Sixth, Noisy PSV proved safe and feasible in a population of patients with mild to moderate acute hypoxemic respiratory failure in the short term. Compared to conventional PSV, noisy PSV increased the variability of tidal volumes, and was associated with improved patient-ventilator synchrony, at comparable levels of gas exchange.• Noisy PSV proved safe and feasible in patients with hypoxemic acute respiratory failure• Noisy PSV increased the variability of tidal volumes compared to conventional PSV• Noisy PSV was associated with better patient-ventilator synchrony than conventional PSVANOVA: Analysis of variance; ARDS: Acute respiratory distress syndrome; BE: Base excess; CV VT: Coefficient of variation of tidal volume; EIT: Electrical impedance tomography; FIO2: Fraction of inspired oxygen; HR: Heart rate; MAP: Mean arterial pressure; NAVA: Neurally adjusted ventilatory assist; PaCO2: Arterial partial pressure of carbon dioxide; PaO2/FIO2: Ratio of arterial partial pressure of oxygen and fraction of inspired oxygen; PAV: Proportional assist ventilation; Paw mean: Mean airway pressure; Paw peak: Peak airway pressure; PEEP: Positive end-expiratory pressure; PL: Transpulmonary pressure; PSV: Pressure support ventilation; PTP: Pressure time product; RR: Respiratory rate; SD: Standard deviation; Ti/Ttot: Ratio of inspiratory time to total time of the breathing cycle; VILI: Ventilator-induced lung injury; VT: Tidal volume.Drs. Gama de Abreu, Spieth and Koch were granted a patent on the variable pressure support ventilation mode of assisted ventilation (noisy PSV), which has been licensed to Dräger Medical AG .PMS contributed to the study design, data acquisition, data analysis, and to drafting the manuscript. AG contributed to the data acquisition, to revising the manuscript, and to drafting the manuscript. RH contributed to the data acquisition, data analysis, and to revising the manuscript. AB contributed to the data acquisition, data analysis, and to revising the manuscript. TB contributed to the data acquisition, data analysis, and to revising the manuscript. DS contributed to the data acquisition, data analysis, and to revising the manuscript. MR contributed to the data acquisition, data analysis, and to revising the manuscript. BG contributed to the data acquisition, data analysis, and to revising the manuscript. TK contributed to the data acquisition, data analysis, and to revising the manuscript. SJ contributed to the study design, and to revising the manuscript. PP contributed to the study design, and to revising the manuscript. TK contributed to the study design, and to revising the manuscript. MGA contributed to the study design, data acquisition, data analysis, and to drafting the manuscript. All authors read and approved the final manuscript.


Background. Severe burn trauma leads to an immediate and strong inflammatory response inciting cardiac dysfunction that is associated with high morbidity and mortality. The aim of this study was to determine whether transdermal application of nicotine could influence the burn-induced cardiac dysfunction via its known immunomodulatory effects. Material and Methods. A standardized rat burn model was used in 35 male Sprague Dawley rats. The experimental animals were divided into a control group, a burn trauma group, a burn trauma group with additional nicotine treatment, and a sham group with five experimental animals per group. The latter two groups received nicotine administration. Using microtip catheterization, functional parameters of the heart were assessed 12 or 24 hours after infliction of burn trauma. Results. Burn trauma led to significantly decreased blood pressure (BP) values whereas nicotine administration normalized BP. As expected, burn trauma also induced a significant deterioration of myocardial contractility and relaxation parameters. After application of nicotine these adverse effects were attenuated. Conclusion. The present study showed that transdermal nicotine administration has normalizing effects on burn-induced myocardial dysfunction parameters. Further research is warranted to gain insight in molecular mechanisms and pathways and to evaluate potential treatment options in humans. Look effects , 5. Elevα and IL-1β was inhibited directly via stimulation of the vagus nerve [There is a link between the central nervous system and immunologic mechanisms . The vagus nerve . Tracey us nerve , 11. Mecus nerve , 12. Nicus nerve . Nicotinus nerve , 15. Howus nerve –18. Addius nerve , 20.The present experimental study was designed to evaluate whether the transdermal application of nicotine is feasible and to evaluate potential beneficial effects on myocardial function after severe thermal injury.The university committee for the use and protection of animals and the Lower Saxony State Office for Consumer Protection and Food Safety approved the present study (study protocol # 05/1052). We created seven study groups with five animals each. This included one control group (CTRL). Microtip catheterization was done after 12 h or 24 h according to the respective treatment. That resulted in the additional six groups BURN 12 h and BURN 24 h, BURN + NICOTINE 12 h, and BURN + NICOTINE 24 h and SHAM 12 h and SHAM 24 h . The stuMicrotip catheterization of the left ventricle was carried out in experimental animals of the CTRL group without any previous treatment and in the BURN groups, BURN + NICOTINE groups, and SHAM groups 12 or 24 hours after experimental burn injury or sham trauma, respectively. The right carotid artery was surgically exposed by midline sternotomy. Using microsurgical techniques, a vascular incision large enough to induce the microtip catheter was created . The correct catheter position was confirmed by the appearance of the characteristic pressure curves and fluoroscopy imaging . Cardiacp < 0.05. The results are illustrated as means ± standard deviation (SD).We used Prism 5 software for statistical analysis  performing Analysis of variance (ANOVA) followed by Tukey's post hoc test. Statistical significance was set at The results of the microtip catheter for systolic and end-diastolic blood pressure measured 12 and 24 hours after burn trauma showed significantly decreased values for the BURN groups compared to the respective CTRL groups. For both physiological parameters analyzed, nicotine administration increased BP levels significantly compared to the untreated BURN groups except for end-diastolic blood pressure after 24 h. However, the baseline BP value of the control group was not completely reestablished by nicotine application.t = 12 h post burn injury, the mean values of the BURN group for the systolic blood pressure were significantly decreased compared with values measured in the CTRL group (p < 0.001). Nicotine partially normalized the effect of the burn trauma and lead to a systolic blood pressure of 106.3 ± 5.5 mmHg (p < 0.001). The same trend was found at t = 24 h after experimental burn procedure. The average systolic BP level of BURN 24 h group of 93.6 ± 5.1 mmHg was restored by nicotine application to 101.2 ± 8.6 mmHg (p < 0.001).After time p < 0.001). The nicotine administration resulted in a significantly higher end-diastolic pressure 12 h after burn trauma whereas the difference after 24 h was statistically not relevant .The results of the end-diastolic blood pressure are shown in Figures For the assessment of cardiac function during systole the duration of systole and contractility were measured in terms of maximum blood pressure rise per second.p < 0.001).The duration of the systole was on average 0.083 s in CTRL group . Interestingly, SHAM and BURN + NICOTINE groups displayed slightly higher values for cardiac contractility than CTRL animals .A significant increase of maximum blood pressure rise per second was observed when results of BURN groups were compared to BURN + NICOTINE groups  for the assessment of cardiac function during the diastolic phase of the cardiac cycle. With regard to the relaxation it is important that a higher negative value indicates a faster relaxation.The duration of diastole after burn injury was on average 0.96 after 24 h and 0.99 s after 12 h . Nicotine treatment induced a relaxation similar to sham animals .Animals subjected to burn trauma showed a markedly slower relaxation compared to their SHAM and CTRL counterparts (Figures Concerning the heart rate no significant differences were found 12 and 24 h after burn injury. The heart rate values ranged from 309.3 ± 3.2 beats/min (Intense burn trauma imposes life-threatening consequences to the victim. The multifactorial pathogenesis of burn-induced cardiac dysfunction has been extensively evaluated and described. This study was conducted to evaluate whether the known immunomodulatory effect of nicotine can improve cardiac function after burn trauma.Previous experiments of our research group were looking at direct electrical stimulation of the vagus nerve and we could prove attenuation of proinflammatory cytokine production after electrostimulation of the parasympathetic axis , 22. Addα and IL-1 thereby leading to normalization of blood pressure after a burn trauma [α and IL-1 and the systolic blood pressure [The present study showed that the administration of nicotine partially restores or normalizes decreased systolic blood pressure following burn injury. The results published by the groups of Sambol and Adams also revealed decreased systolic blood pressure at 24 hours after burn trauma . Howevern trauma . Thus, tpressure .β result in total peripheral resistance loss [β and thereby leads to an increased total peripheral resistance [α, IL-1β, and IL-6 are reduced which diminishes and, at best, abolishes their negative impact on cardiac contractility [The left ventricular systolic blood pressure has a direct relationship to the arterial blood pressure that is based on the intravascular blood volume, stroke volume, and the total peripheral resistance. Burn trauma affects all of these three parameters. Capillary leakage results in severe fluid loss and decreased intravascular blood volume; the decreased contractility of the ventricle generates reduced stroke volume and circulating proinflammatory cytokines such as IL-1nce loss , 27. Nicsistance . In addiactility . Stimulaactility , as alsoFor end-diastolic blood pressure levels burn injury also resulted in decreased levels. This parameter is essentially determined by the intravascular volume and contractile force of the left ventricle. So it may be deduced that the increase of the end-diastolic blood pressure of BURN + NICOTINE groups compared to BURN groups is a result of an impact on left ventricular function. This would be contradictory to the measurements of the other parameters of myocardial function in the present study, indicating a positive effect of nicotine administration on left ventricular function. A second explanation for the increase in end-diastolic blood pressure according to nicotine application is based on the posttraumatic intravascular volume. The large burn-induced volume loss followed to the capillary leak results in a decreased intravascular volume and consecutively in a decreased end-diastolic blood pressure. In this context, Ipaktchi et al. were able to show that immunosuppressive therapy after burn trauma reduces the capillary leakage significantly . This grThe BURN groups showed significantly higher values for duration of systole compared to the control group. This was accompanied by significantly decreased values for the maximum blood pressure rise per second and a shorter duration of diastole. Previous studies also revealed a burn-induced contractile dysfunction , 26. AddHeart rate showed no significant differences. This is consistent with the results of several authors , 26, 31.In the present study, we found that in a rat model of severe burn injury the trauma causes decreased blood pressure and a decrease in contraction and relaxation velocity of the heart. Adding on to the current knowledge base, further experiments will be done to explore the potent anti-inflammatory mechanisms of activation of the parasympathetic neural system. Our encouraging results that led to restoration of nearly normal myocardial function parameters have already prompted us to follow up on this path.Whether nicotine may also affect the lethality of severe burn trauma was not the subject of these investigations. This would be of great importance for further studies.


Introduction: Herbal medicines are traditionally prescribed to manage blood pressure.Objectives: We aimed to evaluate effect of sour tea pill containing the herb’s extract versus captopril on the treatment of hypertension.Patients and Methods: In our crossover clinical trial 20 patients were enrolled in the study and advised for life style modification then the participants were randomly divided into 2 groups. Sour tea pills was prescribed at a dose of 500 mg and captopril at a dose of 12.5 mg twice daily. In order to improve precision and final measurement, ambulatory blood pressure monitoring (ABPM) was performed both prior and after measuring the hypertension in 2 successive visits. After 6 weeks of therapy, the methods changed and 6 weeks later ABPM was performed three times . The 2 groups were merged together before data analysis.Results: Of the 20 patients, 13 (65%) were male and 7 (35%) were female. No significant difference of sex, age, and job was detected between 2 groups (P ≥ 0.05). Mean decreasing in systolic blood pressure was 7.75 ± 8.3 and 13.3 ± 16.1 mm Hg in the captopril and sour tea groups, respectively. Also, mean decline in diastolic blood pressure decreases was 2.15 ± 4.14 and 5.8 ± 7.8 mm Hg for captopril and sour tea groups, respectively. No side effect was observed in the sour tea pill group in the study.Conclusion: According to the effect of sour tea pill on decreasing blood pressure, without giving priority over captopril, sour tea pill containing the herb’s extract can be prescribed as an adjuvant therapy for lowering the prescribed dosage of captopril. In this study we indicated the antihypertensive effect of sour tea, while its priority over captopril is not proved. It could be administrated as a supportive therapy to minimize the dose of the drug used. Approximately one billion people worldwide are suffering from high blood pressure. Arterial pressure (hypertension) is known as the most common and main risk factor for public health in the developed countries, so that half of the population living in some communities are affected by this health problem. In more than 90% of cases, cause of the disease is unknown which is distinguishable under the title of essential or primary hypertension . Race, aDiuretics, beta-blockers, alpha-adrenergic inhibitors, angiotensin converting enzyme (ACE) inhibitors, vasodilators, angiotensin receptor (ARB) II blockers and calcium-channel antagonists are among the common drugs which are used for the treatment of hypertension and are associated with some complications such as headache, dizziness, heart and/or renal failure -8.Hibiscus sabdariffa) leaves have a remarkable effect on decreasing hypertension  for a 6-week period. To study the electrolyte imbalances and possible renal or liver abnormalities, the patients were examined at 3 treatment stages . In the presence of any complication at any stage, the patient was excluded from the study. The second stage was just commenced after the sixth week of treatment by the substitution of captopril for sour tea pills without washout period.The research followed the tenets of the Declaration of Helsinki. Informed consent was obtained and the research was approved by the Ethics Committee of Kashan University of Medical Sciences.t tests. The groups were also compared using Mann-Whitney U and t tests.Randomization was achieved through using randomized block. Finally, the selected patients were sent to drug stores all located in the neighborhood of the offices to receive their prescriptions. Two groups were merged together before data analysis. The data were analyzed using chi-square, Fisher exact and paired This study was designed to investigate the effect of sour tea on decreasing hypertension for the patients referring to nephrology and hypertension clinic of Kashan. The study included 114 patients of which 94 patients were excluded from the study . At last, 20 patients were studied in the 2 captopril and sour tea groups. All the patients were put in mild and median hypertension categories.P > 0.05). Mean age of the patients in the captopril and sour tea groups was 46.5 ± 12 and 53.3 ± 9 years, respectively. No significant difference of age and job between groups was observed (P > 0.05).As shown, 13 (65%) and 7 (35%) individuals were male and female, respectively. No significant difference was observed among the patients in terms of age . Mean heart rate in the captopril and sour tea groups was 78.9 and 81.8, respectively (P > 0.05).P > 0.05; As the results showed, mean body weight was 79.9 kg and 81 kg in the captopril and sour tea groups, respectively. Mean height was 170 and 169.88 in the 2 groups, respectively. As the findings show, no significant difference of body mass index between 2 groups was detected .Additionally mean systolic blood pressures at sleep time was 137.3 and 139.3 mm Hg, respectively, in the captopril and sour tea groups at the beginning of the study. In this study, no significant difference systolic and diastolic blood pressures at night time and day time between 2 groups was detected (P > 0.05).The result of this study showed an initial dipping in 40% and 70% of the captopril and sour tea groups, respectively, however the difference was not significant between the 2 groups (P > 0.05).Ocular problems were present among all of the patients (100%) in both groups, while evidence of cardiac disease was only found in one patient in the captopril group. In terms of ocular and electrocardiogram (EKG) abnormalities, no significant difference was found between the 2 groups . Diastolic blood pressure at sleep was 134.4 mm Hg initially that became 109.8 mm Hg (a 24.6 mm Hg decrease). Mean diastolic blood pressure at the beginning was 94.7 mm Hg which changed to 92.55 mm Hg after the treatment (a 2.15 mm Hg decrease). Diastolic blood pressure at sleep time was 86.75 mm Hg at the beginning which converted to 70.5 mm Hg (a 16.25 mm Hg decrease). A significant decrease in blood pressure indices was observed after the treatment . Considering systolic blood pressure at sleep time, it was 138.4 mm Hg at the beginning which changed to 125.5 mm Hg (a 12.9 mm Hg decrease). Mean diastolic blood pressure was initially 94.85 mm Hg which became 89.02 mm Hg after the treatment (a decrease of 5.8 mm Hg). Diastolic blood pressure at sleep time was 90.25 mm Hg at the beginning which became 80.5 mm Hg (a 9.75 mm Hg decrease). No significant decrease was observed in blood pressure indices after the treatment (P > 0.05) between the 2 groups. However, the decrease in systolic (P < 0.001) and diastolic (P < 0.05) blood pressure at sleep and day time was significant after the treatment . While in the sour tea group, 55% of the patients with primary dipping and 30% of the patients without primary dipping showed secondary dipping. The difference between the 2 types of primary dipping and secondary dipping was significant in the sour tea group (P < 0.05).As shown, 55% of the subjects in captopril group with primary dipping and 35% of the sour tea group without primary dipping revealed secondary dipping. The difference between the two dipping status was not significant in the captopril group (P > 0.05). However, of the 4 abnormal HDL-C tests in the sour tea group, 3 cases became normal after the treatment (P > 0.05). Low-density lipoprotein cholesterol (LDL-C) and triglyceride tests in both groups, and total cholesterol in the captopril group showed no significant difference  tests which 3 cases remained abnormal after the treatment that difference was not significant . Also, of the 10 abnormal AST cases in the captopril group, only one case was abnormal after the treatment which was not significant (P > 0.05). ALT changes were significant in both groups after the treatment (P < 0.05). Blood urea nitrogen (BUN), creatinine, and potassium test results were all normal in the two groups before and after the treatment  which 6 cases remained abnormal after the treatment that difference was not significant .The author would like to appreciate the Research and Educational Deputies of Kashan University of Medical Sciences.