Introduction: The present research investigated the effects of two different types of music on cardiovascular responses in essential hypertensive men in comparison with healthy men based on introversion and extraversion.Methods: One hundred and thirteen hypertensive men referred to Madani Heart Hospital in Tabriz completed the NEO-FFI Questionnaire and after obtaining acceptable scores were classified in four groups: introvert patients, extravert patients, introvert healthy subjects, and extravert healthy subjects (each group with 25 samples with age range 31-50). Baseline blood pressure and heart rate of each subject was recorded without any stimulus. Then subjects were exposed to slow-beat music and blood pressure and heart rate were recorded. After15 minute break, and a little cognitive task for distraction, subjects were exposed to fast-beat music and blood pressure and heart rate were recorded again.Results: Multivariate analysis of covariance (MANCOVA) test showed that extravert patient subjects obtained greater reduction in systolic blood pressure and heart rate after presenting slow-beat music compared with introvert patients . And extravert healthy subjects obtained greater reduction in heart rate after presenting slow-beat music compared with introvert healthy subjects (P= 0.036). However, there are no significant differences between introvert and extravert groups in systolic and diastolic blood pressure and heart rate after presenting fast-beat music.Conclusion: Based on our results, introvert subjects experience negative emotions more than extravert subjects and negative emotions cause less change in blood pressure in these subjects compared with extravert subjects. According to the World Health Organization (WHO) three in every ten deaths in 2011 were due to cardiovascular diseases.5 This phenomenon is one of the public concerns, and its prevalence is increasing globally, especially in developed countries.6 The WHO has estimated that out of every eight deaths worldwide, one is caused by hypertension, making hypertension the world’s third leading cause of death.7Hypertension is a phenomenon that has an important role in cardiovascular diseases.11 Introversion/extraversion is a dimension with a range between two extremes, and within this range, there are people that are neither extravert nor introvert. About the difference between introversion and extraversion, Eysenck suggests the concept that extraverts have fairly strong inhibitory processes, but poor excitability. Additionally, with robust nervous systems, they have a high capacity for accepting stimulation. Hence, extraverts’ brains react to stimuli more slowly and weakly, leading to inclination toward strong sensory stimulation. Introverts have strong stimulatory processes. In terms of the cortex, they are inherently more motivated, with brains that react faster and more strongly to stimuli, and have a low threshold for stimulation.14 The inhibition theory leads to a series of behavior predictions that have generally been experimentally confirmed. For example, extraverts are interested in listening to loud music, bright colors, smoking, and drinking.15Many studies have investigated the effects of psychological variables on physiological indices.18 Mood swings such as happiness, sorrow, anxiety, and anger may also be associated with change in physiological indices.19 Since results obtained about impact of mood on cardiovascular responses are inconsistent, it can be assumed that personal differences in other areas like personal characteristics could probably modulate the association of mood states with cardiovascular responses.Music plays an important role in social and working lives of the young and the old alike.This study is a quasi-experimental research. Study subjects consisted of 211, 30- to 50-year-old men including 113 male patients with essential hypertension confirmed by cardiologist, and 98 healthy men, matched with the patients for demographic variables. After completing the revised short form of NEO-FFI, and gaining an acceptable score (scores of 12 to 24 for introversion dimension and 48 to 60 for the extraversion dimension), the patients and healthy subjects were divided into two groups based on the introversion and extraversion. Each group consisted of 25 participants, totaling 100. In cases where the subjects were not able to understand the concepts, the researcher was clarifying with more information. Convenience sampling was used in this study. Those patients with arrhythmias were excluded from the study. Prior to completing forms, participants were informed of study objectives and explanations were given about the questions and that they could withdraw at any time they wished. Mood was created through slow-beat music (a piece by Mohammad Naeim titled Farah), and fast-beat music . Subjects were asked to be in a silent room and seated position to listen to the music using headset with same volume for both types of music. Before playing the music pieces, systolic and diastolic blood pressures and heart rate of participants were measured.Slow-beat music was played for three minutes, and afterward, their blood pressure and heart rate were measured. Between the two types of music, to eliminate confounding effects, participants rested for 15 minutes. During this time, they carried out a cognitive task (subtracting 7s from 100). Then, fast-beat music was played for three minutes, and again blood pressure and heart rate were measured.20The revised NEO-FFI questionnaire (short form), which contains 60 items and measures five personality traits: neuroticism, extraversion, agreeableness, openness, and conscientiousness. This tools is answered with the 5-point Likert scale . Every personality trait is assessed by 12 items. The content validity of the questionnaire was found by McCrae & Costa, and its reliability for personality trait of neuroticism was reported 90%, for extraversion 78%, for openness 76%, for agreeableness 86%, and for conscientiousness 90%.The digital arm sphygmomanometer: Participants’ systolic and diastolic blood pressures and heart rate were measured before playing the music and also immediately after induction using the digital arm sphygmomanometer.Headset device: Both types of music were played for the participants using this device.P values less than 0.05 were considered statistically significant.Central tendency indicators  were used in descriptive statistics. Multivariate covariance analysis (MANCOVA) test were used in inferential statistics for examining study question. Also, to ensure data normality and to comply with conditions of use of parametric statistics, Kolmogorov-Smirnov test was used. BOX test was used to verify equality of covariance parameters assumption, and levene’s test was used to examine assumption of equality of groups’ co-variances. To ascertain presence of a linear relationship between pretest and post-test scores, the regression slope test was used. Kolmogorov-Smirnov test revealed normal distribution of data (P>0.05). BOX test confirmed equality of covariance parameters, and their insignificant differences (P>0.05). Levene’s test showed equality of study variables variance, and their insignificant differences (P>0.05). Results of the regression slope test showed that there was no significant interaction between group and pre-test scores in none of the physiological indicators . In other words, regression slopes are homogeneous, and assumption of regression slopes was confirmed.In this study, extravert patients compared to introvert patients showed higher reduction in systolic blood pressure and heart rate after hearing soft music. Also, healthy extravert people compared to healthy introvert people showed higher reduction in heart rate after hearing soft music.21 Also, Gray in his theory, points out high sensitivity of Behavioral Approach System (BAS) people to rewarding signs, which somehow reflects extraverts’ early arousal component.22According to Eysenck theory, extravert people compared to introvert people showed more sensitivity to positive emotional stimulus. Thus, if this theory is right, extraverts compared to introverts are more responsive to positive emotional induction.23 In another research, Rafieinia et al. showed that in positive mood situations, extraverts compared to introverts (following music) had more reduction in systolic blood pressure, and in negative mood situations, heart rate of introvert people compared to extraverts had increased.24 De Pascalis et al. found different sensitivities of cardiovascular responses of extraverts and introverts to reward and punishment signs.25 Also, in relation to the moderating role of personality traits, studies by Hamer et al. could be cited, which reveal personality traits and fundamental characteristics significantly influence impacts of emotional stimuli on cardiovascular responses.26 According to results of a study by Yu et al. mood state of boredom is associated with main factors affecting blood pressure through sympathetic activity.19 There is also evidence that shows among the negative emotions, anger and worry have the strongest association with hypertension.27 Fredrickson et al. and Iribarren et al. argue that high levels of negative emotions are associated with higher reactivity of blood pressure to psychological pressure.29Harvey and Hirshman showed the moderating role of personality dimensions of extraversion and introversion in heart rate changes in response to aversive stimuli.30 Also, Russo and Zuckerman showed that extraverts and sensation seekers’ blood pressure was higher compared to people with different personalities.31Nevertheless, studies by Bartusske et al. did not show any distinct readiness in introverts and extraverts toward positive and negative stimuli.The present study had limitations that affect generalizability of its results. Firstly, the study was conducted only on the 30- to 50-year-old. Secondly, participants were selected from male population only, and finally, because the follow up of all patents were not possible, cross over design with switching the order of the music was not performed in this study.In connection, with Eysenck’s theory, since introvert people experience more negative emotions due to sensitivity to punishment and also overactive inhibitory system, and extravert people compared to introvert people are more sensitive to reward, it could be asserted that the results obtained about differences between these groups appear to be logical, as such, introvert patients showed less decrease in cardiovascular responses compared to extravert people. Therefore, introvert patients could use psychiatric counseling for better control of hypertension and prevention of blood pressure fluctuations during the day in addition to medication treatment.This study was reviewed and confirmed by the ethics committee of Tabriz University of Medical Sciences.The authors declare no conflict of interest in this study.


Kidney stone disease has been associated with reduced kidney function and chronic kidney disease (CKD). The objective of the study was to examine kidney function, body mass index (BMI) and the prevalence of cardiovascular disease, hypertension and diabetes in recurrent kidney stone formers.A cross-sectional, case-control study comparing measures of kidney function, BMI and comorbid conditions was conducted in 195 kidney stone patients aged 18 to 70 years with recurrent clinical stone events and 390 age- and gender-matched controls. Wilcoxon-Mann-Whitney, chi-square tests and analysis of covariance were used to compare serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) between the groups.2 in the stone formers and controls, respectively (p < 0.001). After adjustment for body size and comorbid conditions, the difference in SCr and eGFR between cases and controls remained highly significant (p < 0.001). The prevalence of CKD was 9.3 % among stone formers compared with 1.3 % in the control group (P < 0.001). Hypertension and diabetes were significantly more prevalent among the cases that also had higher BMI than controls.The median age of stone formers was 51  years and 108 (55 %) were males. Seventy patients (36 %) had experienced 2–4 clinical stone events, 41 (21 %) 5–10 episodes and 84 (43 %) more than 10. The median SCr was 75 (41–140) μmol/L in the stone formers and 64 (34–168) μmol/L in the control group (p < 0.001). The mean eGFR was 87 ± 20 and 104 ± 22 mL/min/1.73 mRecurrent kidney stone formers have a significantly lower level of kidney function and a markedly higher prevalence of CKD than age- and gender-matched control subjects. The observed deleterious effect of kidney stones on kidney function appears to be independent of comorbid conditions. Kidney stone disease is a common chronic disorder associated with painful stone episodes, lost work days and significant health care costs , affectiAlthough monogenic causes of nephrolithiasis frequently result in ESRD , the relThe objective of this study was to compare kidney function, body mass index (BMI) and the prevalence of cardiovascular disease, hypertension and diabetes in a well-characterized population of Icelandic patients with recurrent clinical stone events and an age- and gender-matched control group from the general population.This was a cross-sectional, case-control study of 195 adult patients aged 18 to 70 years with recurrent kidney stone disease. A written informed consent was obtained from all participants in the study. The study was approved by the National Bioethics Committee of Iceland (NBC 03-002-V3) and the Icelandic Data Protection Authority.Patients with confirmed recurrent clinical stone disease were recruited from two sources, the Kidney Stone Prevention Clinic at Landspitali – The National University Hospital of Iceland (LUH) in Reykjavik and the Icelandic Kidney Stone Registry (IKSR) which was established in 2008 in conjunction with a nationwide study on kidney stone disease [All patients attending the LUH Kidney Stone Prevention Clinic from December 2009 to January 2013 were eligible for participation in the study. Records of all 144 patients who attended the clinic during this period were reviewed. Of 99 patients who met the inclusion criteria, 95 agreed to participate. To increase the sample size, it was decided to also include in the study patients from the IKSR with a history of more than 2 clinical stone events and a documented stone episode after January 1, 2002. Of a total of 287 eligible IKSR cases, 124 individuals residing in the greater Reykjavik area were invited to participate. Of these, 101 accepted the invitation; 16 did not reply and 7 declined. Hence, a total of 195 patients with recurrent kidney stone disease were included in the study.www.landlaeknir.is).The presence of renal disorders other than kidney stone disease was excluded by self-report (interview) and thorough medical record review in all the cases, and by searching the medical information systems at LUH for all ICD-9 and ICD-10 codes suggestive of a specific kidney disease. The above strategy led to the exclusion of one patient with IgA nephropathy who developed stones in a transplanted kidney, leaving the total number of cases at 195. All study subjects were interviewed by two of the investigators and underwent a brief physical examination which included the evaluation of height, weight and blood pressure. Current medication use was recorded. To compare kidney stone patients with the general population, a control group was drawn from a cohort of 1,630 community-dwelling subjects aged 29–87 years, who participated in a cross-sectional study of bone health performed in Reykjavik in the years 2001–2003 . The par2. Two patients who only had a single SCr value available obtained during an acute stone event were excluded from the kidney function analysis along with their corresponding controls. Only a single SCr measurement was available for each control subject. All SCr values were IDMS-standardized and measured at the clinical biochemistry laboratory at LUH.All available SCr levels of kidney stone cases were obtained from the electronic medical record system at LUH, yielding a total of 3,320 values. SCr measurements obtained during clinical stone episodes were excluded as such events may cause acute kidney injury. The eGFR was calculated by the MDRD study equation using the lowest available SCr value within the last year of observation or SCr measured at least 3 months after a documented clinical stone event. CKD was defined as eGFR < 60 mL/min/1.73 mResults of stone analysis were retrieved from medical records and all available medical imaging reports were reviewed in order to differentiate radiopaque from radiolucent stones. Stones visualized on a plain film of the kidney, ureters and bladder were considered radiopaque and were classified as calcium-containing stones.Information on comorbid conditions was obtained through medical history reported by the stone patients and the controls, review of their medical records and/or by searching for the appropriate ICD-9 and ICD-10 diagnostic codes for both cases and controls in the electronic patient information system at LUH. Hypertension was defined as a history of hypertension diagnosed by a physician and/or treatment with antihypertensive medications. Diabetes was defined as a history of a physician diagnosed diabetes and/or treatment with antidiabetic drugs. Cardiovascular disease was defined as evidence for coronary artery disease, cerebrovascular disease or peripheral vascular disease by ICD-9  and ICD-10 (I20-I25 and I60-I79) diagnostic codes suggestive of these disorders. The presence of cardiovascular disease was further confirmed by review of individual medical records.Data are presented as mean ± standard deviation for normally distributed continuous variables and median (range) for continuous variables that are not normally distributed. Wilcoxon-Mann-Whitney, chi-square and Fisher’s exact tests were used to compare stone formers with controls and analysis of covariance (ANCOVA) to compare the two groups with respect to SCr and eGFR, adjusting for BMI, hypertension, diabetes and cardiovascular disease which may affect the outcome variables. The same methods were used to compare a subgroup of patients with calcium stones with their corresponding control subjects. Spearman’s correlation coefficient was used to correlate the number of clinical stone events with measures of kidney function. Statistical analysis was performed with the computer software SPSS version 11 .Characteristics of the 195 recurrent kidney stone formers are outlined in Table 2 in the stone formers and controls, respectively (p < 0.001). The prevalence of CKD was 9.3 % among stone formers compared with 1.3 % in the control group (P < 0.001). All cases with CKD had stage 3 disease and no difference between men (9.4 %) and women (9.2 %) was observed (p = 0.96). The number of clinical stone events and/or surgical stone removal procedures did not correlate with either SCr or eGFR. The prevalence of hypertension was significantly higher among cases than controls (p = 0.003). The distribution of BMI among stone formers was also significantly different from the general population in the year 2011, as 34.4 % of stone formers had BMI > 30 kg/m2 compared with 21.0 % of individuals in the general Icelandic population and 19.5 % of the control subjects (p < 0.001).Table Diabetes was more common among the cases, 7.7 % vs 3.1 % (p = 0.02), whereas the prevalence of cardiovascular disease between the two groups was similar. After adjustment for body size and comorbid conditions, the observed difference in eGFR and SCr between cases and controls remained highly statistically significant  as shown in Fig. A separate analysis was carried out for a subset of calcium stone formers and their respective controls Table . Eight oOf the 18 patients with confirmed radiolucent stones, 2 patients with adenine phosphoribosyltransferase (APRT) deficiency were excluded. Of the remaining 16 patients, 7 (44 %) had CKD compared with none of the corresponding control subjects (p < 0.001). The prevalence of CKD was also significantly higher among the patients with radiolucent stones compared with calcium stone formers (p < 0.001).In the present study, we found a significantly lower level of kidney function and a markedly higher prevalence of CKD in patients with recurrent kidney stone disease than in age- and gender-matched control subjects. Nearly identical results were observed in the subset of idiopathic calcium stone formers. Moreover, kidney stone disease associated with obesity, hypertension and diabetes but not with established cardiovascular disease. The observed deleterious effect of stone disease on kidney function was independent of these comorbid conditions.Adverse renal outcomes, ranging from modest reduction in kidney function  to estab2 is expected to be low [In our study, approximately 9 % of all kidney stone patients and 6 % of calcium stone formers had CKD, which is approximately 6 to 7 times higher than in the control group. These results contrast with findings of other recent studies showing stone formers to be at an approximately twofold risk of CKD , 12, 13 o be low . The exco be low . HoweverThe degree of kidney injury associated with nephrolithiasis has been reported to vary for different stone types. We observed a significantly worse renal outcome in patients with radiolucent stones compared with other types of kidney stones. In the aforementioned study by Worcester et al., stone type was predictive of the level of kidney function which was lowest in patients with cystinuria followed by uric acid stone formers . The invThe pathogenesis of CKD in patients with kidney stone disease likely involves multiple different pathways , 20. ObsIn our study the prevalence of obesity, hypertension and diabetes was higher in stone formers than in the control group. The increased prevalence of these features of the metabolic syndrome in stone formers has previously been reported , 15, 25.Strengths of the current study include the well-defined study population of recurrent stone formers and high participation rate. In addition, by using the lowest SCr in the last year of observation for each patient and excluding from the analysis those who did not have a follow-up SCr measurement available after an acute stone event, we may have avoided an overestimation of CKD prevalence in stone formers. Moreover, cases with another known underlying cause of CKD were excluded from the study sample and two age- and gender-matched subjects were used to control for age-related decline in kidney function. Furthermore, since all emergency and inpatient care in the greater Reykjavik area is centralized at a single institution, complete medical records were available for all cases and controls allowing the assessment of all major stone events and significant comorbid conditions. Finally, as the study participants were almost exclusively non-Hispanic Caucasians our results are likely to be generalizable to the white population living in Europe and North America. The main limitations of the study are a relatively small sample size and the lack of information on stone composition in a significant number of study subjects. Other limitations include potential sources of bias related to ascertainment of variables known to affect kidney function and its estimation. However, by excluding stone patients with other underlying kidney diseases and SCr values obtained during stone episodes and by using the lowest SCr available in the last year of observation for each patient, we believe we have avoided overestimation of CKD. To the contrary, the prevalence of CKD in kidney stone patients may have been underestimated. Finally, the definition of a clinical stone event as acute flank pain associated with hematuria without confirmation by imaging can be considered a limitation. However, the fact that all patients included in the study had recurrent kidney stone disease confirmed by a physician and a number of imaging studies carried out during the course of their disease makes other diagnoses unlikely.Patients with recurrent kidney stone disease experience a decline in kidney function over time and have a significantly higher prevalence of CKD than age- and gender-matched control subjects. Furthermore, the negative impact of stone disease on kidney function is greatest in patients with radiolucent stones. Although obesity, hypertension and diabetes were more frequent among patients than controls, the observed reduction in kidney function and the higher prevalence of CKD appears to be independent of these comorbid conditions. Recurrent stone formers should receive care and follow-up in a multidisciplinary kidney stone clinic. Prospective long-term outcome studies are needed to better define the association between kidney stone disease and adverse renal outcomes.


A high prevalence of abdominal obesity was observed. Predictors of increasing WC were gender, age, FPG, and WHR.Type 2 diabetes mellitus (type 2 DM) has become a disease of public health concern worldwide. Obesity and elevated blood pressure have been shown to be comorbidities of type 2 DM. In this cross-sectional study in Tamale, Ghana, we determined the prevalence of abdominal obesity among type 2 DM patients. Furthermore, we examined the demographic, clinical, and anthropometric predictors of increasing waist circumference in this population. Three hundred type 2 DM patients attending the outpatient diabetes clinic of the Tamale Teaching Hospital, Ghana, were recruited for the study. Waist circumference (WC) and hip circumferences were measured appropriately. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) and fasting plasma glucose (FPG) were taken from the personal health record files of patients. Demographic data were obtained. Pearson correlation and multiple linear regression models were employed to identify predictors of increasing WC. The prevalence of abdominal obesity was 77.0% and was significantly higher in women than in men. A positive correlation was observed between waist-to-hip ratio (WHR) and WC ( Diabetes especially diabetes mellitus (DM) has become a disease of concern for both developed and developing countries , 2. In aType 2 DM has been shown to be associated with obesity . AbdominWith contrasting prevalence, severe complications, and public health significance, a study on the prevalence of abdominal obesity and its predictors in type 2 DM patients are remarkably scarce. Understanding the burden of abdominal obesity and its associated factors is pertinent in guiding diagnosis, management, and prevention of DM in sub-Saharan Africa.The objective of this study was to determine the prevalence of abdominal obesity (measured by WC) in a sample of type 2 DM patients. Furthermore, we examined the demographic, clinical, and anthropometric determinants of increasing waist circumference in this same sample.Three hundred (300) previously diagnosed diabetes patients attending the diabetes clinic of the Tamale Teaching Hospital in Tamale, Ghana, were recruited for this cross-sectional study in 2013. As described elsewhere , all preParticipants aged ≥ 30 years, who have clinical determined type 2 DM based on the WHO criteria , and whoParticipants aged < 30 years and pregnant and lactating mothers were excluded from the study. Also participants with a history of heart failure, type 1 DM, myocardial infarction, acromegaly, hypothyroidism, hypogonadism, and any other chronic diseases, patients on prolonged steroid use, and those who were on active drug treatment for obesity at the time of admission were excluded from the study.Anthropometric measurements of waist and hip circumferences were taken. Waist circumference (WC) was measured midway between the inferior angle of the ribs and the suprailiac crest . Hip cir−1 [Clinical variables such as systolic blood pressure (SBP) and diastolic blood pressure (DBP) and fasting plasma glucose (FPG) values were taken from the personal health record files of the diabetic patients. Elevated blood pressure denoted a mean BP ≥ 140/90 mmHg and/or documented antihypertensive treatment . Impaire−1 . Hypergl−1 . IFG andhttp://www.graphpad.com) and the PASW statistics 18 for Windows. Data are expressed as mean and SD. Continuous data were analyzed using Student's t-test whilst categorical variables were analyzed using Fisher's exact test using GraphPad Prism version 5. Pearson correlation coefficient was used to test the relationship among the various parameters. A Forward:LR method of multiple linear regression models was used to determine the predictors of WC. All correlation and multiple linear regression analyses were done using PASW statistics 18 for Windows. In all statistical tests, a value of P < 0.05 was considered significant.All data were entered into Microsoft Excel 2007 and analysed using GraphPad Prism version 5 . Average systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the participants were 122.8 ± 16.16 mmHg and 84.5 ± 13.83 mmHg. Men had higher mean SBP (P = 0.015) and DBP (P = 0.001) than women. Over 70% of both men and women were found to have uncontrolled diabetes. Among the participants with uncontrolled diabetes, 29.9% (n = 69) had impaired fasting glycaemia and 70.1% (n = 162) had hyperglycaemia. Significantly (P = 0.008), the mean age of the women (57.22 ± 12.32 years) in this study was higher than men (52.83 ± 10.85 years).Mean waist circumference was found to be 95.99 cm and significantly higher in women than in men. The prevalence of abdominal obesity was found to be 77.0% and significantly higher in women than in men , age , and gender .As seen in b = 0.43, P < 0.01), age , and FPGL  were significant predictors of WC. The model explained 48% of the variance in predicting WC. DD did not significantly predict WC.The multiple linear regression models in This cross-sectional study from Tamale, Ghana, among type 2 DM patients attending an outpatient clinic shows a high prevalence of central obesity and a relatively low prevalence of elevated blood pressure. Parameters that significantly predicted increasing waist circumference were gender, age, FPG, WHR, and WC.Evidently, the prevalence of abdominal obesity was found to be 77.0%. This is higher than the central obesity prevalence of 31.2% reported among an apparently healthy population of civil servants in Tamale, Ghana . Our finThe prevalence of elevated BP was found to be 19.0% in this diabetic population. This is lower than the 63.0% reported among diabetes patients in Kumasi, Ghana , 54.2% aIn a univariate analysis, females were severalfold at risk of developing abdominal obesity. This was confirmed by our correlation and multiple linear regression models in which the female gender strongly predicted WHR and WC in a positive direction. Several studies have reported findings that are in agreement with the association between the female gender and obesity among diabetics –33. A siβ = 0.40, 95% CI = 0.40–0.64, P < 0.01) [In identifying factors that influenced WC, our correlation and multiple linear regression models revealed WHR, age, and FPG as independent predictors of WC in a positive direction. As reported in several studies, a positive relationship was found between age and WC making age a strong predictor of WC ( < 0.01) , 37–39.In agreement with our findings, WC significantly predicted the levels of blood glucose in a cross-sectional study in a sample of 5,882 adults from the US 1999–2004 National Health and Nutrition Examination Survey . In a poOur findings should be considered in light of the following limitations. This was a cross-sectional study design that could not establish causality. FPG and blood pressure values were obtained secondarily from the personal health files of the diabetes patients. Although all care was taken to record the values to minimize errors, misreporting might have occurred. In addition, the sample size was not well distributed in terms of gender. Women were significantly higher than men; this affects the representativeness of the sample.A high prevalence of central obesity was found. Predictors of increasing WHR and WC were the female gender, age, and FPG. A relatively low prevalence of elevated blood pressure was found.


Indirect assessment of mean pulmonary arterial pressure (MPAP) may assist management of critically ill patients with pulmonary hypertension and right heart dysfunction. MPAP can be estimated as the sum of echocardiographically derived mean right ventricular to right atrial systolic pressure gradient and right atrial pressure; however, this has not been validated in critically ill patients.This prospective validation study was conducted in patients undergoing pulmonary artery catheterisation during intensive care admission. Pulmonary artery catheter (PAC) measurements of MPAP were contemporaneously compared to MPAP estimated utilising transthoracic echocardiography (TTE)-derived mean right ventricular to right atrial systolic pressure gradient added to invasively measured right atrial pressure.Of 53 patients assessed, 23 had estimable MPAP using TTE. The mean difference between TTE- and PAC-derived MPAP was 1.9 mmHg (SD 5.0), with upper and lower limits of agreement of 11.6 and −7.9 mmHg, respectively. The median absolute percentage difference between TTE- and PAC-derived MPAP was 7.5%. Inter-rater reliability assessment was performed for 15 patients, giving an intra-class correlation coefficient of 0.96 .This echocardiographic method of estimating MPAP in critically ill patients was not equivalent to invasively measured MPAP, based on our predefined clinically acceptable range (±5 mmHg). The accuracy of this method in critically ill patients was similar to the results obtained in ambulatory patients and compared favourably with regard to the accuracy with echocardiographic estimation of systolic pulmonary arterial pressure. The utility of this technique is limited by frequent inability to obtain an adequate tricuspid regurgitant time-velocity integral in critically ill patients. Pulmonary hypertension (PH) is a common problem in critically ill patients and is associated with right heart dysfunction and increased morbidity and mortality. HistoriThe increased availability of point-of-care ultrasound machines in the intensive care unit (ICU) has facilitated the use of echocardiography as an alternative to the PAC for the evaluation of the haemodynamically unstable patient. Estimation of systolic pulmonary arterial pressure (SPAP) from the peak tricuspid regurgitant velocity is the most widely used echocardiographic measure of PH severity and has been validated in a broad range of clinical situations, although concerns about accuracy remain. Mean puRecently, Aduen and colleagues described a new, simpler echocardiographic method of estimating MPAP calculated as mean right ventricular to right atrial (RV-RA) systolic pressure gradient plus right atrial pressure (RAP). Mean RVOur aim in the present study was to establish the accuracy of this new echocardiographic method of MPAP estimation in a critically ill patient population. Furthermore, we attempted to increase the accuracy of our results by direct measurement of RAP, rather than echocardiographic estimation with its associated inaccuracies,11.This prospective validation study was conducted at Flinders Medical Centre Intensive and Critical Care Unit, South Australia, a large metropolitan tertiary ICU, between February 2011 and February 2012. The study was approved by the Flinders Clinical Research Ethics Committee, Southern Adelaide Health Service (450.10). Informed consent was gained from all patients or next of kin where appropriate.Consecutive patients aged 18 years and over admitted to the ICU who had a PAC in situ were assessed for eligibility. Exclusion criteria were patient refusal, inability to obtain informed consent or patient factors making transthoracic echocardiography (TTE) assessment impossible. Patient demographics were recorded.A Sonosite M-Turbo® ultrasound machine with phased array (1 to 5 MHz) transducer was used for echocardiographic assessments. Patients were assessed in the supine or semi-recumbent position. Limited TTE was performed to estimate MPAP and SPAP from the tricuspid regurgitant jet. The view providing the most complete envelope, with the highest-velocity regurgitant jet, was used for measurements.The average of three each of peak and mean RV-RA systolic gradients was calculated and recorded. Peak RV-RA gradient was estimated using the modified Bernoulli equation. Mean RVAll assessments were performed by the same echocardiographer . When available, a second echocardiographer  performed an assessment immediately afterwards, allowing an estimation of inter-rater reliability. The primary echocardiographer was blinded to PAC measurements. The second echocardiographer was blinded to the primary echocardiographer's TTE measurements.The decision to utilise a PAC to guide patient management was determined independently by the treating intensivist. PAC data was recorded during or immediately after echocardiographic assessment. The transducer was zeroed and levelled to the level of the right atrium, taken as 5 cm vertically below the manubriosternal junction, thus minimising the effect of differences in patient position or anteroposterior (AP) chest wall diameter.Measurements obtained from the PAC included SPAP, diastolic pulmonary arterial pressure (DPAP), RAP and pulmonary artery occlusion pressure (PAOP). MPAP was calculated as (SPAP − DPAP) / 3 + DPAP. An averCardiac index was calculated as cardiac output  divided by body surface area. Other mUtilising the concept of equivalence, it was The mean and standard deviation (SD) of the differences between PAC- and TTE-derived measurements of MPAP is reported. Upper and lower limits of agreement (i.e. 2SD) were calculated using Bland-Altman analysis, assumint tests were used to determine the relationship between continuous and categorical variables. Chi-squared test for independence was used to determine the relationship between categorical variables . Inter-rater reliability was assessed using intra-class correlation analysis, utilising a two-way mixed model (single measures) with absolute agreement for measurements. SPSS version 19.0 was used for all statistical analysis.Data are expressed as number (percentage) for categorical variables and mean (±SD) for continuous variables where appropriate. Independent samples A total of 55 patients were screened for study eligibility. Two patients declined participation, leaving 53 patients who were assessed echocardiographically. A further 30 patients were excluded due to inability to obtain a measurable tricuspid regurgitation (TR) envelope. Of those with unmeasurable TR, 13 patients had no detectable TR (43%), 9 had a poor-quality regurgitant envelope (30%) and 8 had poor acoustic windows 27%). The final 23 patients underwent TTE examination to determine MPAP, SPAP and RAP echocardiographically .Echocardiographic estimation of MPAP was not equivalent to invasively measured MPAP according to our narrow predetermined limits of ±5 mmHg. The bias between TTE- and PAC-derived MPAP was small at 1.9 mmHg; however, upper and lower limits of agreement (11.6 and −7.9 mmHg) lay outside our clinically acceptable range. The limits of agreement between TTE- and PAC-derived MPAP were similar for mechanically ventilated and spontaneously ventilating patients, but the study was underpowered to detect a significant difference between these two groups.Our results were similar to those reported by Aduen and colleagues [Inter-rater reliability for the 15 patients who were examined by both echocardiographers was excellent (intra-class correlation coefficient of 0.96); however, only the primary echocardiographer was blinded to PAC measurements, limiting interpretation of this result.Major strengths of this study included contemporaneous TTE and PAC assessments in a heterogenous group of critically unwell patients and direct measurement of RAP. Invasively measured RAP minimised the effect of any error in phlebostatic axis determination on MPAP measurement. The original trial by Aduen and coworkers used mid-thorax level as the phlebostatic axis, which may have affected the measurements obtained.The PAC was used as the reference standard. Dynamic response and reproducibility of the pulmonary arterial waveform are known to vary considerably with PAC. IdeallyHeart rate was not shown to affect accuracy of MPAP estimation. In patients with atrial fibrillation (AF), it was noted that there was large beat-to-beat variability in the magnitude of the tricuspid regurgitant jet and pulmonary arterial pressure trace. Eight of 23 patients (35%) were in AF at the time of echocardiographic assessment. When subjects were analysed according to their underlying heart rhythm, the groups were not dissimilar, although the study was underpowered to detect significant differences. Determining the accuracy of this method of MPAP estimation in patients with AF would require averaging measurements over a larger number of cardiac cycles or ideally simultaneous TTE and PAC analysis for a single cardiac cycle.A significant limitation of the study was the inability to estimate MPAP echocardiographically in the majority of patients screened. Only 23 of 53 patients (43%) assessed echocardiographically had adequately visualised TR to allow estimation of MPAP, leaving the study underpowered. A previous study by Bouhemad and colleagues observed the presence of TR in 85% of hypoxemic mechanically ventilated critically ill patients. It is lIncreased AP chest wall diameter, mechanical ventilation and male gender were associated with reduced ability to obtain MPAP estimates. Difficulty obtaining MPAP estimates in men may be secondary to increased AP chest wall diameter . It was expected that TTE assessment would be more accessible in medical patients, as opposed to post-cardiothoracic surgical patients-21. PostHaemodynamic variables associated with inability to estimate MPAP included lower SPAP and PAOP and higher MAP. Lower SPAP was predictably associated with reduced ability to measure TR, as increased SPAP is known to be associated with increased severity of TR. There wThis method of echocardiographic estimation of MPAP has not, at this time, entered into routine clinical practice. Subsequent study has demonstrated similar accuracy and precision to formulas deriving MPAP from SPAP. As statTransthoracic echocardiographically estimated mean pulmonary artery pressure utilising mean right ventricular to right atrial systolic pressure gradient added to invasively measured right atrial pressure in critically ill patients was not equivalent to invasively measured mean pulmonary arterial pressure from right heart catheterisation based on a predefined clinically acceptable range of ±5 mmHg. The accuracy of this method in critically ill patients was comparable to results obtained in ambulatory patients and compAP: anteroposterior; APACHE IIIj: acute physiology and chronic health evaluation version IIIj; BMI: body mass index; CI: cardiac index; DPAP: diastolic pulmonary arterial pressure; ICU: intensive care unit; MAP: mean arterial pressure; MPAP: mean pulmonary arterial pressure; PAC: pulmonary artery catheter; PAOP: pulmonary artery occlusion pressure; PH: pulmonary hypertension; PSV: pressure support ventilation; RAP: right atrial pressure; RV-RA: right ventricular to right atrial; SD: standard deviation; SIMV: synchronised intermittent mandatory ventilation; SPAP: systolic pulmonary arterial pressure; TR: tricuspid regurgitation; TTE: transthoracic echocardiography.The authors declare that they have no competing interests.RL contributed to study design, data acquisition, analysis and interpretation, and drafting and revising of the submitted manuscript. UW conceived the study, contributed to study design, data acquisition and interpretation, and drafting and revising of the submitted manuscript. AB contributed to study design, data interpretation and drafting and revising of the submitted manuscript. All authors have read and approved the final manuscript. RL takes responsibility for (is the guarantor of) the content of the manuscript, including the data and analysis.


Objective. Diabetic retinopathy (DR), the most common microvascular complication of diabetes mellitus (DM), can cause severe visual impairment and blindness. To prevent the development of DR, identifying the associated risk factors for patient classification is critical. We conducted a cross-sectional study to determine whether body constitution (BC) is an independent predictor of DR. Method. 673 type 2 DM (T2DM) patients were recruited from a medical center, all received DR examination and body constitution questionnaire to assess BC. Other risk factors for DR were also recorded, including life style, history of diabetes, and blood pressure, etc. Multiple logistic regression analysis was conducted to calculate the odds ratios (ORs) for DR. Results. The prevalence of DR was significantly lower in Yang deficiency patients compared with non-Yang deficiency patients (24.69% versus 38.18% P = 0.02). After adjusting for other risk factors, we observed that patients exhibiting Yang deficiency BC were less likely to present with DR . Conclusion. In addition to traditional risk factors, Yang deficiency BC might be an independent predictor of DR among T2DM patients and the results can be used as evidence for traditional Chinese medicine patient classification.  Diabetic retinopathy (DR), the most common microvascular complication of diabetes mellitus (DM), has become a major cause of visual impairment and blindness worldwide –4, thus The pathogenesis of DR is complex and not fully understood, and considerable efforts have been expended in identifying the possible risk factors for the development and progression of this disease –15. Effe tong bing yi zhi in Chinese.Traditional Chinese medicine (TCM), one of the most important and frequently used types of complementary and alternative medicine –23, is aThe relationships between BC and DM , 33, insWe conducted this cross-sectional study form February 2010 to February 2011 at the Diabetes Health Promotion Center of Taichung Veterans General Hospital . The study protocol was approved by the Institutional Review Board of Taichung Veterans General Hospital (C10007). A total of 887 individuals diagnosed with T2DM were referred by endocrinology and metabolism subspecialists from an outpatient clinic, and 191 subjects older than 75 years were excluded. Written informed consent was obtained from each subject prior to participation in the study. Every subject received a diabetic retinopathy examination and was included in the enrollment group only when the possible risk factors for DR were completely collected: body constitution measurement, sociodemographic history , lifestyle, diabetic related history, blood pressure, lipid profile, renal parameters for diabetic nephropathy, and diabetic neuropathy examining results. Twenty-four subjects were excluded because of incomplete laboratory tests, and 673 T2DM patients were included in the final analysis. never happened) to 5 . The final score of each constitution was calculated by summing the scores of all items on each subscale, with a higher score implying a greater deviation from the constitution. The diagnostic cut-off points for Yang deficiency, Yin deficiency, and Phlegm stasis were 30.5 [α of each constitution subscale in previous studies has been between 0.88 and 0.90 [All of the participants were administered a body constitution questionnaire (BCQ) consisting of three independent constitution subscales, including 19 items on Yang deficiency , 38, 19 ere 30.5 , and 26.ere 30.5 , respectere 30.5 , and Croand 0.90 , 38, 40.Central fundus photographic imaging was performed following the standardized protocol. Both eyes of each subject were photographed using a nonstereoscopic 45° digital nonmydriatic camera . The fundus photographs were examined in a masked manner by experienced and trained endocrinology and metabolism subspecialists. The DR severity of each eye was graded according to the International Clinical Diabetic Retinopathy and Diabetic Macular Edema Disease Severity Scales . BecauseSeveral critical risk factors for DR were derived to control for the confounding influence. The sociodemographic and biological characteristics of the 673 participants, including sex, age, height, waist, lifestyle, duration of DM, oral hypoglycemic agent use, and insulin usage, were investigated through personal interviews at the Diabetes Health Promotion Center of Taichung Veterans General Hospital. After more than 12 hours of fasting, a series blood samples were collected for measuring fasting blood sugar, glycosylated hemoglobin (HbA1c), total cholesterol, total triglyceride, high density lipoprotein, low density lipoprotein (LDL), and creatinine (Cr). The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease four-variable equation: eGFR = 186 × serum creatinine − 1.154 × age − 0.203 × 1.212 (if black) × 0.742  . t-test for continuous variables. We used multiple logistic regression analysis to calculate the odds ratios (ORs) for DR. Hierarchical models for covariant variables were considered for determining whether BC is an independent predictor of DR. First, crude ORs were calculated without adjustment. We then sequentially entered sociodemographic factors, lifestyle, diabetic factors, blood pressure, and lipid profiles into the model. Finally, renal parameters and diabetic neuropathy were added into the final model. A two-sided significance level was set at P < 0.05. We performed all analyses using SAS version .The data were presented as mean ± SD for continuous variables and as number (%) for categorical variables. Differences between groups were compared using a chi-square test for categorical variables and aA total of 343 (51%) males and 330 (49%) females composed the study group. Of the 673 participants, 81 (12%), 174 (25.9%), and 86 (12.8%) patients were diagnosed with Yang deficiency, Yin deficiency, and Phlegm stasis BC, respectively. P = 0.02).A total of 226 (33.6%) patients have DR, including PDR and NPDR. P = 0.018). After adjusting for all of the variables, including Yin deficiency, Phlegm stasis, sociodemographic factors, lifestyle, diabetic factors, blood pressure, lipid profile, renal parameters, and diabetic neuropathy, Yang deficiency BC remained significantly associated with DR .The unadjusted and hierarchically adjusted ORs for DR associated with different BC were shown in Substantial efforts have been expended to discover the risk factors associated with DR among T2DM patients. Male sex, blood pressure, duration of diabetes, HbA1c, and albuminuria had been identified to be associated with DR among T2DM patients across different ethnic groups , 44, 45.An individual's BC is formed by Yin and Yang and the imbalance between Yin and Yang renders individuals more prone to certain diseases , 46. Yan yi qi wen yang and demonstrate the effect of promoting blood circulation [Hemodynamic abnormalities, including increased retinal blood flow and blood pressure, might lead to the development and progression of DR –57. Yangculation . Blood pAngiogenesis is another vital pathogenic pathway in diabetic retinopathy , 57 and Previous studies have successfully provided evidence for TCM patient classification by using machine learning algorithms –64, and The questionnaire, BCQ, with favorable reliability and validity can be easily applied by Western physicians to assess the BC status and has been used in clinical research , 50. In Our study has three major limitations. First, the abnormal constitution theoretically occurs before a disease, but the time sequence of a cross-sectional study design cannot determine the causal relationship between BC and DR. A cohort study might be necessary to mitigate this doubt. Second, because the patients willing to join the study might have been more aggressive in improving their health conditions, a potential selection bias exists. To mitigate the impact of bias, we considered the lifestyle and sociodemographic factors in the multiple logistic regression analysis. Finally, although we included major confounding factors, other unmeasured variables might exist because this was an observational study.Distinguishing T2DM patients who exhibit a high or low risk of complication development is crucial for health management. This study suggests that BC is independently associated with DR. T2DM patients with Yang deficiency BC had a 55% significantly reduced likelihood of DR. For patient classification, using BCQ to assess the BC is convenient, inexpensive, and noninvasive and should be adopted in clinical practice. Identifying the association between DR and BC confirms BCQ construct validity. Our study results might guide future study to survey the longitudinal association between DR and BC.


Pulse pressure (PP) reflects increased large artery stiffness, which is caused, in part, by arterial calcification in patients with chronic kidney disease. PP has been shown to predict both cardiovascular and cerebrovascular events in various patient populations, including kidney transplant (KTX) recipients. Osteoprotegerin (OPG) is a marker and regulator of arterial calcification, and it is related to cardiovascular survival in hemodialysis patients. Here we tested the hypothesis that OPG is associated with increased pulse pressure. We cross-sectionally analyzed the association between serum OPG and PP in a prevalent cohort of 969 KTX patients . Independent associations were tested in a linear regression model adjusted for multiple covariables. PP was positively correlated with serum OPG . Additionally, a positive correlation was seen between PP versus age , the Charlson Comorbidity Index , serum glucose , BMI  and serum cholesterol . PP was negatively correlated with serum Ca, albumin and eGFR. The association between PP and OPG remained significant after adjusting for multiple potentially relevant covariables . We conclude that serum OPG is independently associated with pulse pressure in kidney transplant recipients. Cardiovascular (CV) disease is the leading cause of death in kidney transplant (KTX) recipients1346Accelerated age-related arterial remodeling and also vascular calcification lead to the loss of large and small vessel distensibility in patients with CKD and end stage kidney disease (ESKD). These changes manifest in increased vascular stiffness, frequently assessed by pulse wave velocity (PWV)Most1318Studies have indicated a role for osteoprotegerin (OPG), a soluble decoy receptor of the osteoclast activator RANKL, in arterial calcification and atherosclerosis2223262729Studies in kidney transplant recipients revealed that serum OPG declined during the first 2 weeks after KTX and decreased further during the next 2 weeks34In this cross-sectional prevalent cohort study we tested the hypothesis that elevated serum OPG is associated with increased PP, an easily available surrogate of arterial stiffness and vascular calcification, independent of potential confounding variables in kidney transplant recipients.All prevalent kidney transplant recipients 18 years of age or older (n = 1214) followed at a single transplant clinic at Semmelweis University in Budapest, Hungary were invited to participate in this observational cohort study. Exclusion criteria were acute rejection within the last 4 weeks, current hospitalization, transplantation in the previous 3 months, acute infection or active bleeding. Of the 993 subjects enrolled, 982 (99%) had baseline blood samples that were available for osteoprotegerin (OPG) assay. All subjects were recruited and baseline assessments were conducted between February 2007 and August 2007 . The study methods have been previously describedThe study was approved by the Ethics Committee of the Semmelweis University (49/2006). Before enrolment, patients received detailed verbal and written information about the aims and protocol of the study and signed informed consent. All experiments were performed in accordance with relevant guidelines and regulations.Routinely available laboratory data were extracted from the patients’ charts and from the hospital’s electronic laboratory database. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation°C for future use. Serum osteoprotegerin was measured with an immunoassay kits based on a solid-phase sandwich enzyme-linked immunosorbent assay (ELISA) .Serum samples were also collected at the time of the baseline assessment and stored at −70 We used the modified Charlson Comorbidity Index (CCI)Standard maintenance immunosuppressive therapy at our institution consisted of prednisolone, either cyclosporine A microemulsion formulation (CsA) or tacrolimus, combined with mycophenolate-mofetil (MMF) or azathioprine or sirolimus.We used descriptive statistics to compare clinical and biochemical characteristics across tertiles of baseline serum OPG. Data were summarized using proportions, means  or medians  as appropriate. Normality of the distribution of continuous variables was checked with the Kolmogorov-Smirnov test. Variables with skewed distribution were natural log-transformed for all analyses. Correlation between serum OPG and PP versus continuous variables was tested with Pearson correlation analysis. To compare variables between tertiles of serum OPG, one-way analysis of variance (ANOVA) or the Chi-square test was used.All variables which correlated with PP with a level of significance <0.01 in these analyses  were included in a multivariable linear regression model. Because of the relatively large number of the variables entered in the final model, variables were entered in five blocks. First serum OPG alone was added; block B included age, sex, presence of diabetes, body mass index (BMI), the Charlson comorbidity index and cumulative end stage kidney disease (ESKD) vintage; the next block included the use of immunosuppressive medications: steroids, cyclosporine, tacrolimus, azathioprine, mycophenolate-mofetil and sirolimus; block D included eGFR, serum albumin, glucose and cholesterol, the final block included serum calcium, phosphorus, PTH, the use of active vitamin D and the use of phosphate (PO4) binders. All variables were retained in the final model. Non-linear association between OPG versus PP was tested using the squared OPG term in the regression model and restricted cubic spline. Variance influence factors (VIF) were used to indicate collinearity between independent variables in the multivariate regression model. For all analysis, two-sided p values are reported and results have been considered statistically significant if p < 0.05.® Corp. Armonk, NY) and STATA MP version 13.1 .Data were analyzed using the IBM SSPS Statistics for Macintosh 22.0 software  among patients with diabetes vs non-diabetics . PP was also significantly correlated with age, body mass index, hemoglobin level, total serum cholesterol, eGFR, serum albumin and serum glucose levels and the Charlson Comorbidity Index .2 = 0.233, beta = 0.143; p < 0.001)  . Additio< 0.001) .Here we demonstrated for the first time, in a large prevalent cohort of KTX patients that serum OPG levels were independently associated with pulse pressure, a surrogate marker of arterial stiffness and a cardiovascular risk factor. These results are compatible with the potential contribution of osteoprotegerin and also of CKD-MBD to increased CV risk in KTX recipients.et al. found that higher PP was associated with recipient age, systolic and diastolic blood pressure, presence of diabetes and cardiovascular disease in KTX recipientsPP increases with declining eGFR in patients with CKD. It is also associated with age, the presence of diabetes mellitus and hypertension, serum phosphorus and PTH levels in this patient populationElevated pulse pressure is a marker of arterial stiffness and is clearly associated with adverse cardiovascular outcomes42744482223252627Regardless of the yet unclear mechanistic role of OPG in vascular calcification, the clinical relevance of OPG lies in its prognostic potential. Serum OPG consistently predicted the presence and severity of coronary artery disease or mortality6262729345234In this study we wanted to assess the association between PP and OPG. We considered PP primarily as a surrogate of vascular stiffness. However, there is a complex relationship between PP and systolic and diastolic BP  and their predictive association with cardiovascular outcomes. Initially it had been thought that DBP was the most damaging component of BP. Subsequent epidemiologic studies, however, called attention to the relevance of SBP over DBP in inducing cardiovascular and renal damage56Several limitations of our study should be considered when interpreting our results. Patients from a single center were enrolled; therefore our results are not to be generalized without further considerations. Patients who were not participating in the study may have been different from participants, which is a potential source of bias. We think, however, that it is unlikely that this would have qualitatively changed our results. Only Caucasian patients participated which may make comparisons with multiethnic populations difficult. Moreover, our patients form a heterogenic group selected at various moments in their evolution after renal transplantation and with various degree of kidney dysfunction so that OPG levels varies. Finally, we did not measure vascular stiffness in this research that would have provided additional new information about vascular characteristics.In conclusion we have demonstrated that OPG is independently associated with pulse pressure in renal transplant patients. These results support the potential role of disordered bone and mineral metabolism in vascular calcifications and stiffness in kidney transplant recipients. Prospective studies will be necessary to demonstrate the pathophysiologic link between disordered bone and mineral metabolism and vascular calcification in KTX patients. Those studies will need to be informed by basic research generating new knowledge using cell culture experiments and animal models. They will need to demonstrate a prospective association between changing bone metabolism and increasing vascular stiffness/calcification by utilizing multiple biomarkers of bone metabolism. This may be complemented by dual-photon x-ray absorptiometry or quantitative CT assessment of bone mineral density and structure. Vascular calcification will need to be determined by appropriate imaging, preferably CT scanning of coronaries and/or the aorta. This needs to be complemented by validated measurement of vascular stiffness. In addition to these studies, potential intervention trials that aim at modulating bone turnover, may demonstrate the effect (or the lack thereof) on vascular calcification of interventions that modify bone turnover.How to cite this article: Nemeth, Z. K. et al. Serum osteoprotegerin is associated with pulse pressure in kidney transplant recipients. Sci. Rep.5, 14518; doi: 10.1038/srep14518 (2015).


Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response—particularly in those prescribed aldosterone antagonists at the time of RDN.We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres.n = 253) and mean daytime ABP was 170/98 mmHg . Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg . Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p < 0.001 for trend). Use of aldosterone antagonist did not predict response (p > 0.2).Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg  contains supplementary material, which is available to authorized users. Hypertension contributes to 62 % of all strokes, 49 % of global heart disease burden and causes an estimated 7.1 million deaths a year , 4.Reduction of sympathetic outflow is one proposed alternative to drug treatment for reducing high blood pressure. Invasive surgical sympathectomy was shown to lead to significant blood pressure reductions over 70 years ago; however, this procedure was abandoned due a high complication rate . Renal aEarly observational data and open-label, randomized studies suggested substantial reductions in blood pressure following a single percutaneous procedure , 9. ReduMore recently, a rigorously conducted randomized trial added renal denervation (RDN) to a stepped anti-hypertensive drug program and demonstrated incremental blood pressure lowering with RDN . HoweverThe efficacy of this technology therefore remains uncertain and further randomized trials are required. In the meantime, more data are required on the nature of the patients who have already undergone the procedure, their response to treatment and identification of factors that may affect subsequent blood pressure response. Such data would better inform the design, conduct and interpretation of future trials.This article reports the UK experience with RDN for treatment-resistant hypertension. It examines the nature of the blood pressure response seen on ambulatory monitoring and the impact of drug changes post denervation on the results. Finally, this study examines the interaction of RDN with the use of aldosterone antagonists.At the time of instigation of the UK Renal Denervation Affiliation (May 2014), background research by the study team identified 21 centers that had performed five or more procedures in the UK. The aim of this study was to give as complete as possible a representation of the UK national experience with RDN to date, by collating retrospective data from all procedures performed on patients with uncontrolled hypertension.Each center was contacted by email and/or telephone and invited to participate in the registry. Eighteen of those centers agreed to contribute and provided the data that form the basis for this manuscript. These data represent the results of cases performed for treatment-resistant hypertension, as defined by prior international consensus statements  and in aAnonymized data were collated locally using a spreadsheet specifically designed for the study and then submitted to a central coordinating center , where it was analyzed. The project was independent of any financial support from industry and is an exclusively investigator-led initiative.‘Responders’ to RDN are defined according to prior convention , by a reT test or ANOVA were used for continuous variables. Logistic regression models were used to examine the interaction of aldosterone antagonist use with blood pressure response following RDN after adjustment for factors previously thought to interact with response to RDN from prior literature. These models were also used to look for other potential baseline predictors of blood pressure changes after RDN. A p value of <0.05 was considered statistically significant. Statistical analyses were performed using SPSS software v20.0 .Data are presented as mean ± standard deviation (SD) unless stated. Between group variations were analyzed using Chi Square test for categorical variables and where normality was demonstrated, a n = 204 (81 %)]; Symplicity Spyral [n = 10 (4 %)]; Boston Vessix [n = 3 (1 %)]; St Jude Enlightn [n = 26 (10 %)] and Covidien Oneshot [n = 10 (4 %)]. Mean age of patients was 57 years; 53 % were female; 88 % Caucasian and 26.5 % were diabetic  and detailed assessments to rule out secondary hypertension before the procedure (screening details are shown in Table n = 253) with an average daytime ambulatory blood pressure (ABP) of 170/98 mmHg . Fifty-eight percent of the cohort had loss of normal nocturnal dipping on ABP. The median number of antihypertensive drugs prescribed before RDN was 5.0 including 96 % ACEi/ARB; 86 % thiazide or a loop diuretic and 55 % aldosterone antagonist prescription at the time of denervation . At 8.5 months follow-up, the mean reductions in daytime ASBP by quartile of starting daytime ASBP were: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively .Figure p = 0.001 for quartile trend), but in the lowest quartile, this was not matched by a statistically significant ASBP response. Overall, 65 % patients were defined as responders, with a ≥10 mmHg fall in OSBP. A similar percentage (62 %) had a ≥5 mmHg fall in daytime ASBP.Office systolic BP (OSBP) also exhibited significant falls across each of the four quartiles (p > 0.2 as univariate predictor). This remained the case after adjustment for the following potential confounders: age, gender, diabetes, estimated glomerular filtration rate (eGFR), number of drugs taken and starting office blood pressure (p > 0.2). There remained no association when ASBP was substituted for OSBP within the model. The only baseline characteristic that predicted subsequent fall in BP after RDN was blood pressure, as measured by office or ABP.Use of aldosterone antagonist at the time of RDN did not predict the degree of blood pressure response (p < 0.001 for both findings). This blood pressure reduction does not appear to be related to changes in anti-hypertensive medications made after denervation and use of aldosterone antagonists did not affect blood pressure response following the procedure. Patients in the two highest quartiles of daytime ambulatory systolic blood pressure at baseline exhibited significant ambulatory blood pressure reductions, whilst those in the lowest quartile exhibited little response.This investigator-led study reports the results of RDN procedures for 253 people with treatment-resistant hypertension, performed in 18 UK specialist centers using five different technologies. It shows significant reductions in both office and daytime ambulatory blood pressure of 22/9 and 12/7 mmHg, respectively, after a mean follow-up period of 11 months . By comparison, the mean number of cases per center in HTN-3 was 4.1 .Results show a fall in office BP of 22/9 mmHg at 11 months. Clearly, such data are open label and therefore have to be observed with caution, but this is a well screened and treated cohort, having previously been looked after by an average of 1.6 specialists with a named interest in hypertension. More than 85 % of subjects were managed in dedicated hypertension clinics prior to their denervation and relatively few drug increases were attempted after their procedure, despite the severity of their hypertension, suggesting a stable drug regimen was in place prior to their treatment.Three times as many drugs were withdrawn following denervation as were added, with otherwise balanced dose-titrations observed across the cohort. This suggests that drug changes following RDN may have served to reduce the observed treatment effect of denervation, rather than magnify it. Clearly, however, whatever drug regimens were pursued, office blood pressure is prone to unconscious confounding, as described by others , 33. AltAmbulatory blood pressure is a stronger predictor of outcome than office or home blood pressure readings and a better measure of true blood pressure than office readings. It is less prone to variability or confounding and makes pseudoresistant hypertension unlikely .In this clinical cohort, a high proportion of patients were assessed using ABP. Some patients could not tolerate the repeated measures of ABP, which is understandable, given that some had very high blood pressures (office SBP >240) at the time of assessment. Despite this, follow-up ABP results were available in over 70 % of subjects.Importantly, our cohort showed good pre-procedural approximation between office and ambulatory BP  suggesting little white-coat element across the cohort.Furthermore, subjects were prescribed an average of five medications at the time of their procedure, with a relatively high use (55 %) of aldosterone antagonists. To our knowledge, this is the highest proportion of subjects using aldosterone antagonists in any population of RDN patients reported to date. Despite these proactive drug strategies, mean pre-procedural daytime ABP remained 170/98 mmHg, which is, to our knowledge, as severe a cohort of hypertensives as have been studied with denervation to date.Prior studies suggest an important role for aldosterone antagonism in the area of treatment-resistant hypertension . The recIn this UK cohort of subjects, the use of aldosterone antagonists was not associated with a difference in blood pressure after RDN but this does not in any way question the efficacy of spironolactone in a resistant population. In this population, RDN was reserved for patients who were resistant to all recommended treatments and therefore we are observing a ‘treat to target’ effect, whereby other drugs are being used to compensate for the presence or absence of a spironolactone effect before a decision on RDN is made. Aldosterone antagonism use was not randomized within our cohort and therefore, by definition, the groups were not balanced and cannot be directly compared for efficacy of the drug. Rather, we report this to establish whether spironolactone acts as a predictor of blood pressure fall after RDN and it does not.The pattern of ABP quartile response to RDN is an interesting finding from this study. The relationship between starting office blood pressure and magnitude of fall in BP has been previously described for office BP and we replicate this finding with our data. It has been suggested that this could represent a regression to the mean artefact, but ABPM is more resistant to that bias than office BP . The larGiven the strength of the association of fall in ASBP with ‘true’ starting BP observed in our cohort (as defined by daytime ASBP) these findings suggest that the most likely way to demonstrate the effectiveness of RDN in a randomized, blinded trial, where unconscious confounding of office response cannot bias the result and treatment effect sizes tend to be smaller , may be Upcoming trials in the field of renal denervation have been proposed in patients with moderate hypertension (ABP of 140-170). Such patients most closely approximate to subjects in quartiles 1 and 2 of our study. Given that these trials are sham-controlled, we may expect to see results closer to those of daytime ABP, rather than open-label office pressure . RigorouGiven the morbidity and mortality associated with uncontrolled hypertension, the need for treatment options over and above medications remains apparent, especially for those with few remaining medical options. Whilst we await further randomized trials in this area, results from this cohort of UK subjects with severe, treatment-resistant hypertension and few remaining medical options suggest that, on average, blood pressure control improved following RDN, especially in those with ambulatory blood pressure readings in the highest range.This is an open-label retrospective registry with no outside funding source and therefore no independent verification of results was obtained. It is therefore limited by this study design. However, data quality appeared good, as supported by the relatively high frequency of reporting of ABP results and the close correlation between office BP and ABP results. Results also appear consistent across 18 sites.This study did not mandate measures of adherence to prescribed medications and therefore variable levels of compliance pre- and post-procedure could have had a confounding impact on results. However, there is no reason to suspect changes in behavior occurred according to starting blood pressure and subjects within each quartile of starting ABP were prescribed similar numbers of pharmacological agents. Recent data have also shown blood pressure reductions after RDN in proven compliant subjects .Future studies of RDN should, though, incorporate a direct assessment of adherence, such as urine antihypertensive drug analysis to look for confounding from variable drug compliance on results. Ultimately, however, novel measures of blood pressure reduction are needed for both adherent and non-adherent subjects and both these groups require study within separate, dedicated, randomized trials.Reporting of ABP is not universal. ABP was tried in almost all patients within this cohort, but with a starting BP of >200 mmHg in many of these patients, the device was not tolerated for a 24-h period. Furthermore, many of these subjects travelled long distances to an RDN center for review and therefore repetition by the performing center was not feasible. Despite these limitations and the absence of reimbursement for RDN in the UK, 73 % use is a higher rate of use of ABP than in other funded registries to date.This real-world study demonstrates that renal artery sympathetic denervation is associated with a significant reduction in both office and ambulatory blood pressure in well-characterized subjects with treatment-resistant hypertension.Ambulatory blood pressure reductions were shown to be greatest in those with the highest starting ambulatory blood pressures, whilst those with blood pressures in the lowest quartile of baseline ambulatory blood pressure showed little response. Use of aldosterone antagonist did not affect the subsequent blood pressure response after denervation and drug changes after denervation did not appear to account for the blood pressure fall seen in the cohort at follow-up.Online Appendix 1 (DOCX 98 kb)Below is the link to the electronic supplementary material.


Background: Corticosteroids are increasingly used in renal transplant patients to minimize organ rejection after transplantation. In attempts to reduce corticosteroids adverse effects, transplant professionals are customary attempted to taper off, and permanently stop corticosteroids after few months of administration with other immunosuppressants.Objective: To evaluate clinical benefits and risks of late corticosteroid withdrawal in renal transplant patients treated with tacrolimus (TAC) or mycophenolate mofetil (MMF), or both.Methods: A meta-analysis was performed of published randomized controlled trials that reported outcomes in kidney transplant patients who were randomized to corticosteroids maintenance or late withdrawal under concomitant immunosuppression by TAC, MMF or both. Outcomes included acute graft rejection; graft failure rate; all-cause mortality; incidence of post-transplant diabetes; change in serum creatinine and total cholesterol; and change in pediatric standardized height z-score. PubMed and Google Scholar were used in literature search between 1999 and April 1, 2010. Data were combined using unweighted random effects model.Results: Nine studies randomized 1907 patients met the inclusion criteria: TAC (n=1); MMF (n=6); both (n=2). Compared to maintenance therapy, late corticosteroid withdrawal was associated with 34% increase in the risk of acute graft rejection (95% CI for OR: 0.47–3.82); 35% and 5% reductions in the risk of graft failure and patient’s all-cause mortality ; and 4% increase in post-transplant diabetes risk (95% CI for OR: 0.45–2.41). Late corticosteroid withdrawal was associated with substantial reduction in total cholesterol levels , but did not reduce serum creatinine levels . Stopping corticosteroids was associated with better pediatric growth outcomes.Conclusion: Late corticosteroid withdrawal under TAC and/or MMF-lead immunosuppression after kidney transplantation could provide benefits in terms of total cholesterol, patient and graft survival, and pediatric growth. This strategy, however did not reduce the risk of acute graft rejection, post-transplant diabetes mellitus, and deterioration in serum creatinine levels. Organ rejection is one of the serious complications of kidney transplantation. Corticosteroids are increasingly used to reduce organ rejection after transplantation. However, corticosteroids have many adverse effects including—but not limited to—hypertension, hypercholesterolemia, glucose intolerance, growth retardation in children, greater incidence of infections, and bone weakness. In attempts to reduce the incidence of graft rejection rates as well as the adverse effects of corticosteroids, transplant professionals are customary attempted to taper off, and permanently stop corticosteroids after few months of administration. Unfortunately, the randomized controlled trials (RCTs) conducted in the 1990s showed increasing rates of acute graft rejection . CyclospIn this study, we performed a meta-analysis of RCTs to evaluate clinical benefits and risks of late corticosteroid withdrawal in kidney transplant patients with concomitant immunosuppression by TAC, MMF, or both.Data sources and searchesPubMed and Google Scholar search was independently performed by the authors to find human studies published between 1999 and April 1, 2010 using the search terms kidney transplant, renal transplant, randomized clinical trial, tacrolimus, mycophenolate mofetil, as well as combinations of these terms. The bibliographies of the retrieved literature were also searched for other relevant studies.A comprehensive Study selectionClinical trials that met the following criteria were included: randomized controlled trials in kidney transplant patients regardless of age; kidney transplant patients on corticosteroids with concomitant immunosuppression by either TAC or MMF, or both. Late corticosteroid withdrawal in one comparison group was required, which was defined as withdrawing corticosteroids at least three months after transplantation; and the other comparison group was defined as kidney transplant patients who received maintenance corticosteroid therapy with either TAC or MMF, or both. Using either of cyclosporine or azathioprine as concomitant immunosuppressants in addition to the above agents is considered acceptable in the study inclusion criteria. Clinical trials that enrolled organ transplant patients other than kidney, early corticosteroid withdrawal , or if the concomitant immunosuppression was by cyclosporine and azathioprine in addition to other agents were excluded.Data extraction Standardized forms are used to extract data from selected studies for patient demographics; inclusion and exclusion criteria; treatment regimens; duration of follow-up ; total number of patients enrolled; allograft source and characteristics; and clinical outcomes.Clinical outcomes Clinical outcomes of interest included the incidence of acute graft rejection; graft failure rate; all-cause mortality; incidence of post-transplant diabetes mellitus; change in serum creatinine and total cholesterol; and change in pediatric standardized height z-score. The definitions of clinical end-points were similar across the trials; three studies reported serum creatinine values in µM/L -5, and tData synthesis and analysis ® .Summary odds ratio (OR) and mean difference values with their corresponding 95% confidence intervals (CI) were calculated using unweighted random effects model to combine results from selected studies. A priori 5% level of significance for Type-I error (α) was specified to determine statistical significance. All statistical analyses were conducted using SAS software, ver 9.2 of the SAS System for WindowsOverview of trialsPubMed; 136 from Google Scholar; 11 secondary bibliographies) potentially eligible studies were identified, and 247 were excluded for not meeting the selection criteria. Nine RCTs were identified for inclusion  months after transplantation, a total of 86 acute graft rejections ; 48 graft failures ; 26 all-cause deaths ; and 34 post-transplant diabetes mellitus  were observed . CompareLate corticosteroid withdrawal was associated with both statistically non-significant 35% and 5% reductions in the risks of graft failure and all-cause mortality . ARR and NNT for graft failure were 1.03% and 97, and those for all-cause mortality were 0.19% and 526.Stopping corticosteroids at least three months after kidney transplantation was associated with statistically non-significant 4% increased risk of post-transplant diabetes mellitus compared to the corticosteroid maintenance therapy . ARR was 0.93%, and NNT was about 108.A statistically significant reduction in the mean total cholesterol was greater in the corticosteroid withdrawal group , however; no reduction in serum creatinine was observed  in comparison to the maintenance therapy group.>3 months post-transplantation) therapy or corticosteroid maintenance therapy under continuation of concurrent immunosuppression by either TAC or MMF, or both. The clinical outcomes of interest included the incidence of acute graft rejection; graft failure; all-cause mortality; post-transplant diabetes; changes in serum creatinine and total cholesterol levels; and changes in standardized z-score of height in pediatric patients.It is known that continued immunosuppression therapy with corticosteroids in kidney transplant patients reduces the risk of acute graft rejection, however; the long-term complications of such therapy are well-established . ProlongAlthough statistically not significant, our findings indicate that late corticosteroid withdrawal in kidney transplant patients is associated with 34% increase in the risk of acute graft rejection (95% CI for OR: 0.47–3.82); and 4% increase in the risk of post-transplant diabetes mellitus (95% CI for OR: 0.45–2.41). However, this strategy resulted in 35% and 5% reductions in the risk of graft failure and patient’s all-cause mortality, respectively . Stopping corticosteroid therapy was associated with a statistically significant substantial reduction in total cholesterol levels , but did not reduce serum creatinine levels . Two studies showed that corticosteroids withdrawal was presented with better growth outcomes in pediatric kidney transplant patients [Moreover, late corticosteroid withdrawal can be compared with maintenance therapy in terms of more clinically significant measure, the NNT , which cOur study demonstrates statistically non-significant results that show late corticosteroid withdrawal could reduce the risks of long-term complications associated with immunosuppression in kidney transplant patients, however; it did not show that such strategy could reduce the risk of acute graft rejections and the incidence of diabetes mellitus after kidney transplantation. Nevertheless, it shows clinically significant end-points in terms of NNT values for acute rejection and graft failure.i.e., publication bias. Unlike published studies, unpublished works could impart bias because they are not subjected to the peer review process. Finally, meta-analysis is a retrospective research that is highly dependent upon the inherent limitations, strengths, and quality of the included studies. A detailed study protocol was developed prior to the literature search, data extraction, and data analysis phases, which minimized the potential for systematic errors.The present meta-analysis has several limitations. First, the results should be interpreted with caution, because many variables were not uniformly distributed across the selected trials. Heterogeneity was apparent in terms of study population characteristics, follow-up and randomization times, outcome measurement time, and treatment regimen characteristics. These differences imparted to the statistical differences in the effect size between the individual studies  and 4. SGiven the heterogeneity between the trials, a random effects model was deemed appropriate. In addition, unweighted method is considered more valid in meta-analysis research, because the weights are random entities, and should not be treated as fixed alternatives, which unfortunately is the case in most of the published meta-analyses.Late corticosteroid withdrawal under TAC and/or MMF-lead immunosuppression after kidney transplantation could provide benefits in terms of total cholesterol, patient and graft survival, and pediatric growth. This strategy, however did not reduce the risk of acute graft rejection, post-transplant diabetes mellitus, and deterioration in serum creatinine levels. Additional large scale, multicenter RCTs are required to further evaluate the long-term clinical outcomes associated with late corticosteroid withdrawal and assessing corticosteroid-sparing effects of TAC and MMF in kidney transplant patients.