A recent genome wide association study in 1017 African Americans identified several single nucleotide polymorphisms that reached genome-wide significance for systolic blood pressure. We attempted to replicate these findings in an independent sample of 2474 unrelated African Americans in the Milwaukee metropolitan area; 53% were women and 47% were hypertensives.STK-39 and CDH-13) found to be associated with systolic and diastolic blood pressures by other genome wide association studies in European and Amish populations. TaqMan MGB-based chemistry with fluorescent probes was used for genotyping. We had an adequate sample size (80% power) to detect an effect size of 1.2-2.0 for all the single nucleotide polymorphisms for hypertension as a binary trait, and 1% variance in blood pressure as a continuous trait. Quantitative trait analyses were performed both by excluding and also by including subjects on anti-hypertensive therapy (after adjustments were made for anti-hypertensive medications).We evaluated sixteen top associated SNPs from the above genome wide association study for hypertension as a binary trait or blood pressure as a continuous trait. In addition, we evaluated eight single nucleotide polymorphisms located in two genes  showed borderline association (p = 0.006) with hypertension status using recessive model and systolic blood pressure (p = 0.02), but was not significant after adjusting for multiple comparisons. In quantitative trait analyses, among normotensives only, rs12748299 was associated with SBP (p = 0.002). In addition, several nominally significant associations were noted with SBP and DBP among normotensives but none were statistically significant.This study highlights the importance of replication to confirm the validity of genome wide association study results. Hypertension is a major contributor to the global disease burden with world-wide prevalence estimated to be ~ 26%, totaling ~ 1 billion people . Adoptio-7. Subsequently, several additional GWAS have been published, including 2 large-scale meta-analyses, demonstrating sporadic and inconsistent associations of SNPs with either blood pressure or hypertension [Genome-wide association studies (GWAS) are one strategy that is being exploited to identify the genetic contributions to hypertension. This strategy has been facilitated by the unraveling of the human genome, the HapMap project, and the availability of dense computer chips for genetic sequencing. In contrast to candidate gene approaches, GWAS offers the potential to identify novel mechanisms in the pathophysiology of hypertension. The first large GWAS for hypertension, performed by the Wellcome Trust Case Control Consortium (WTCCC) among British subjects (with 2000 cases and 3000 controls) in the , revealertension -17. Notaet al identified several SNPs reaching genome-wide significance for systolic blood pressure in or near genes: PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H [SLC24A4  and CACNA1H , are potential candidate genes for blood pressure regulation and the latter is also a drug target for a class of calcium channel blockers. Some of the significant SNPs were replicated in a sample of West Africans [et al in an independent population of African American subjects from the mid-western United States. In addition, in these African American subjects, we also sought to replicate SNP variants recently identified by GWAS in European and Amish populations, and further confirmed in the study by Adeyemo et al [In the first ever GWAS in African Americans , Adeyemo CACANA1H . Two of Africans . Indepenmo et al ,14,18.A total of 2474 eligible subjects were genotyped of whom 53% n = 1311) were women. Fifty-three percent (n = 1299) of the subjects were normotensives, and 47% (n = 1175) were hypertensives  when all the subjects were considered together as well as when normotensives were analyzed separately. Among hypertensives, in addition to rs12757682 and rs1867226, rs2146204 was also not in Hardy-Weinberg equilibrium.Case-control association analyses were done separately for each SNP with hypertensives as cases and normotensives as controls using PLINK association analyses. We did not observe any statistically significant difference in the allele frequency or in the genotype distribution of the 24 SNPs between cases and controls .Quantitative trait associations were carried out using PLINK between these SNPs and systolic and diastolic blood pressure on subjects both with and without inclusion of treated hypertensive subjects  showed no significant associations of blood pressure with any of the 24 SNPs after adjustment for multiple comparisons. However, the following several borderline associations were observed without statistical adjustment for multiple comparisons , in all untreated subjects (normotensives plus untreated hypertensives), in normotensives alone or in hypertensives alone Table . IndepenPMS1, SLC24A4, YWHA7, IPO7, and CACANA1H with systolic and diastolic blood pressure. However, among normotensives only, one SNP (rs12748299) showed a significant association with systolic blood pressure even after adjusting for multiple comparisons, but was no longer significant after adjustment for age, sex, BMI and serum creatinine. This SNP was previously marginally associated with hypertension as a binary trait in the study by Adeyemo et al, but had not reached genome-wide significance in their study either. It is located on chromosome 1 in the intergenic region and its biological plausibility is unknown at this time.In this sample of African Americans, none of the SNPs evaluated were convincingly associated with hypertension as a binary trait or with blood pressure level as a quantitative trait. Thus, we were unable to confirm previously reported associations between aldehyde dehydrogenase 1 family, member A2, ALDH1A2) and systolic blood pressure, and rs17365948  and systolic and diastolic blood pressure. The biological plausibility of these associations is currently unknown . Similarly, rs12757682 which is also located on chromosome 1 in the intergenic region, showed borderline association with systolic blood pressure among normotensives. Among hypertensives, borderline associations (p > 0.002) were noted between rs1550576 , rs6997709 (8q24), rs7961152 (12p12), rs11110912 (12q23), rs1937506 (13q21) and rs2398162 (15q26)) from WTCCC in the Family Blood Pressure Program (FBPP) cohort [negatively associated with systolic and diastolic blood pressure among European Americans. The same SNP showed a significant but opposite effect with systolic blood pressure in Hispanic Americans and was not associated in African Americans [Similarly, Ehret Inconsistent results among several small-scale GWAS -14,20 suet al.On a similar note, a large GWAS for blood pressure among African Americans, the Candidate Gene Association Resource (CARe) Study, has recently been published. In a meta-analysis across five community-based cohorts, two novel loci were identified that reached statistical significance: rs2258119 on chromosome 21 with systolic blood pressure and rs10474346 on chromosome 5 with diastolic blood pressure [et al carried out a GWAS of systolic and diastolic blood pressure in Amish subjects [STK39) were found and they confirmed these associations in an independent Amish and 4 non-Amish Caucasian samples [et al found that several SNPs in this gene were associated with the blood pressure (9/136 for systolic blood pressure and 33/136 for diastolic blood pressure) in African Americans. Variants in STK39 may influence blood pressure by increasing STK39 expression and consequently altering renal sodium excretion [et al.Even though the evidence for a genetic contribution remains robust, the effect of environment may be a major modifier, and this may be the reason for inconsistent data. Many common everyday activities can profoundly affect blood pressure, such as salt intake, exercise, stress, etc., and many of these are not quantitated in population-based studies. To minimize environmental and genetic variability, Wang subjects . Strong  samples . Adeyemoxcretion . We wereet al in a GWAS of a German population and is known as Cadherin 13-Heart (CDH13) [CDH13 is a calcium-dependent cell adhesion glycoprotein and may mediate interaction between cells in heart. Several SNPs in this locus were also found to be associated with systolic and diastolic blood pressures among African Americans by Adeyemo et al. We tested the association of 4 of these SNPs with hypertension as a binary trait and blood pressure as a quantitative trait in our sample. We confirmed a borderline association (insignificant when considered with multiple tests) of rs17177428 and rs7200009 with blood pressure as quantitative trait among hypertensive and normotensive subjects. Again, this association was not tested in CARe study by Fox et al.Another novel locus contributing to blood pressure was identified by Org  (CDH13) . CDH13 iAs evidenced by these studies, identification of genetic contributors to hypertension remains challenging for several reasons. Population heterogeneity, environmental effects, and sample size all contribute to these failures. Our study is also subject to these criticisms. In addition, as already eluded to, inheritance of blood pressure is polygenetic where in a single gene or combination of genes act in concert with above mentioned environmental exposures to contribute only a modest effect on blood pressure. Indeed, genetic variants identified by GWAS contribute to only a small effect on blood pressure (1-2 mmHg). Although this may have a population-based impact, this effect may not be discernible among individuals. Moreover, the difficulty of obtaining a standardized blood pressure phenotype cannot be over emphasized.We also acknowledge the limitations of using commercially available tag SNPs. While it is possible to identify genetic variation with tag SNPs without genotyping every SNP in the chromosomal region and are widely used in genome-wide association studies, it may make replication of target SNPs difficult due to differences in linkage disequilibrium between two samples. For this reason, many studies have now adopted the technique of "local replication" in which SNPs surrounding tag SNP are also targeted, especially for SNPs that are not directly replicated from previous studies .et. al. may account for non-replication of the GWAS. Since African Americans as an ethnic group are quite diverse with different origins, we recruited only the individuals whose parents were both born in the United States, with English as their first language, to achieve some uniformity in ethnicity. However, this may not have been sufficiently homogeneous population and the differences in the results may reflect different population admixture rates [Apart from inherent difficulties in identifying genetic determinants of hypertension due to the phenotype itself as well as methods, we acknowledge that the differences between the populations investigated by our study and Adeyemo re rates ,24. SincThere were several strengths to our study. Cases and controls were clearly defined with normotensives having blood pressures in the lower third of the population distribution of blood pressure (~ 3 SD below the untreated hypertensive means) to eliminate the bias of cases masquerading as controls or vice versa. Subjects with secondary hypertension were excluded including those with renal insufficiency. In addition, the mean age of the cases and controls are in mid-forties, which is sufficiently young to capture genetically determined blood pressure increases and old enough to capture most primary hypertensives. However, it is still possible some mis-classification of cases and controls might have occurred.While they are relatively easy to perform, interpretation of the results of successful association studies is neither straightforward nor always replicable. In addition, overestimation of genetic effect size in initial studies due to "winner's curse" may cause follow-up studies to be underpowered and so to fail . ResultsThe study was approved by the Froedtert Memorial Lutheran Hospital/Medical College of Wisconsin Institutional Review Board. Unrelated African Americans subjects between the ages of 18-55 years were recruited from a variety of community resources and health care providers within the Milwaukee area. Subjects were defined as African Americans based on self-identification, birth in the continental United States, both parents reported as being African Americans, and English as the native language. All subjects were evaluated during a single outpatient visit and were considered to have hypertension if standardized outpatient measurement of systolic blood pressure was ≥ 140 mmHg, diastolic blood pressure was ≥ 90 mmHg and/or if they were taking antihypertensive medications. Blood pressures of normotensives were in the lower third of the distribution of population blood pressures. Pregnant subjects, subjects with diabetes mellitus (fasting blood glucose ≥ 126 mg/dL (6.93 mmol/L) or random blood sugar > 200 mg/dL (11 mmol/L), and subjects with serum creatinine concentrations ≥ 1.3 mg/dL (114.92 μmol/L) were excluded.After subjects provided informed consent, standardized measurements of blood pressure and anthropometric measurements including height, weight, and waist circumference were acquired. Blood pressures were taken by trained and certified personnel according to the American Heart Association guidelines by the Shared Care Method using a sphygmomanometer . After bet al among AAs were selected for the study [STK39 and CHD13) identified in European and Amish populations [et al [SNPs associated with hypertension and blood pressure in the genome wide association study by Adeyemo he study . As showulations ,14 and rs [et al  in AfricDNA was extracted manually from peripheral white blood cell pellets using reagents from Qiagen  and precipitated using isopropanol . TaqMan 2 -test. In case-control analyses, odds ratios for hypertension were calculated using the major allele as reference. When analyzing systolic and diastolic blood pressures as continuous traits, to account for the treatment effect amongst those on anti-hypertensive medications, we used stepped addition of blood pressures to treated subjects based on number of drugs a subject was taking. As previously described by others [Continuous variables were reported as means ± standard deviation (SD). Differences in the distributions of all selected phenotypes between hypertensive and normotensive subjects were determined either by Student's t-test or by Wilcoxon rank sum test, depending upon the distribution of variables. Both SAS software version 9.1  and PLINK  were usey others , steppedP-values < 0.002 were deemed as significant after adjustment for multiple tests. One-way ANOVA was conducted to assess if there was a difference in the blood pressure among all 3 genotypes for each SNP. Multiple linear regression analyses were carried out with systolic and diastolic blood pressures as continuous dependent variables and multiple logistic regression with hypertension as categorical dependent variable. SNPs were represented as categorical variables either as minor allele or as homozygous genotype of minor allele in both logistic regression and linear regression analyses. Other independent variables included gender, age, BMI, and creatinine in the same model.Power calculations were performed using the program Quanto v1.1  [ia, USA) . Power fNHANES: National health and nutrition examination survey; GWAS: Genome wide association study; SNP: Single nucleotide polymorphisms; WTCCC: Wellcome trust case control consortium; PMS1: Post-meiotic segregation increased 1; IPO7: Importin 7; CACANA1H: Calcium channel voltage-dependent: T type: alpha 1H subunit; BMI: Body mass index; ALDH1A2: Aldehyde dehydrogenase 1 family member A2; YWHAZ: Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta polypeptide; FBPP: Family blood pressure program; DNA: Deoxyribonucleic acid; STK 39: Serine threonine kinase 39; CDH13: Cadherin 13- heart; CHARGE: Cohorts for heart and aging research in genomic epidemiology; Global BPgen: Global blood pressure genetics; CARe: Candidate gene association resource; P4HA2: Prolyl 4-hydroxylase alpha polypeptide II; ADH 7: Alcohol dehydrogenase 7 (class IV) mu or sigma polypeptide; HTN: Hypertension; Chr: Chromosome; rs: reference SNP number; SLC24A4: Solute carrier family 24 (Na/Ca/K exchanger) member 4; SV2B: synaptic vesicle glycoprotein 2B; NRXN3: Neurexin3; ABCC4: ATP-binding cassette (ABC) sub-family C (CFTR/MRP): member 4; PRC1: Protein regulator of cytokinesis 1; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; MAF: Minor allele frequency.The authors declare that they have no competing interests.SK participated in design the study, data acquisition, interpret and analyze the data and drafted the manuscript. SG helped interpret the data, JK participated in design and data acquisition, CG participated in design and data acquisition, ShK helped data analyses and manuscript writing, MK assisted in data acquisition and review of the manuscript, AC participated in design of the study, SP participated in design, analyses and interpretation of the data and drafting manuscript, TK participated in design, data acquisition, interpretation and data analyses and drafted the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/13/27/prepubTable S1. Genotype distribution of all 24 SNPs in cases and controls. Table S2 - Quantitative trait analyses. Table S3- Quantitative trait analyses in normotensive and hypertensive subjects. Table S4 - List of single-nucleotide polymorphisms (SNPs) genotyped. Table S5- Results of current study in comparison to study by Adeyemo et. al. Table S6 - Power calculation of effect size detectable based on minor allele frequency in case-control analyses.Click here for file


Dyslipidemia after kidney transplantation is a frequent finding and is multifactorial. Immunosuppressive agents such as cyclosporine (CsA) can cause hypercholesterolemia.As there were few reports with conflicting evidence on whether CsA related dyslipidemia is dose related and that CsA monitoring assays  is a better predictor for dyslipidemia development; hence, the current study, in a large sample size, was designed to answer these questions.In the current retrospective cross sectional study, 1391 kidney transplant recipients were enrolled. All patients received CsA plus mycophenolatemofetile or azathioprine and prednisolone. Serum creatinine, CsA blood levels and lipid profile were measured after 12-14 h fasting. Mann-Whitney and Kruskal-Wallis, Pearson`s test and logistic regression were used for data analyses.Mean age of 1391studied population was 38.7 ± 15 years old. Hypercholesterolemia and hypertriglyceridemia were observed in 58.9% and 86.6%, respectively and they were more significantly detected in cadaveric kidney transplantation. Dyslipidemia had weak correlation with age of recipient, serum creatinine, C0 and C2 levels of CsA. At logistic regression, serum creatinine was the only risk factor for hypercholesterolemia development after kidney transplantation .Dyslipidemia is a common finding after kidney transplantation and has no correlation with CsA level. According to conflicting data on the precise effect of different factors in inducing dyslipidemia, prospective large sample size studies should consider better control of dyslipidemia. Lipid abnormalities are frequent findings among renal transplantation recipients, although renal function is often normal or near normal . BesidesThere are conflicting evidence and few reports on whether CsA-related side effects are dose dependent phenomenon and if C0 level is a better predictor than two hour post dose (C2) level of CsA for dyslipidemia evolution , 7-10. TIn the current retrospective, cross-sectional study, 1391 kidney transplant recipients in several Kidney Transplant Centers, Tehran, Iran from April 2008 to January 2011 were enrolled. During this period, all patients were referred to a single laboratory for measurement of all biochemical parameters tests such as lipid profile. The patients with any infections, rejections, hypothyroid state or patients who used beta belockers, thiazids or OCPs were excluded. The current study was approved by the Local Ethics Committee of Baqiyatallah University of Medical Sciences.All patients received CsA  plus mycophenolatemofetil (1–2 g per day) or azathioprine (1–2 mg/kg per day) and prednisolone .The clinical and biochemical data recorded for all patients were sex of recipients and donors, donor source (living or cadaveric), serum creatinine (Cr) concentration, CsA levels, and lipid profile (triglyceride (TG), cholesterol (Chol), HDL- cholesterol and LDL- cholesterol). All the mentioned biochemical variables were measured < 3 months, 4-12 months and > 1 year after kidney transplantations. Blood samples were obtained in the morning after 12-14 hours fasting.According to NCEP ATP III,  hyperchoContinuous variables were expressed mean ± SD. Since none of the variables had normal distribution, non-parametric tests  were used to determine differences between the two and several groups. Pearson’s test was used to evaluate correlation between dyslipidemia and CsA blood levels. Data were analyzed using computer software program SPSS version 17.0 at P < 0.05 as level of significance.Mean age of 1391 subjects of the study population was 38.7 ± 15 years old, 849 (61%) male and 542 (39%) female. Seventy-five percent of patients received transplant kidney of living unrelated patient and 7% of living related patient and 6% of cadaveric . HyperchThe cholesterol and triglyceride level 4-12 months after transplantation were significantly higher than their level in less than 3 months and more than 1 year after kidney transplantation. The lowest level of HDL and the highest level of LDL were detected more than 1 year after transplantation . DyslipiDyslipidemia is a common complication after renal transplantation and hypertriglyceridemia is the most common type of dyslipidemia, although the current study finding on dyslipidemia prevalence is compatible with other studies, according to different dyslipidemia definitions, the type of dyslipidemia is not similar in studies , 12-16.Hypercholesterolemia and low HDL were significantly higher in cadaveric than living unrelated and related patients, probably due to more prevalent delayed or impaired graft function following cadaveric kidneys, which need more immunosuppressive drug than living kidney transplantation . DyslipiIn the present study, trough CsA concentration and C2 level of CsA were used to guide therapy. Precision of these parameters is related to strong correlation between them and dyslipidemia development. The current study found weak correlation between dyslipidemia, trough and C2 level of CsA. Despite the stable renal function in the patients under study, slight decrease in creatinine clearance can result in decreasing cholesterol clearance and hypercholesterolemia. The major power of the current study was the large sample size, and the most important limitations were not being prospectively designed, lack of data regarding diabetes, statins using, and BMI.In the current study dyslipidemia was a common finding after kidney transplantation and had no correlation with CsA level but serum creatinine concentration and female sex are two major predictors for hypercholesterolemia and hypertriglyceridemia development respectively. Therefore, to reduce hypercholesterolemia after kidney transplantation normal renal function maintaining should be strongly considered.


Background This study uses data from the World Health Organization’s Study on Global Ageing and Adult Health (SAGE) to examine patterns of hypertension prevalence, awareness, treatment and control for people aged 50 years and over in China, Ghana, India, Mexico, the Russian Federation and South Africa.Methods The SAGE sample comprises of 35 125 people aged 50 years and older, selected randomly. Hypertension was defined as ≥140 mmHg (systolic blood pressure) or ≥90 mmHg (diastolic blood pressure) or by currently taking antihypertensives. Control of hypertension was defined as blood pressure below 140/90 mmHg on treatment. A person was defined as aware if he/she was hypertensive and self-reported the condition.Results Prevalence rates in all countries are broadly comparable to those of developed countries . Hypertension was associated with overweight/obesity and was more common in women, those in the lowest wealth quintile and in heavy alcohol consumers. Awareness was found to be low for all countries, albeit with substantial national variations . This was also the case for control  and treatment efficacy . Awareness was associated with increasing age, being female and being overweight or obese. Effective control of hypertension was more likely in older people, women and in the richest quintile. Obesity was associated with poorer control.Conclusions The high rates of hypertension in low- and middle-income countries are striking. Levels of treatment and control are inadequate despite half those sampled being aware of their condition. Since cardiovascular disease is by far the largest cause of years of life lost in these settings, these findings emphasize the need for new approaches towards control of this major risk factor. The six countries comprise a total study population of 35 125 people aged 50 years and over. The period of data collection varied by country, ranging between 2007 and 2010. Overall individual response rates among those eligible within households and agreeing to participate in the survey varied from 52.4% in Mexico to 92.3% in China (Supplementary Table A1 (available as Supplementary data at IJE online) provides more detailed information about response rates to different questionnaire items. Ethical clearance was obtained from local research review boards at each participating SAGE site and the WHO Ethical Review Committee. Informed consent was obtained from each respondent prior to interview. Further information about the SAGE survey design and methods is available from a published data resource profile.We use new publicly available data from the World Health Organization (WHO) Study on Global Aging and Adult Health (SAGE). This comprises nationally representative household surveys in China, Ghana, India, Mexico, South Africa and the Russian Federation. Respondents were selected using a multi-stage, stratified, random cluster sampling design with every individual having a known non-zero probability of being selected. The primary sampling units were stratified by region and location  and, within each stratum, enumeration areas were selected. Details are available on the SAGE website .Blood pressure (BP) was measured using a Boso Medistar Wrist Blood Pressure Monitor Model S. Validation studies of similar wrist blood pressure monitoring devices indicate that they are capable of providing accurate measurementsRespondents were asked to remain seated and relaxed, and the importance of positioning their arm level with their heart was emphasized. BP was measured three times, with 1 min between each measurement. Participants were asked to self-report: ‘Have you ever been diagnosed with high BP (hypertension)?’ Those answering ‘yes’ were further asked: ‘Have you been taking any medications or other treatment for it during a) the last 2 weeks? b) the last 12 months?’ Height was measured using a stadiometer and weight was measured using an electronic weighing scale that was periodically calibrated. All interviewers were provided with a week of training, including demonstrations and audiovisual aids. Before launching the main phase of the study, a pretest was carried out on 1446 respondents, with 5% of respondents being retested within 7 days with an identical instrument. The SAGE main study also included a retest component on 5% of respondents. These studies show a moderate reliability in these measures with trained lay interviewers .Hypertension was considered to be present if the mean of the last two measurements was ≥140 mmHg (systolic blood pressure) or ≥90 mmHg (diastolic blood pressure) or if respondents were currently taking antihypertensives. Hypertensive participants were classified as controlled (i.e. on antihypertensives and blood pressure <140 or <90 mmHg). Those who were aware of their hypertension were classified into controlled and uncontrolled. Finally, among all those who were currently on treatment for hypertension, respondents were classified into those who were effectively treated (normotensive on measurement) and those who were not effectively treated (hypertensive on measurement).Appendix 1 (available as Supplementary data at IJE online). For those receiving treatment, we applied similar models  to determine the factors that were associated with effective treatment  compared with ineffective treatment .All data analysis was weighted, using individual weights that were post-stratified based on the UN Population Standards data.Adjusted individual-level multivariable analysis showed positive associations with increasing age and body mass index (BMI) consistently across countries. Women had higher odds of hypertension in all countries but China. Increasing BMI was strongly associated with hypertension. This was consistent across countries, and the large variations in the prevalence of overweight/obesity across the SAGE countries  were a key determinant for the national variations in prevalence reported in There were large national variations in the proportion of hypertensive participants who were aware of their condition  and who Supplementary Table A2 (available as Supplementary data at IJE online) shows large national variations in the effective treatment of blood pressure among people taking antihypertensive medication, ranging from 24% in South Africa to 55% in India. Supplementary Table A2 (available as Supplementary data at IJE online) shows that effective treatment of blood pressure was inversely associated with increasing BMI in three of the six countries. For the other factors there was no consistent pattern of association across the SAGE countries.This study examines the factors associated with prevalence, awareness and treatment of hypertension for large nationally representative samples of older people in LMICs. This analysis focuses on people over the age of 50 years, since people over this threshold have markedly increased risks of cardiovascular disease (CVD) and will derive greatest benefit from drug treatment in terms of numbers needed to treat. WHO guidelines for prevention of CVD also indicate that people aged 50 and over are the age range of highest risk and therefore of relevance for intervention with a polypill.,We found high prevalences of hypertension in all countries, with the highest being 78% for South Africa. Around half those sampled were aware of their condition, but only a very small proportion (4.1% to 14.1%) achieved blood pressure control. The prevalence levels of hypertension observed in this study are broadly consistent with those reported by previous national surveys of older adults conducted in China and Mexico.,In common with most epidemiological assessments of hypertension prevalence, blood pressure was measured thrice, at intervals of 1 min. In clinical practice blood pressure would be measured on at least three separate occasions spaced over longer periods of time before a diagnosis of hypertension was made and, if this is done, lower prevalences will be found due to regression to the mean.,For all six countries, prevalence increased sharply with age, although this effect was more notable in some countries (such as Mexico) than others (such as Ghana). This is in keeping with the findings of the other national studies in China and Mexico.,,Although only a few studies have examined awareness, treatment and control for older people in LMICs, the findings that are available broadly concur with those we report. For example, the 2000/01 China national survey reported that 46% of people aged 60 years and over were aware of their condition and 9% had it controlled.,Associations between wealth, education and health insurance status, on one hand, and prevalence, treatment and control, on the other, are more complex and challenging to interpret. Whereas the pooled data show that poorer groups are just as likely to experience hypertension as richer ones, there are varying patterns of social gradient across the six countries. Standard models of epidemiological transition posit that the strength and direction of social gradients will be related to a country’s general level of socio-economic development., Studies show that similar automated wrist devices to measure blood pressure compare well with gold-standard measurements using sphygmomanometers and trained health personnel.High prevalence among older adults in South Africa and Ghana raises the possibility that all countries across sub-Saharan Africa may already be experiencing globally unprecedented rates of hypertension. This corresponds with the results of a synthetic estimate of the global mean blood pressure trends which found highest levels in sub-Saharan Africa.Supplementary Table A3, available as Supplementary data at IJE online).This shows the need for a more nuanced appreciation of relationships between development and NCDs than is often made in the general literature.,National variations in hypertension do not correlate with economic and social development, based on indicators such as wealth, education and urbanization , which funded the WHO Study on global AGEing and adult health (SAGE) on which this analysis is based. Part of the analysis was funded by the Economic and Social Research Council (grant ES/K003526/1).This work was supported by the


There have been numerous studies assessing the association of diet and blood pressure but little is known about the association between less commonly used nutritional supplements and blood pressured. The purpose of this study was to quantify the use of dietary supplements and their potential association with blood pressure in a large population-based cohort of adults in the Midwest.The Personalized Medicine Research Project cohort was the population source for the current study. The current study includes subjects with Dietary History Questionnaire (DHQ) data available as well as at least one clinical blood pressure measurement recorded in their electronic medical record. After excluding extreme outlying measurements, median systolic and diastolic blood pressure measurements were calculated for each individual and were compared for subjects who did and did not report taking one of a list of 37 different supplements listed on the DHQ more than once per week over the previous 12 months.9,732 subjects had both blood pressure and DHQ data available. They ranged in age from 18 to 98 years (mean 56 years) and 3,625 (37%) were male. Nine of 37 supplements showed evidence for association with blood pressure: coenzyme Q10, fish oil, iron, bilberry, echinacea, evening primrose oil, garlic, goldenseal and milk thistle. With the exception of the mineral iron, mean systolic and diastolic blood pressures were higher for users of the specific supplements than non-users.These results should not be interpreted as causal, nor can the direction of the association be assumed to be correct because the temporality of the association is unknown. We hope the observed significant associations will foster future research to evaluate blood pressure effects of dietary supplements. One in three US adults has high blood pressure, defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥ 90 mmHg or taking an antihypertensive medication or having been told at least twice by a physician or other health professional that one has high blood pressure . Less thThe purpose of this study was to quantify the use of dietary supplements and their potential association with blood pressure in a large population-based cohort of adults in the Midwest. Existing data were employed for hypothesis generation about potential relationships between dietary supplement use and blood pressure. Where data exist, this can be a very cost effective approach, the first step being hypothesis generation, and the second step being hypothesis testing with a prospective study design that would allow determination of temporality.The Personalized Medicine Research Project (PMRP)  cohort wIn 2009, approximately six years after more than 18,000 subjects had been enrolled into PMRP, the National Cancer Institute Dietary History Questionnaire (DHQ)  was mailCompleted DHQs were returned by 63% of the living cohort for whom current addresses were available and who consented upon initial enrollment to future contact. The current sub-study of PMRP included subjects with DHQ data available as well as at least one clinical blood pressure measurement recorded in their Marshfield Clinic electronic medical record. The specific dietary supplements listed on the DHQ that were analyzed for the current study were: B-6, B-complex, brewer’s yeast, cod liver oil, coenzyme Q10, fish oil, folic acid/folate, glucosamine, hydroxytryptophan, iron, niacin, selenium, zinc, aloe vera, astragalus, bilberry, cascara sagrada, cat’s claw, cayenne, cranberry, Dong Kuai, echinacea, evening primrose oil, feverfew, garlic, ginger, ginkgo biloba, ginseng, goldenseal, grapeseed extract, kava, milk thistle, saw palmetto, St. John’s Wort, and valerian.Blood pressure measurements for the sub-study cohort were retrieved as available from the Marshfield Clinic electronic medical record. Measurements associated with hospital stays were excluded as were blood pressure measurements recorded on days with emergency room or urgent care visits. For women, blood pressure measurements were excluded for the seven months prior to childbirth and for one month after delivery. After excluding extreme outlying measurements for individuals based on their personal range of blood pressure measurements, median systolic and diastolic blood pressure measurements were calculated for each individual using all results available within +/− 1 year of the dietary questionnaire . Similarly, the body mass index of each individual was obtained as the median of measures available in the electronic record within +/− 1 year of the dietary questionnaire .Means of the per-person median systolic and diastolic blood pressure measurements were compared for subjects who did and did not report taking one of a list of 37 different supplements listed on the DHQ more than once per week over the previous 12 months. General linear models were used to adjust the comparisons for age, gender, body mass index, and current smoking status (as reported on baseline questionnaires). These variables were included in the linear models because of known association with blood pressure and because the data were relatively complete for the cohort, thus minimizing bias that could result from missing data. Data were analyzed with SAS® statistical software . A p-value < 0.05 was required in this initial screening for statistically significant associations, without adjustment for multiple comparisons.As of January 1, 2011, 19,981 subjects were enrolled in PMRP. Of these subjects 9,732 (49%) had both blood pressure and DHQ data available. They ranged in age from 18 to 98 years (mean 56 years) and 3,625 (37%) were male. The men were slightly older than the women (mean 59.5 for men and 54.2 for women), had slightly higher systolic and diastolic blood pressure measurements  in systolic and/or diastolic blood pressure was observed between users and non-users of nine of the specific dietary supplements: coenzyme Q10, fish oil, iron, bilberry, echinacea, evening primrose oil, garlic, goldenseal and milk thistle Table . The larIn the subset of subjects with no hypertension-related diagnoses, mean diastolic blood pressure was significantly lower for users of vitamin B6, cod liver oil, zinc and ginger and significantly higher for users of bilberry and goldenseal Table . Mean syTo our knowledge, this is one of the largest published studies of population-based estimates of dietary supplement use and their relationship to usual blood pressure. With the exception of the mineral iron, mean systolic and diastolic blood pressures were higher for users of the specific supplements which showed significant associations. These results should not be interpreted as causal, nor can the direction of the association be assumed to be correct because the temporality of the association is unknown. Rather, the significant associations should be considered hypothesis generating and used to foster future research with prospective study designs.Coenzyme Q10, also known as ubiquinone, is an antioxidant which may act to decrease blood pressure by acting directly on vascular endothelium. Authors of a meta-analysis of clinical trials concluded that coenzyme Q10 has the potential to substantially lower blood pressure in people with hypertension , while tAlthough not statistically significant to a very small sample size, one prior study in healthy volunteers found higher systolic blood pressure and lower diastolic blood pressure in subjects supplemented with echinacea in comparison with placebo .Mean blood pressure was significantly lower in a study of normotensive rats that were injected with ginkgo biloba extract . In a reSimilar to most previous studies ,14, we fThe authors of two reviews of the influence of garlic on blood pressure  and cardThere is a large body of evidence supporting an inverse association between blood pressure, hypertension and dietary intake of omega-3 fatty acids that are commonly found in fish. The authors of two meta-analyses published in 1993 concluded that there was dose–response blood pressure lowering effect of fish oil on blood pressure, perhaps through a vasodilation effect ,18. Two Iron is a trace element and essential nutrient. Several large epidemiological studies have demonstrated an inverse association between iron intake and blood pressure -24.A number of data limitations need to be considered when reviewing these results, remembering that the data were intended for hypothesis generation, not hypothesis testing. First, the DHQs were collected after the majority of subjects had been recruited into the biobank and 4% of the cohort had died. To the extent that blood pressure was associated with mortality, there is the potential for bias in the observed associations between blood pressure and dietary supplement use. Second, temporality was not considered. Potential inverse associations could have resulted from changed behavior after a hypertension diagnosis. Blood pressure and height and weight measurements taken from medical records have the potential for inaccuracy because the measurements were not taken in a standardized fashion. We have attempted to minimize potential bias from inaccurate measurements by imposing rules about which data points to use or remove for individuals.These results should not be interpreted as causal, nor can the direction of the association be assumed to be correct because the temporality of the association is unknown. Despite these limitations, these data are intriguing and suggest areas for further research, where sufficient evidence does not already exist, into potential dietary supplements that could be used to lower blood pressure or for which use should be cautioned in people with hypertension.The authors declare that they have no competing interests.CAM participated in the design of the study and drafted the paper. RLB conducted the statistical analyses. CR assisted in data collection and interpretation. RAD participated in the design of the study and the acquisition of data. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6882/13/339/prepub


Microcirculatory driving pressure is defined as the difference between post-arteriolar and venular pressure. In previous research, an absence of correlation between mean arterial blood pressure (MAP) and microcirculatory perfusion has been observed. However, the microcirculation may be considered as a low pressure compartment with capillary pressure closer to venous than to arterial pressure. From this perspective, it is conceivable that central venous pressure (CVP) plays a more important role in determination of capillary perfusion. We aimed to explore associations between CVP and microcirculatory perfusion.We performed a post-hoc analysis of a prospective study in septic patients who were resuscitated according a strict non-CVP guided treatment protocol. Simultaneous measurements of hemodynamics and sublingual Sidestream Dark Field imaging were obtained 0 and 30 minutes after fulfillment of resuscitation goals. Data were examined for differences in microcirculatory variables for CVP ≤ or > 12 mmHg and its evolution over time, as well as for predictors of a microvascular flow index (MFI) < 2.6.In 70 patients with a mean APACHE II score of 21, 140 simultaneous measurements of CVP and sublingual microcirculation (vessels < 20 µmeter) were obtained. (MFI) and the percentage of perfused small vessels (PPV) were significantly lower in the ‘high’ CVP (> 12 mmHg) group as compared to patients in the ‘low’ CVP (≤12 mmHg) group . Perfusion pressure (MAP–CVP) and cardiac output did not differ significantly between both CVP groups. From time point 0 to 30 minutes, a significant increase in MFI  but not in PPV, was observed, while CVP and perfusion pressure significantly decreased in the same period. In a multivariate model CVP > 12 mmHg was the only significant predictor for a capillary MFI < 2.6 , P = 0.026).We observed a significant association between a higher CVP and impairment of microcirculatory blood flow. Further research is needed to elaborate on our hypothesis generating findings that an elevated CVP may act as an outflow obstruction of organ perfusion. Resuscitation of critically ill patients is based on the generally accepted paradigm that cardiovascular optimization is needed to ensure adequate oxygen delivery to the tissue. However, whether corrections of systemic hemodynamics are translated into improvement of oxygen delivery at the capillary level often remains unclear in the clinical setting. Indeed, the common finding in studies using microcirculatory monitoring is the absence of a clear association between microcirculatory and macrohemodynamic variables, especially in conditions of sepsis . This ap2) of ≥ 70% and a cardiac index (CI) ≥ 2.5 L/min/m2. Systemic hemodynamic assessment was achieved through continuous invasive monitoring of arterial blood pressure and continuous cardiac output and SvO2 measurements using a pulmonary artery catheter . Stepwise goal-directed protocolized resuscitation consisted of 1) repeated infusions of at least 250 mL of crystalloids, colloids, or blood products, until the increase in left ventricular stroke volume was < 10%. An upper limit of pulmonary artery wedge pressure of 18 mmHg was used as an extra precaution to avoid fluid overload.; 2) treatment of inadequate systemic oxygen supply (defined as CI < 2.5 L/min/m2 or SvO2 < 70%) with dopamine administered at up to 10 μg/kg per minute and additional enoximone in case of an inadequate response to dopamine; and 3) treatment with norepinephrine in case of MAP < 60 mmHg despite the aforementioned steps. For this post-hoc analysis, macro- and microhemodynamic data obtained directly after fulfillment of resuscitation endpoints (T0) as well as 30 minutes thereafter (T30) were analyzed. During the study period, therapeutic goals and resuscitation protocol remained unchanged. The study was approved by the local ethics committee . Written informed consent was obtained from all included patients or their legal representative in accordance with local legislation.This study is a post-hoc analysis of a single center prospective study of the microcirculation in patients ≥ 18 years of age with confirmed sepsis, included within 4 hours of intensive care unit (ICU) admission . Patient2. Offline software-assisted analysis  yields information on both red blood cell velocity (convective oxygen transport) and capillary density (diffusion distance): the semi-quantitative microvascular flow index (MFI), ranging from 0 (no flow) to 3 (continuous flow), and percentage of perfused vessels (PPV) provide information on convexity, whereas total vessel density (TVD) and perfused vessel density (PVD) provide information on diffusion [A SDF camera  is a form of handheld intravital microscopy enabling direct visualization of the microcirculation . In shoriffusion . SDF imaiffusion ,13.2, CVP as a continuous variable, CVP > 12 mmHg and MAP.Data on SDF imaging, hemodynamic variables, inotrope dose and lactate, collected at 0 (T0) and 30 minutes (T30) after fulfillment of resuscitation goals, were analyzed to examine the relationship between CVP and sublingual microcirculation. Microcirculatory variables were restricted to small vessels (< 20 μm) only. Statistical analysis was performed using SPSS 18 . Differences in microcirculation and macrocirculation were evaluated for two CVP groups: CVP ≤ 12 mmHg (low CVP) and CVP > 12 mmHg (high CVP). This cut-off value is the lower limit of the advised CVP goal 12–15 mmHg) for the resuscitation of mechanically ventilated septic patients according to the Surviving Sepsis Campaign (SSC) guidelines . Further mmHg forEvolution over time (i.e. between T0 and T30) was also evaluated for both microcirculation and macrocirculation.The Kolmogorov-Smirnov test was used to test whether data were distributed normally; a Student’s T-test was used to test for differences between groups. Data are presented as mean ± standard deviation unless specified otherwise. A P <0.05 was considered statistically significant.Seventy patients with an APACHE II score of 21 ± 6.5 were included; ICU mortality was 21%. Table 2 was significantly higher in patients in the ‘low’ CVP group, and lactate levels significantly lower. A non-significant difference in perfusion pressure was observed  were obtained in patients with a CVP ≤ 12 mmHg. CVP in the ‘high’ CVP group (CVP > 12 mmHg) was significantly higher in comparison to the low CVP group . MFI and PPV were significantly lower in patients with a ‘high’ CVP   inflow pressure of the microcirculation may significantly differ from MAP as a result of post-arteriolar pressure drop and 2) the microcirculation may be considered as a low pressure compartment, with hydrostatic pressures slightly above CVP. However, diffusion distance seems to be unaffected, as reflected by the absence of a significant difference in TVD and PVD between CVP groups as well as over time. This may be explained by the fact that upregulation of the number of perfused capillaries, to compensate for a reduction in convective oxygen transport, may occur outside the timeframe of our observations .Data on the effect of elevated venous pressure on microcirculatory blood flow are limited: SDF imaging of renal blood flow in pigs showed a decrease in renal MFI in intra-abdominal hypertension, which is a model for venous outflow obstruction . In an eIt is conceivable that raising CVP under specific circumstances may be beneficial to tissue perfusion . However2 may both be explained as confounders, exaggerating the observed differences in microcirculatory perfusion. Extravascular pressures such as intra-abdominal pressure and positive end expiratory pressure (PEEP) settings may also have influenced CVP. PEEP level did not differ significantly between groups, nor did it change over time. In this study, data on intra-abdominal pressure are lacking. However, correction for these potential confounders in multivariate analysis did not eliminate the observed differences in microvascular perfusion between CVP groups. Moreover, the potential confounding factors may also serve as additional markers of impaired organ perfusion, underlining the importance of the observed differences between the groups.Our study has several limitations. Due to the post hoc design of the study, we were limited in the ability to explore the complex relationship between venous pressure and microcirculatory blood flow. Therefore, it is of utmost importance to stress that our finding is merely hypothesis generating. Imbalances between the two CVP groups in inotrope use, lactate levels and SvOSDF imaging of the sublingual microcirculation was performed, but venous pressure was not measured at this level. It is imaginable that venous pressure in the superior vena cava is not representative for venous pressure at the sublingual site and that this might have influenced the association between venous pressure and the sublingual microcirculation.We are also aware of the fact that microcirculatory blood flow is determined by other factors than inflow and outflow pressures alone. Not only may there be a further pressure drop within the capillary and venular compartment, it is also of note that microcirculatory flow regulation is not a static process. In reality, vasomotion is the constant opening and closing of capillaries under influence of downstream hypoxic signals . HoweverOur data were limited to a short time frame in the early course of sepsis resuscitation. Therefore, extrapolation of our findings to a larger time window is difficult. It was decided to limit the evaluation of SDF and CVP data to the measurements obtained at 0 and 30 minutes, because we observed a tendency towards progression of MFI towards 3 in the majority of patients during the 24 hour study period in the original data set . Due to The observed association between elevated CVP and impairment of microcirculatory perfusion is in line with physiological theory that microcirculatory perfusion pressure is predominantly determined by CVP as an outflow obstruction. This may have especially potential consequences for the use of a elevated CVP levels as a resuscitation endpoint. Clearly, our study was intended merely to explore the possibility of an association between microcirculatory parameters and elevated CVP in sepsis. The study design does not allow for making assumptions regarding causality. Further research is needed to clarify the role of elevated CVP in microvascular dysfunction in sepsis.Microcirculatory perfusion pressure can be defined as post-arteriolar pressure minus venular pressure and is much closer to venous pressure as to arterial pressure.An increased venous pressure is associated with impairment of microcirculatory perfusion in patients with severe sepsis and septic shock.This observation needs to be elucidated further in terms of a causal relationship, but could have potential consequences for resuscitation guidelines that are based on the assumption that elevated CVP will automatically improve organ perfusion.APACHE: Acute physiology and chronic health evaluation; CVP: Central venous pressure; CI: Cardiac index; ICU: Intensive care unit; MAP: Mean arterial pressure; MFI: Microvascular flow index; PEEP: Positive end-expiratory pressure; PPV: Percentage of perfused vessels; PVD: Perfused vessel density; SDF: Sidestream dark field; SOFA: Sequential organ failure assessment; SSC: Surviving sepsis campaign; SvO2: Mixed venous oxygen saturation; TVD: Total vessel density.C. Ince is the inventor of SDF technology, which is commercialized by MicroVision Medical. He has been a consultant for this company in the past, but he has broken all contact with this company for more than four years now, and he has no competing interests other than his commitment to promote the importance of the microcirculation in the care of critically ill patients.NV contributed to the study design, performed statistical analysis and wrote the manuscript draft. CI contributed to the study design and revised the manuscript critically. ECB was involved in data collection, SDF imaging and analysis, study design and writing the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2253/13/17/prepub


Phosphate plays a central role in the pathophysiology of CKD-MBD and the progression of chronic kidney disease (CKD) and contributes to the disproportionate cardiovascular risk faced by patients with CKD. Adaptation of nephrons attempting to preserve phosphate homeostasis requires endocrine tradeoff that fuel adverse events of hyperphosphatemia in CKD—secondary hyperparathyroidism, calcium and vitamin D derangements, vascular calcifi cation, and metabolic bone disorder.In fact, in advancing CKD there is a multitude of biochemical, physiological, and clinical alterations, and mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in CKD has advanced significantly in the past five decades. The principal hormones that regulate renal phosphate handling are parathyroid hormone (PTH), which is produced by the parathyroid gland, and fibroblast growth factor (FGF)-23, which is produced by osteocytes and osteoblasts in bone. In healthy individuals, increasing serum phosphate concentration induces secretion of PTH and FGF-23, and Kloto decline.It has been established (and now accepted by nephrologists) that observational studies strongly suggest that phosphorus is associated with cardiovascular risk, and definitive prospective animal studies are supportive. However, prospective studies demonstrating that modulation of the putative risk factor affects clinical outcomes are lacking, and phosphorus, as yet, does not qualify as a cardiovascular risk factor.This special issue provides an identification of the complex mechanisms that determine the phosphorus and calcium metabolism in CKD-3 and CKD-4; a verify the association of serum phosphate and related factors in ESRD-related vascular calcification. It has also addressed mineral metabolism in patients with CKG in the Era of KDIGO Guidelines, the effect of vitamin D on clinical outcomes in chronic kidney disease, and the effect of paricalcitol on vascular calcification and cardiovascular disease in uremia. Finally, were also discussed the effect of the use of non-calcium-phosphate binders in the control of vascular calcifications; the clinical significance of FGF-23 in patients with CKD, the the relationship between arterial stiffness and vascular damage; the treatment of severe metastatic calcification and calciphylaxis in dialysis patients; the clinical impact of hypercalcemia in kidney transplant patients.Biagio Raffaele Di IorioBiagio Raffaele Di IorioMarkus KettelerMarkus KettelerDomenico RussoDomenico RussoAngela WangAngela Wang


Aortic pulse wave velocity is altered by normal aging, as well as vessel wall pathology. We evaluated aortic compliance and its relationship to age in normals and patients with heart failure.Aortic compliance (AC) can be evaluated noninvasively and its reduction with aortic pathology and age in normals has been demonstrated with both MRI and Doppler echo methods. Aortic pulse wave velocity (PWV), a measurement of the flow pulse traveling along aorta as a surrogate for AC, can be assessed using a single breath-hold phase contrast (PC) imaging technique. Congestive heart failure is often associated with a chronic cardiac remodeling process in which the myocardium either cannot eject blood very well (systolic heart failure); or the myocardium is stiff and ventricular chambers do not fill with blood easily (diastolic heart failure). We hypothesize that aortic stiffness is increased in the CHF population and its age dependency differs from that in normals.As normal controls, 196 healthy volunteers gave informed consent  and were screened to exclude hypertension, hyperlipidemia and cardiovascular disease. Twenty two CHF patients had been referred for clinical CMR study with LVEF < 55%. Using the ‘candy cane’ view of aorta, an axial plane through the ascending and descending aorta at the pulmonary artery level was prescribed and a through-plane velocity encoded PC cine imaging was acquired with VENC of 150 cm/s, TR/TE/FA = 98ms/2.9ms/15° and voxel spatial resolution 1.3×2×6 mm3 on a 1.5T MRI scanner. The distance traveled by the aortic pulse wave, ΔD, was determined as the distance along the center line between the axial sections as imaged in the ‘candy cane’ image. For flow pulse onset, the cross correlation between the first halves of the ascending and descending aortic flow curves was calculated by varying the relative time shift between them. The Δt was the time shift at the maximal correlation. We then calculated PWV=ΔD/Δt. Linear regression was used to determine the relationships between PWV and age at both groups.PWV in CHF and in normals correlate with age, as shown in the Figure as left graph and right graph of scatter plots, respectively. The linear regression in normals is: PWV (m/s) = -5.548 + 0.2601*Age; while in CHF patients: PWV (m/s) = -1.277 + 0.1879*age; However, the relationship is stronger in normals. Young and elderly patients with CHF had lower PWV than normals, likely due to reduced stroke volume and blood pressure in the CHF group.Aortic stiffness increases with age in CHF patients, but the slope seems to differ from CHF patients to normals.None.


Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage). Blood pressure and renal parameters were recorded in both conscious and anesthetized  rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ∼20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone.Transgenic rats with inducible expression of the mouse  Tremendous strides have been made in this field and there are several treatments for reducing blood pressure in most patients. Nevertheless, basic research to establish causal pathways may lead to more effective management of existing hypertension or importantly provide a foundation for life-style advice in the pre-hypertensive phase. This endeavor is facilitated by the use of appropriate animal models. One such model is the cyp1a1-Ren2 rat, a transgene has been integrated into the Y chromosome. This transgene places mouse Ren2 cDNA expression under the control of an inducible cytochrome p450-1a1 promotor Ren2, primarily in the liver, leads to increased circulating renin levels, activation of the renin-angiotensin-aldosterone system and a rise in blood pressure. This rise in pressure is accompanied by a sustained elevation of circulating renin. Intrarenal synthesis of angiotensin II cyp1a1-Ren2 rat, and the model is therefore complementary to approaches using chronic infusion of angiotensin II, in which renin activity is suppressed.In the cyp1a1-Ren2 TGR and focuses on sodium transport in the distal convoluted tubule. Several lines of evidence led us to hypothesize that hypertension in the TGR model originates in the kidney and reflects an impaired ability to excrete sodium. First, dietary sodium loading exacerbates hypertension vasa rectaRen2 activation The current study was designed to resolve key mechanisms leading to hypertension in the cyp1a1-Ren2 TGR causes sustained activation of the thiazide-sensitive co-transporter by angiotensin II in the distal tubule. Renal injury is predominantly vascular, precedes the development of hypertension and may involve mineralocorticoid-dependent pathways.We find that induction of hypertension in the Systolic blood pressure and diastolic blood pressure increased significantly during the 24 hours following the second dose of I3C . Over thRen2 induction. Glomerular filtration rate rose significantly, at least until day 4  and the epithelial sodium channel  account for the majority of sodium transport in the ASDN and the contribution of each was assessed pharmacologically. At baseline, thiazide-sensitive transport was responsible for the reabsorption of ∼5% of the filtered sodium load. This increased progressively during Ren2-transgene induction , declined over the induction period but this was not statistically significant until the final day . Body weight was found not to change significantly, with end-weight being 96.5±1.2% of start weight. 24 h urinary aldosterone excretion was increased ∼20 fold over the induction period  contingency between the duration of transgene induction and microvascular injury. After 1 day of treatment, medial myocyte vacuolation was evident in arcuate and the larger interlobular arteries, indicative of vasospasm  and normalized thiazide-sensitive sodium reabsorption . Kidneys from five spironolactone treated rats were examined histologically: in two cases there was no evidence of vascular injury; in the other three, variable fibroid necrosis was observed.Chronic administration of losartan blunted the hypertensive response to transgene induction , increassorption . Kidneyssorption  and nor sorption . Mineralcyp1a1-Ren2 TGR. We show that the early phase of hypertension, characterized in this model by circulating angiotensin II in the high physiological range In this study we investigated the early renal adaptation to RAAS activation in the The synergistic effect of angiotensin II and sodium intake on blood pressure has long been known but underlying mechanisms are not fully understood. Angiotensin II promotes sodium retention and volume expansion, particularly if sodium intake is high cyp1a1-Ren2 TGR have demonstrated that hypertension is associated with enhanced sodium reabsorption reduction in proximal tubule sodium reabsorption cyp1a1-Ren2 TGR Previous studies in Slc4A8 in the collecting duct Slc4A8 plays only a minor role in our studies.Thiazides are considered to be selective inhibitors of transport by NCC, but recently it has been shown that they also inhibit sodium reabsorption through In order to be physiologically active, NCC must be phosphorylated on threonine and serine residues in a regulatory domain in the N-terminus per se reduces NCC expression in the apical membrane of the DCT Previous studies have shown that both angiotensin II and aldosterone can independently increase NCC-mediated sodium transport in the DCT Chronic infusion of either hydrochlorothiazide or losartan was an effective antihypertensive measure. Both treatments also increased fractional sodium excretion, implying that renal sodium retention is a key hypertensive mechanism in this model. In support of this hypothesis, reciprocal transplantation studies in AT1AR null and wild-type mice show that renal AT1R mediate the chronic hypertensive effects of angiotensin II infusion by promoting renal sodium reabsorption The afferent arteriole, glomerulus and post-glomerular structures were relatively protected from injury throughout the experiment: mild albuminuria developed by day 4 and was further increased coincident with raised renal vascular resistance. Our data suggest that protection from barotrauma reflects maintenance of efficient autoregulation Pressure-independent renal injury, involving both angiotensin II and aldosterone cyp1a1-Ren2 TGR. Our data show that angiotensin II, aldosterone and sodium status act in concert to cause hypertension and renal impairment and underscore the key role of thiazide-sensitive sodium transport in the long-term regulation of blood pressure. Approximately 1/3rd of the blood pressure rise was resistant to thiazide or losartan treatment. A similar proportion of hypertension persists in AT1R null mice infused with angiotensin II Renal, vascular and endocrine measurements have established distinctive aetiologies of hypertensive and renovascular disease following the conditional over-expression of renin in Experiments were performed under a UK Home Office Project License and protocols were approved by The University of Edinburgh. All surgery was performed under anaesthesia  and all efforts were made to minimize suffering.cyp1a1-Ren2 TGR on a Fischer (F344) background, from a colony maintained in the university's animal house. Rats, aged 12–14 weeks, were given free access to water and commercial rat chow, containing 0.3% sodium by weight  and were maintained under controlled conditions of temperature (21±1°C), humidity (50±10%) and light/dark (light 7am–7pm).Experiments were performed on male Cyp1a1-Ren2 TGR (n = 5) under ketamine/medetomidine anaesthetic, with buprenorphine used as a reversal agent and analgesic. After recovery, one-week equilibration was given during which restoration of the circadian rhythms for blood pressures, activity and heart rate was confirmed. Experimental data were then recorded and decoded using Art 4.0 software .Radiotelemetry devices  were implanted into the thoracic aorta of cyp1a1-Ren2 transgene was induced by administering the naturally occurring xenobiotic, indole-3-carbinol , by gastric gavage at 10am; this was repeated on the following 6 days. Data were obtained on the hour, processed to means, smoothed using a 5-point rolling average and used to observe circadian patterns in blood pressure, activity and heart rate  received an equivalent volume of vegetable oil over a 7-day period. Time-points are designated as control (n = 8), day 2 (n = 9); day 4 ( = 9) and day 8 (n = 9). In each group, mean arterial blood pressure and renal function were measured twenty-four hours after the final gavage treatment, as follows. Following thiobutabarbital anaesthesia , a cannula was inserted into the right jugular vein through which a solution, containing (in mmol/l): 120 NaCl, 10 LiCl, 15 NaHCO3 and 5 KCl, was infused (1 ml/h/100 g IV). The infusate also contained 0.5% p-amino hippuric acid (PAH) and 0.5% FITC-inulin. A cannula, containing heparin-saline, was placed in the right carotid artery for collection of blood and measurement of mean arterial blood pressure. The bladder was catheterized for collection of urine and a tracheostomy was performed to maintain a clear airway.Separate cohorts of One hour after the completion of surgery, rats underwent the following protocol: three consecutive collections of urine were made, each of 60 minutes. A sample (75 µl) of arterial blood was drawn at the start and then after each urine collection period for the measurement of haematocrit, FITC-inulin and PAH.After the first urine collection, amiloride was administered . After the second urine collection, hydrochlorothiazide was administered  alongside the amiloride. The drugs were delivered in a DMSO vehicle (2% v∶v), which, in a separate group of rats (n = 7), had no effect on renal function or blood pressure (data not shown). Finally, a 1 ml sample of arterial blood was taken for measurement of plasma electrolytes and the kidneys frozen at −80°C and used for Western blot. Animals were then killed by an overdose of anaesthetic.The concentration of Na, K and Li in plasma and urine was measured using ion-selective electrodes . The effect of amiloride on sodium excretion was taken as the difference between excretion rates in the first and second urine collections; that of hydrochlorothiazide was taken as the difference between excretion rates in the second and third urine collections.FITC-inulin and PAH concentrations were measured as described Cyp1a1-Ren2 transgenic rats (n = 8) were housed individually in metabolism cages with free access to powdered rat chow and water. Rats were acclimatized and after a 4-day control period, I3C was administered on each of 7 consecutive days, as described above. Urine was collected every 24-hours. Albumin was measured using commercial assays , aldosterone by ELISA Ren2 transgene was induced over a period of three days before being anesthetized for renal function studies, as described. A three-day induction was selected as a time-point at which significant changes to tubular function were not associated with a decline in renal haemodynamics or major destructive vascular lesions.Hydrochlorothiazide , spironolactone  or losartan  were administered by osmotic minipump , implanted on day 0 under isofluorane anaesthesia. A control group of rats (n = 6) received vehicle  alone. After implant, the Total protein was extracted from one kidney by homogenization and differential centrifugation in ice-cold buffer, containing 250 mM sucrose, 10 mM triethanolamine and 2% protease inhibitor cocktail, pH 7.6 . Protein solubilized in sample buffer  was separated by SDS-PAGE and blotted to PVDF membrane by semi-dry transfer. Immunoblotting was performed using polyclonal antibodies against NCC  and αENaC  and horseradish peroxide-conjugated secondary antibodies. Immunodetection was quantified by densitometry using ImageJ after treatment of the blots with ECL reagents. Equal loading of total protein was confirmed in the GAPDH  immunoblot.Kidneys were immersion-fixed in 10% neutral buffered formalin for 48 h followed by paraffin embedding. Four-micron sections were examined blind by a Consultant Pathologist (C.O.B.). Kidneys from at least three rats per experimental group were examined. For each, 2 complete hemisections of the left kidney were blocked and all vascular profiles in each hemisection examined at 4 different levels in the block. Two were stained with hematoxylin and eosin and two with Periodic Acid Schiff, giving 8 levels per case. Analysis of microvascular injury was performed using an ordered categorical scale according the presence of destructive microvascular arterial or arteriolar lesions characterized by intramural necrosis and/or fibrinoid change. A score of “one” indicates non-confluent necrosis and isolated myocyte death; “two” indicates a single foci of necrosis per section; “three” indicates 2–3 foci; and “four” indicates >3 foci of destructive vascular lesions. Undamaged sections were scored zero.2 analysis.Data are presented as mean ± SE. Comparisons were made using either one- or two-way analysis of variance, as appropriate: post-hoc comparisons were made using the Holm-Sidak test. For scoring of microvascular injury, contingency tables were generated for X


Background. Previous reports provided inconsistent data on the occurrence of postoperative delirium and emphasized its considerable impact on outcome. This study sought to evaluate the incidence and predictors of delirium, together with its relation to cerebral ischemia in a large cohort of cardiac surgery patients in a tertiary high-volume center. Methods and Results. Consecutive patients (n = 8792) were prospectively enrolled from 2003 to 2008. Exclusion criteria were history of psychiatric disorders, use of psychoactive drugs, alcohol abuse, and data incompleteness. Finally, 5781 patients were analyzed in terms of 100 perioperative patient-specific and treatment variables. The incidence of postoperative delirium (DSM IV criteria) was 4.1% and it coexisted with cerebral ischemia in 1.1% of patients. In bivariate analysis, 49 variables were significantly linked to postoperative delirium. Multivariate analysis confirmed that delirium was independently associated with postoperative stroke (logistic odds ratio (logOR) = 2.862, P = 0.004), any blood transfusions , age > 65 years , carotid artery stenosis , urgent/emergent surgery , fasting glucose level, intraoperative oxygen partial pressure fluctuations, and hematocrit. Area under ROC curve for the model was 0.8933. Conclusions. Early identification of nonpsychiatric perioperative determinants of delirium facilitates its diagnosis and might help develop preventive strategies to improve long-term outcome after cardiac surgery procedures. Despite the undeniable progress in surgical techniques and perioperative care of cardiac patients, composite rate of mortality and postoperative morbidity still remains considerable, which is vastly attributable to neuropsychiatric complications , 2. AccoSince the available management is purely symptomatic (neuroleptic and sedative agents)  and auxiThe study was performed in a tertiary high-volume cardiac surgery center. Consecutive patients were prospectively enrolled between January 2003 and December 2008. A flow chart of subjects is delineated in minus minimal value) of arterial blood gas parameters  during the surgery under general anesthesia (with 100% oxygen supply) we categorized these variables on the basis of their quartile distribution, taking <ΔQ1 as the cutoff for extremely low, ΔQ1–3 as a reference interval of no variation and >ΔQ3 as the cutoff for extremely high variations.Delirium was diagnosed postoperatively by the attending physician  according to the criteria of Diagnostic and Statistical Manual of Mental Disorders IV edition (DSM-IV) , which aμg/kg) and the use of non-depolarizing muscle relaxant (pancuronium 1.0-2.0 mg/kg or cisatracurium 0.15–0.2 mg/kg). The anesthesia was sustained with the technique of total intravenous anesthesia  or with combined intravenous and inhalational anesthesia . Muscle relaxation was sustained with the repeated doses of muscle relaxant. Intubation was achieved using 6.5–9 mm single- or double-lumen endotracheal tube (for one lung ventilation). We used pressure-control or volume-control mechanical ventilation with 100% oxygen, simultaneously monitoring respiratory rate and volume, airway pressure, end-tidal-CO2 and blood oxygen saturation. Patients were hemodynamically monitored in a continuous fashion . Body temperature was measured using thermistor-based esophageal temperature probe. Foley catheter was inserted and urine output was continuously assessed. Antibiotic prophylaxis of 1st generation cephalosporin was administered to every operated patient for at least 72 h after induction. Intravenous fluids were supplemented at the rate of 80–150 mL/h depending on hydration status .All patients were anesthetized in coherence with the unified protocol involving oral premedication with midazolam (7.5 mg–15 mg) and induction with intravenous etomidate (0.15 mg/kg) or propofol (1.0–2.5 mg/kg) and fentanil (7.0–10.0 2/min and pressure of 60–70 mmHg. The majority of surgeries were conducted in moderate hypothermia (32°C), except for the aortic dissection surgery requiring deep hypothermia. Rewarming rate was 0.5–1.0°C/5 min. On completion of all anastomoses, protamine was given to reverse the effect of heparin and return the ACT to preoperative levels.Surgical management varied depending on the type of procedure and surgeon's preference. Median sternotomy was the predominant approach with the exception of minimally invasive surgeries which involved lateral thoracotomy. On-pump cardiac surgery involved administration of full dose low molecular weight heparin (3 mg/kg) to achieve a target-activated clotting time (ACT) of ≥480 seconds before commencement of cardiopulmonary bypass (CPB), along with the insertion of cannula into the ascending aorta and right atrium. In the off-pump group, heparin (1 mg/kg) was administered before the start of the first anastomosis to achieve an ACT of 250 to 350 seconds. High-potassium (20–30 mmol/l) cardioplegic solution (4 : 1) was reversely injected into the coronary arteries . Standard circuit tubing set was used, which included a roller pump and a membrane oxygenator with the flow rate throughout bypass of 2.0–3.0 l/mt-test or analysis of variance, and Mann-Whitney U-test or Kruskal-Wallis test were used for those nonnormally distributed. As far as qualitative variables are concerned, Mantel-Haenszel chi-square or Fisher's exact test was applied. In bivariate analysis, delirium  was defined as a dependent variable, whereas independent variables were designated from amongst perioperative parameters. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. Variables with a “P” value < 0.1 were consecutively subjected to a multivariate stepwise logistic regression model. Logistic ORs with 95% CIs were subsequently estimated. After the assessment of area under the receiver operator curve, the goodness of fit for logistic regression model was verified with Hosmer-Lemeshow test. A “P” value < 0.05 was considered significant.Statistical analysis was performed using SAS 9.2  software. Continuous variables are expressed as mean and standard deviation  or as median and interquartile range (IQR) . The type of distribution was verified using Shapiro-Wilk test. Qualitative variables are expressed as crude values and percent. Between-group differences for normally distributed quantitative variables were assessed using Student The characteristics of the study population are shown in P < 0.001). Compared to non-psychotic population, delirium significantly prolonged (P < 0.001) the time of ICU stay by 3.5 days  for subjects without and by 6.5 days  for those with cerebral ischemia. Total inhospital stay was also significantly longer (P < 0.001) by 5 days  for those without and by 9 days  for those with cerebral ischemia.Delirium developed postoperatively in 236 subjects  and cerebral ischemia alone was present in 148 patients . Coexistence of delirium and cerebral ischemia occurred in 65 patients . Median time of delirium was 3 days  for those without and 6 days  for the patients with cerebral ischemia (P < 0.1) association with postoperative delirium regardless of cerebral ischemia (Tables P < 0.0001), was the most powerful single determinant of delirium. Conversely, past medical history of cerebral ischemia failed to show any association with perioperative delirium. Among other determinants of neuropsychological complications, a noteworthy association was found for packed red blood cells transfusion , age older than 65 years , urgent mode of surgery , high perioperative risk calculated with EuroSCORE  and a history of chronic obstructive pulmonary disease . Although we reported only 16 cases of former CABG, the need for recurrent surgical revascularization strongly correlated with the risk of neuropsychiatric complications .In bivariate analysis it was found that 49 variables had a significant  [β-blockers, angiotensin-converting enzyme inhibitors), as well as decreased variations of blood pressure during the cardiopulmonary bypass [Although postoperative cerebral ischemia affected only 2.6% patients, our analysis indicated stroke as the most reliable predictor of delirium. In line with present study, Manji et al. documented that postoperative occurrence of seizures  corresponds with an increased rate of neuropsychological derangements, defined as delirium and/or stroke, as opposed to non-epileptic individuals  . The red< 0.001) , 20, 21.< 0.001)  and an a< 0.001) . The raty bypass .The study has several shortcomings, which may limit application of its results to all populations. First, it is based on the experience of a single medical center. On the one hand, it insures data and procedure consistency, but on the other hand, application of our results to other patient populations is limited. Second, although we enrolled consecutive patients, some of them were excluded due to data incompleteness. Consequently, only about 2/3 of patients were included, which may potentially be the source of selection bias. More to the point, this prospective observational study was conducted between 2003 and 2008 and may not address some advances of perioperative management in the last five years. Third, as the study population is relatively old, the impact of dementia is of great importance, and in some cases clinical differentiation between delirium and cognitive disorders was difficult or even impossible. Moreover, procedure-related depression and anxiety were not investigated. Fourth, it could result in underestimation of delirium prevalence that the diagnosis of delirium was not based upon uniform bed-site algorithms, such as Confusion Assessment Method (CAM), Delirium Observation Screening (DOS), or Delirium Rating Scale (DRS). However, the proximity of tertiary psychiatric center and a meticulous assessment during a routine checkup at least twice a day should have provided acceptable sensitivity of delirium screening. We realize that it requires additional psychological tests and a long-term observation so we decided to exclude patients with any psychiatric disorders in anamnesis and to assess nonpsychiatric variables only. Fifth, the occurrence of cerebral ischemia could be underestimated (silent ischemia with no deficits) because only those subjects with evident neurologic disorders underwent computed tomography examination. Although numerous medications may increase likelihood of delirium, the authors were unable to evaluate their impact on the results because of the heterogeneity of pharmacological treatment. For the same reason this study did not aim at evaluating the significance of perioperative pharmacological neuroprotection, which has been recently brought up by several investigators –32. FinaDelirium belongs to frequent psychiatric complications in cardiac surgery setting. Most of nonpsychiatric predictors of delirium are in direct relation with decreased cerebral perfusion and oxygen supply. Improper perioperative anesthetic management and the complications ensuing from the urgency of surgery are of great clinical significance. Early identification of the determinants of delirium may facilitate its diagnosis. It is advisable to utilize the abovementioned risk factors in the bed-site algorithms of perioperative risk assessment to improve the outcome of cardiac surgery patients with psychosis.