Anaesthesia is frequently complicated by intraoperative hypotension (IOH) in the elderly, and this is associated with adverse outcome. The definition of IOH is controversial, and although management guidelines for IOH in the elderly exist, the frequency of IOH and typical clinically applied treatment thresholds are largely unknown in the UK.We audited frequency of intraoperative blood pressure against national guidelines in elderly patients undergoing surgery. Depth of anaesthesia (DOA) monitoring was also audited due to the association between low DOA values and IOH with increased mortality (as part of “double” and “triple low” phenomena) and because it is a suggested management strategy to reduce IOH.Twenty-five hospitals submitted data on 481 patients. Hypotension varied depending on the definition, but affected 400 patients (83.3 %) using the AAGBI standard. Furthermore, 2.9, 13.5, and 24.6 % had mean arterial blood pressures <50, <60, and <70 mmHg for 20 min, respectively, and 136 (28.4 %) had systolic blood pressure decrease by 20 % for 20 min. DOA monitors were used for 45 (9.4 %) patients.IOH is common and use of DOA monitors is less than implied by guidelines. Improved management of IOH may be a simple intervention with real potential to reduce morbidity in this vulnerable group. Older patients are vulnerable to perioperative complications due to a combination of physiological frailty and comorbid disease and now constitute an increasing proportion of the surgical population . The latter methodology is part of a national programme of network-based, trainee-led collaborations that aim to deliver audit, research and quality improvement projects.Maintaining intraoperative blood pressure and depth of anaesthesia within broadly normal limits are thus generally accepted standards, supported by recent evidence and national guidelines, and might influence outcomes for elderly patients. It is known that established standards are not met in the hip fracture population  or jet ventilation were excluded. Audit standards and definitions were identified from consensus statements, research and national guidance. The AAGBI standard, ‘a fall in systolic blood pressure of more than 20 % from pre-induction baseline… is a suitable limit’ , which are typically documented every 5 min. The values were taken at 5-min intervals for both non-invasive and invasive monitoring. Preoperative blood pressure was determined using a reading from pre-assessment clinic, the theatre care plan or ward observation chart . Pre-induction blood pressure documented was the blood pressure taken immediately prior to the induction of anaesthesia. Where multiple hypotensive episodes occurred, total cumulative hypotensive time was calculated. If different degrees of hypotension occurred at separate time points, the lowest value was taken to calculate the degree of drop from the pre-induction pressure. The frequency of recording DOA values varies, but is typically every 15 min. Types of DOA monitoring and cumulative duration of scores less than 40 were documented.p < 0.05. Continuous data is presented as median (IQR [range]), categorical data as number (proportion).Statistics were calculated using R version 3.2.0 . Data were examined for normality using the Shapiro-Wilk test. Paired data was compared using the Wilcoxon matched pairs test. Categorical data analyses were made using chi square test with Fisher’s correction. All tests were two tailed, and significance was taken as Twenty-five hospitals submitted data for 481 patients. The median number of patients per hospital was 19 . Results were received from 11 (44.0 %) district general hospitals, 11 (44.0 %) teaching hospitals and 3 (12.0 %) single specialty hospitals. One case was not completed beyond detail on gender and was therefore excluded from analysis. Paper-based anaesthetic records were used in 411 (85.6 %) cases whilst printed computerised records were available in 6 (24.0 %) hospitals and therefore used for 69 (14.4 %) cases. Incomplete recording of blood pressure was present in 12 cases on paper notes (2.5 %) compared with 0 cases with an electronic record. The patient and surgery characteristics, frequency of systolic hypotension and prolonged IOH are shown in Table p = 0.02), the effect size was small, median preoperative blood pressure 140/77 mmHg, and pre-induction 140/78 mmHg (Table The method for measuring intraoperative blood pressure was recorded in 478 cases (99.4 %), and 89 (18.6 %) patients in this group had invasive monitoring. Preoperative blood pressure values were not documented in 47 cases (9.8 %). Stage 1 hypertension ; 129 (26.8 %) patients had mean arterial pressures less than 55 mmHg at some point during their surgery; this persisted for over 20 min in 45 (9.6 %) patients.Figure χ2 = 0.3634). Additionally, there were no significant differences in the occurrence of intraoperative systolic hypotension between the different types of regional anaesthesia (χ2 = 0.5774).Regional anaesthesia was used in combination with general anaesthesia in 95 (19.9 %) cases, most commonly in orthopaedic surgery  and colorectal surgery . There were no significant differences IOH (>20 % of pre-induction systolic baseline) incidence in patients who received combined regional and general anaesthesia techniques in comparison with those who received general anaesthesia alone (Depth of anaesthesia monitoring was used in 46 (9.6 %) patients in 11 (44.0 %) hospitals, although 24 (52.2 %) patients’ data came from 2 hospitals. Twenty-nine (63.0 %) patients had intraoperative total intravenous anaesthesia (TIVA) and 17 (37.0 %) had inhalational anaesthesia. In those patients where DOA monitors were used, 37 (80.4 %) used BIS and 9 (19.6 %) used Entropy. Thirty-seven (80.4 %) of these patients had a DOA scores <40. In 33 (89.2 %) patients, this was combined with a systolic blood pressure reduction greater than 20 %. Twenty-seven (73.0 %) patients had a DOA score <40 for longer than 20 min.We have demonstrated that IOH, as described by current definitions, is extremely common in the centres studied. Although this did vary dependant on definition, a large proportion (39 %) experienced a drop ≥40.1 %, a degree of IOH that has previously been associated with excess stroke, myocardial ischaemia and kidney injury. DOA monitoring was not used as often as suggested by NICE guidelines  and hypotension are associated with harm (Sessler et al. PLAN is a trainee-led collaborative research and audit network supported by the London Academy of Anaesthesia. The structure is similar to other trainee networks (South West Anaesthetic Research Matrix We have demonstrated that IOH is widely prevalent in elective and unscheduled surgery in older patients in a UK setting. DOA monitoring, which might be used to minimise excessively deep anaesthesia and associated hypotension, is infrequently used. Our results suggest the need for a larger national UK investigation of practice to further clarify the clinical threshold employed for treatment of IOH in the context of patient factors and outcome. Although prospective interventional studies are required to establish an effect of tighter blood pressure control, it is unlikely that a drop of >40 % should be tolerated. Greater awareness of this issue may enable local quality improvement and improved outcomes. National studies using trainee networks have the potential to deliver these goals.


A noninvasive system for determining left ventricular (LV) filling pressure may help to improve personalized fluid removal goals in hemodialysis patients. We previously showed that the change in photoplethysmography (PPG) pulse amplitude measured by finger PPG during a Valsalva maneuver correlates with invasively measured left ventricular end-diastolic pressure (LVEDP). This key PPG change, the ratio of finger PPG pulse amplitude at end-Valsalva to baseline, is known as the Pulse Amplitude Ratio, PAR. The objective of this study was to determine how PAR changes after fluid removal in hemodialysis.We tested subjects with end-stage renal disease, before and after hemodialysis. Each subject performed a Valsalva maneuver with an effort of 20 mmHg for 10 s, guided by the device display. Finger PPG was recorded continuously before and during the maneuver. PAR was calculated automatically.p < 0.0003) with an average fluid removal of 3.07 ± 1.08 l. Correspondingly, PAR decreased from 0.74 ± 0.24 to 0.62 ± 0.23 (p = 0.003). The change in PAR was correlated with baseline PAR .Twenty-seven subjects  ages 25–75 years were tested. Access sites were AV-fistulas of the arm predominantly. Weight decreased from 99.7 ± 36.9 kg to 97.0 ± 36.0 kg (An index of left heart filling pressure obtained noninvasively using finger photoplethysmography during the Valsalva maneuver is sensitive enough to detect reductions in filling pressure after fluid removal with hemodialysis. Further studies are warranted to determine if this method can be used to guide fluid removal during hemodialysis. Hemodialysis patients undergo volume shifts during their dialysis in an attempt to reach optimal dry weight. The significance of dry weight achievement lies in that fluid accumulation between dialysis has been demonstrated to be a predictor of death and cardiovascular complications . Aiming Assessing cardiac filling pressure clinically is challenging, especially with current non-invasive strategies , since many tests are neither sensitive nor specific . The ValRecently, we have developed a hand-held, battery-powered device that guides patients in performing a Valsalva maneuver at 20 mmHg expiratory effort for 10 s while recording finger photoplethysmography. It automatically calculates pulse amplitude ratio (PAR), the amplitude at end-Valsalva divided by the amplitude at baseline. The objective of this study was to determine if PAR is sensitive enough to detect changes in left heart filling pressure that accompany fluid removal in hemodialysis.Participants were recruited from Johns Hopkins Bayview Medical Center and DaVita J.B. Zachary Dialysis Center from February 2012 to July 2013. Eligible patients included those between the age of 20–85 years who are receiving chronic, intermittent hemodialysis as an inpatient at Johns Hopkins Bayview Medical Center or outpatient at DaVita J.B. Zachary Dialysis. Patients were excluded if they had acute onset of renal failure with less than three dialysis sessions during their inpatient stay, if an inpatient required dialysis at the bedside, patients in the intensive care unit, and patients unable or unwilling to perform a Valsalva maneuver. All participants provided written informed consent. The procedures followed were in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 2000, and the Johns Hopkins University Institutional Review Board reviewed and approved the protocol.Participants were tested while in a seated position (outpatient) or in a semi-recumbent position (inpatient), within 15 min prior to their hemodialysis session and again 15 min after their hemodialysis session was completed. The device’s photoplethysmography transducer was attached to either their middle or ring finger on the hand opposite of the hemodialysis access site. For example, if the subject had an arterio-venous (AV) fistula in their right upper extremity, the photoplethysmography transducer was used on the left middle or ring finger (belonging to the extremity without the AV fistula); if the patient had a left subclavian catheter, the right hand was used. A mouthpiece attached to a pressure transducer input into the device was given to the participant to hold in the contralateral hand. Participants were coached using a graphical user interface on the screen of the device. The screen displayed the expiratory pressure signal, and provided upper and lower limits for the participant to maintain an exhalation effort of 20 mmHg for 10 s. The pressure and photoplethysmography signals were recorded simultaneously. A minimum of three and a maximum of six successful expiratory efforts were acquired.The patient had the same coach before and after hemodialysis. All coaches were trained and had demonstrated the ability to adequately teach participants prior to enrolling formal subjects. Further, the device’s design allows for standardization of the Valsalva performance; therefore, minimizing inter-observer error.“Years of hemodialysis” was defined as years requiring hemodialysis without discontinuation. For example, if a subject was on hemodialysis in the past and had stopped , then restarted, the time of restarting to the time of recruitment was defined as “years of hemodialysis”. Only five subjects had prior hemodialysis that was discontinued .Transduced signals were input into the device. Filtering parameters of the photoplethysmography signal were 10-Hz low pass and 0.01-Hz high pass. An exhalation effort achieved within 3 s and sustained between 18 and 25 mmHg for 10 s was required in order for the device to record the data. If three successful attempts could not be achieved, whether before or after hemodialysis, the subject was documented as “unable to complete”; any data obtained from such a subject was not used towards analysis. Waveforms were analyzed using software accompanying the digital acquisition system. For each Valsalva effort, the amplitudes of three typical cycles of the baseline photoplethysmography waveform were averaged. The amplitude of the cycle just before 10 s into the Valsalva maneuver was measured. We did not use multiple cycles when calculating pulse amplitude during the Valsalva maneuver because the amplitude changes continuously during the maneuver. The average PAR over all the acceptable efforts was obtained before hemodialysis and again after hemodialysis.t tests. Relationships between PAR and other variables were ascertained using simple linear regression. Analyses were conducted with SigmaPlot 11.0 .All values are reported as mean ± standard deviation unless otherwise specified. We examined the distribution of variables and change in variables by assessing symmetry of box plots. We did not opt to formally test the normality of these variables because of the expected low statistical power of such a test with the sample size we have. We would not have been able to determine whether a non-significant p-value really meant normality or was due to larger than desired type two error. Coefficient of variation was calculated for each set of baseline PAR measurements as standard deviation / mean. The average coefficient of variation was calculated over all the subjects tested. Statistical comparisons between pre-dialysis and post-dialysis variables were performed using paired A total of 29 subjects were recruited between the two sites; however, 2 of the subjects could not complete the required number of successful Valsalva maneuvers and were excluded from the final analysis. Therefore, 27 subjects, of which 6 were female, were reviewed and their data is presented below. The mean age was 53.2 ± 13.4 years, with the range being between 25 to 75 years. Table With regard to the renal characteristics of the subjects Table , the medFigure Table p = 0.003); however, no other vital signs changes were statistically significant. Weight and body mass index changes did have significant changes as well . The mean volume removed was 3.07 ± 1.08 L, with a range of 0.6 L to 5.0 L. Correspondingly, there was a significant decrease in PAR, from 0.74 ± 0.24 to 0.62 ± 0.23 . The change in PAR was not correlated with volume removed , volume removed per starting weight , change in weight , or relative change in weight . Also, the percent change in PAR was not correlated with volume removed , volume removed per starting weight , change in weight .There was a statistically significant change in diastolic blood pressure before and after hemodialysis . The patient’s weight decreased by 4.7 kg (179.6 kg to 174.9 kg) with a change in PAR 0.06. There was a fall in both systolic and diastolic blood pressures (from 137 to 108 mmHg systolic and from 75 to 55 mmHg diastolic). Heart rate did not change (93 beats per minute to 86 beats per minute). Of note the patient was on no anti-hypertensive medications.In this study, we investigated whether a noninvasive index of left heart filling pressure using finger photoplethysmography during the Valsalva maneuver is sensitive enough to detect changes that occur after one session of hemodialysis. The index is the ratio of pulse amplitude at end-Valsalva to pulse amplitude at rest . We used a hand-held, battery-powered device with an automated graphical user interface that guides the subject and calculates PAR. We found that PAR measured by the device does change significantly with one session of hemodialysis. The implication is that the change in left ventricular filling pressure that occurs with volume removal during dialysis can be detected noninvasively. Therefore, it is worth investigating whether PAR can be used to detect residual left ventricular pressure overload between dialysis sessions, or whether PAR can predict intradialytic hypotension.We also found that the change in PAR with hemodialysis correlated with baseline PAR; i.e., when pre-hemodialysis PAR was higher, the decrease in PAR with hemodialysis was greater. This suggests that when pre-hemodialysis LVEDP is higher, the decrease in LVEDP with hemodialysis is greater. This probably reflects the nonlinear pressure-volume relation in the left ventricle, where a given change in volume produces a greater change in pressure at higher starting points on the curve . The corThe change in PAR was not correlated with the amount of volume removed or with the change in weight. This is also probably due to the nonlinear pressure-volume relation. Each subject may have been on a different starting point on their pressure-volume curve, and each subject’s pressure-volume curve may differ from that of the others. Hence, a given volume removed with HD cannot predict the magnitude of the resulting decrease in LVEDP. This concept may help to explain some of the limitations of using volume and weight changes to manage dialysis patients.Blood pressure responses to the Valsalva maneuver and their correlation with cardiac volume or pressure was first demonstrated several decades ago, and later by others , 19, 20.PAR is a continuous variable, best measured using a continuous waveform. PAR has been shown to reflect left heart filling pressure using indwelling pressure transducers , 19 and Other non-invasive techniques have been investigated for assessing changes after hemodialysis fluid removal. One technique is ultrasound Doppler imaging to evaluate the ratio of early transmitral flow velocity (E) to early diastolic mitral annular velocity (E’), because E/E’ has been shown to reflect left ventricular filling pressure , 25. In Lung ultrasound to detect pulmonary congestion (extravascular lung water) has been studied . Lung waHand-carried ultrasound (HCU) to assess IVC diameter has been shown to predict patients who developed intradialytic hypotension . HCU is Central venous oxygen saturation (ScO2) from dialysis catheters has shown promise in predicting intradialytic hypotension during hemodialysis . There wBasso et al. compared several techniques for assessing the fluid status of chronic hemodialysis patients before and after hemodialysis, including bioimpedance spectroscopy, ultrasound lung comet score, B-type natriuretic peptide (BNP), and IVC diameter . Each teThe use of PAR based on a noninvasive waveform during the Valsalva maneuver was shown in one study to yield prognostic information in hemodialysis patients . A noninOur study had several limitations. First, the number of patients evaluated was relatively small, 27. Although a statistically significant change in PAR was demonstrated, a larger number of subjects will need to be studied to establish the utility of PAR by finger photoplethysmography in guiding volume management in hemodialysis patients. Second, we did not quantify the amount of urine the recruited patients typically make in a day. Third, although we have previously shown that PAR by finger photoplethysmography correlates with invasively measured LVEDP in patients undergoing a cardiac catheterization for clinical reasons [Silber], we did not invasively measure LVEDP in these dialysis patients. Since hemodialysis patients may have calcification of their vasculature, which may impact PAR values obtained on distal extremities, it would be useful in a future study to determine the PAR-LVEDP relation specifically in a cohort of dialysis patients undergoing clinical cardiac catheterization. Fourth, we did not investigate whether the type of hemodialysis access played a role in PAR values obtained (e.g. comparing AV-fistulas with catheters). Again, future studies with a larger population will be needed to explore this further.In conclusion, an index of left heart filling pressure (PAR) obtained noninvasively using finger photoplethysmography during the Valsalva maneuver is sensitive enough to detect reductions in filling pressure after fluid removal with hemodialysis. Further studies are warranted to determine the clinical utility of PAR to help guide individualized goal-setting of fluid removal in dialysis.


Several clinical and genetic variables are associated with influencing high on treatment platelet reactivity (HTPR). The aim of the study was to propose a path model explaining a concurrent impact among variables influencing HTPR and ischemic events. In this prospective cohort study polymorphisms of CYP2C19*2, CYP2C19*17, ABCB1, PON1 alleles and platelet function assessed by Multiple Electrode Aggregometry were assessed in 416 patients undergoing percutaneous coronary intervention treated with clopidogrel and aspirin. The rates of major adverse cardiac events (MACE) were recorded during a 12-month follow up. The path model was calculated by a structural equation modelling. Paths from two clinical characteristics (diabetes mellitus and acute coronary syndrome (ACS)) and two genetic variants (CYP2C19*2 and CYP2C19*17) independently predicted HTPR . By use of those four variables a novel score for prediction of HTPR was built: in a factor-weighted model the risk for HTPR was calculated with an OR of 3.8  for a score level of ≥1 compared with a score of <1. While MACE was independently predicted by HTPR and age in the multivariate model , the coexistence of HTPR and age ≥75 years emerged as the strongest predictor of MACE. Our study suggests a pathway, which might explain indirect and direct impact of variables on clinical outcome: ACS, diabetes mellitus, CYP2C19*2 and CYP2C19*17 genetic variants independently predicted HTPR. In turn, age ≥75 years and HTPR were the strongest predictors of MACE. CYP2C19*2  and the CYP2C19*17 (gain-of-function mutation), have been associated with response variability to clopidogrel in some studies Within the past years, platelet function studies have shown that up to 50% of clopidogrel treated patients have high on-treatment platelet reactivity (HTPR) To our knowledge, a concurrent impact among different variables influencing HTPR and ischemic events has not been reported. Therefore, the aim of the current paper was to investigate the interaction of clinical and genetic risk factors of HTPR in relation to cardiac ischemic events.This paper reports a sub-analysis of a previously published prospective observational cohort study Whole blood aggregation was determined using Multiple Electrode Aggregometry (MEA) on a new generation impedance aggregometer  directly after blood sampling at the Department of Clinical Pharmacology at the Medical University of Vienna. The system detects the electrical impedance change due to the adhesion and aggregation of platelets on two independent electrode-set surfaces in the test cuvette CYP2C19*17  was genotyped with a commercially available validated drug metabolism genotyping assay  with the ABI Prism Sequence Detector 7000 (Life Technologies) in accordance with manufacturer's instructions. CYP2C19*2  was genotyped with real-time allelic discrimination assay on an ABI Prism Sequence Detector 7000 (Life Technologies) according to standard procedures. Primers 5′- GATATGCAATAATTTTCCCACTATCATTG-3′ and 5′-GGTGTTCTTTTACTTTCTCCAAAATATCAC-3′ were used to amplify a sequence of the CYP2C19 gene containing the single nucleotide polymorphism 681G>A (rs4244285). The sequence of the G allele-specific probe was 5′-FAM-TTATTTCCCGGGAACC-3′ and the sequence of the A allele-specific probe was 5′-VIC-ATTATTTCCCAGGAACC-3′. SNPs in ABCB1 (rs1045542) and PON1 (rs662) were genotyped using commercial TaqMan SNP Genotyping Assays  on a ViiA 7 Real-Time PCR System (Life Technologies) following the manufacturer's instructions. After PCR, fluorescence yield for the two different dyes was measured and presented in a two-dimensional graph to obtain the allelic discrimination plot and identify individual genotypes. Correctness of genotyping was evaluated for randomly selected samples by direct sequencing of PCR products with the use of BigDye Terminator v. 3.1 sequencing kit and 3130xl Genetic Analyzer (Life Technologies). No discrepancies were observed between real-time discrimination and sequencing strategies.Genotyping was performed after inclusion of the last participant at the Institute of Molecular and Forensic Genetics, Collegium Medicum of the Nicolaus Copernicus University in Bydgoszcz, Poland. Genomic DNA was extracted from blood according to the standard procedures. The clinical endpoint was the composite of major adverse cardiac events  during a 12-month follow up. Stent thrombosis was defined according to the Academic Research Consortium criteria as the occurrence of an ACS with either angiographic or pathological confirmation of thrombosis 2-test when applicable. Kaplan-Meier curves with the Breslow test were used for survival analyses. The Bonferroni correction was used for multiple comparisons. A multivariate Cox regression model was used to determinate independent predictors of MACE. The univariate logistic regression analysis was used to estimate variables responsible for HTPR and was a first step in the factor analysis. The effect of each variable on HTPR and MACE was tested using path analysis modelling, wherein the model fit was examined, as well as the significance of the direct and indirect effects , diabetes mellitus, age, renal failure (creatinine clearance <60 mg/ml) and ACS at admission). Other gene environment interactions were tested in an exploratory factor analysis.Based on a 22% rate of a composite of major adverse events in the group with high on treatment platelet reactivity (HTPR) compared to 8% in the group without HTPR The following indicators were used to assess the goodness of fit of the models: Comparative Fit Index and Root Mean Square Error of Approximation. The maximum likelihood estimation method for structural equation modelling was used to test the conceptual model, examining the relationships among latent variables. The rationale for using the structural equation modelling instead of logistic regression in our paper is explained below. Logistic regression allows investigation of relationship between isolated independent variables and a single dependent variable. Therefore, regression analysis alone is inadequate when examining the interplay between the independent variables and several dependent variables. The structural equation modelling is more effective and more appropriate for analyzing complex models. The major difference between these two approaches is the mulicollinearity (when predictor variables are highly correlated). Whereas in a structural equation modelling, mulicollinearity is necessary, in a regression analysis mulicollinearity is problematic.For the development of score predicting HTPR variables were selected by structural equation modeling and by forward and backward logistic regression. All statistical calculations were performed using commercially available statistical software .Patient demographics and co-medications are shown in CYP2C19*2 carriers (27.6% heterozygote and 2.6% homozygote), 40% were CYP2C19*17 carriers (33.9% heterozygote and 5.8% homozygote), 78% had an ABCB1 C3435T genotype (55.6% heterozygote and 22.0% homozygote) and 50% were carriers of PON1 Q192R allele  emerged as HTPR predictors , ACS  and edictors . CYP2C19CYP2C19*2 and *17 (hetero or homozygote) as well as from clinical characteristics as ACS on admission and diabetes mellitus were independent predictors of HTPR . In detail, Diabetes was weighed by factor 2, ACS by factor 1, CYP2C19*2 by factor 1 and CYP2C19*17 by factor -1 (DACC score). Thus, a score ranging from -1 to 4 was developed. Hereby, we found an increasing incidence of HTPR by cumulative number of score variables  occurred in 52 patients (12.5%). Cox multivariate adjusted model confirmed that HTPR and age independently predicted MACE: patients with HTPR were at 2-fold higher risk  independently predicted HTPR but not MACE.Two clinical characteristics (ACS and diabetes mellitus) and two genetic variants  will have a HTPR. If this is the case, and if the patient is older than 75 years of age, the probability to develop MACE increases by factor 3 as compared to a younger patient without HTPR. Based on this example, the score might be useful in the clinical practice. Noteworthy, another score for prediction of HTPR has been already proposed. The weighted PREDICT score includes ACS, diabetes mellitus, left ventricular function, renal failure, age and 12 receptor inhibitors such as prasugrel or ticagrelor also achieved a stronger platelet inhibition in patients with HTPR under clopidogrel CYP2C19*2 allele but not in homozygous carriers Until now, only geno- and phenotyping but not scoring systems were used to personalize the antiplatelet therapy. Several studies have demonstrated that HTPR can be reduced with higher loading or maintenance doses of clopidogrel, or by switching to prasugrel or ticagrelor. Administration of a 150 mg maintenance dose of clopidogrel or up to four repeated loading doses of clopidogrel resulted in more intense inhibition of platelet aggregation in a major subset of patients but not in all 12 receptor or insulin receptor substrate IRS-1) were not considered in our study. Moreover, due to the limited sample size, the study would not have enough power to include into the model and score the differentiation between homo- and heterozygotes of the CYP2C19*2 or 17* polymorphisms or to test the predictors of bleeding events. Most importantly, the absence of a validation cohort makes the generalizability of the DACC score difficult to predict.We are aware of the fact that the antiplatelet drug response is a multifactorial phenomenon, which cannot be solely explained by identified risk factors, because baseline differences in platelet aggregation are even observed in patients naive to antiplatelet treatment. As a further limitation, additional procedural factors during coronary intervention that might play an important role  or further genetic variants (e.g. ITGB3 encoding the integrin Beta3 of the GpIIb/IIIa receptor, P2YCYP2C19*2 and CYP2C19*17 genetic variants independently predicted HTPR. In turn, age ≥75 years and HTPR were the strongest predictors of MACE. Further studies are needed to investigate the usefulness of our finding.Our study suggests a pathway, which might explain the association between the genetic and clinical variables influencing the phenotype of response to clopidogrel. Furthermore, the proposed model also shows indirect and direct impact of several variables on clinical outcome: ACS, diabetes mellitus,


Cardiovascular Magnetic Resonance (CMR) with adenosine stress is a valuable diagnostic tool in coronary artery disease (CAD). However, despite the development of MR conditional pacemakers CMR is not yet established in clinical routine for pacemaker patients with known or suspected CAD. A possible reason is that adenosine stress perfusion for ischemia detection in CMR has not been studied in patients with cardiac conduction disease requiring pacemaker therapy. Other than under resting conditions it is unclear whether MR safe pacing modes (paused pacing or asynchronous mode) can be applied safely because the effect of adenosine on heart rate is not precisely known in this entity of patients. We investigate for the first time feasibility and safety of adenosine stress CMR in pacemaker patients in clinical routine and evaluate a pacing protocol that considers heart rate changes under adenosine.We retrospectively analyzed CMR scans of 24 consecutive patients with MR conditional pacemakers (mean age 72.1 ± 11.0 years) who underwent CMR in clinical routine for the evaluation of known or suspected CAD. MR protocol included cine imaging, adenosine stress perfusion and late gadolinium enhancement.n = 18) and second or third degree AV block (n = 6). Under a pacing protocol intended to avoid competitive pacing on the one hand and bradycardia due to AV block on the other no arrhythmia occurred. Pacemaker stimulation was paused to prevent competitive pacing in sinus node dysfunction with resting heart rate >45 bpm. Sympatho-excitatory effect of adenosine led to a significant acceleration of heart rate by 12.3 ± 8.3 bpm (p < 0.001), no bradycardia occurred. On the contrary in AV block heart rate remained constant; asynchronous pacing above resting heart rate did not interfere with intrinsic rhythm.Pacemaker indications were sinus node dysfunction (Adenosine stress CMR appears to be feasible and safe in patients with MR conditional pacemakers. Heart rate response to adenosine has to be considered for the choice of pacing modes during CMR. Cardiovascular magnetic resonance (CMR) as a non-invasive imaging modality is firmly established in the clinical workup for patients with known or suspected CAD. It has become the gold standard for chamber quantification and detection of left ventricular wall motion impairment in ischemic cardiomyopathy –3. Post In patients with sinus node dysfunction (SND) and AV-block underlying or concomitant CAD is common , 9. In bIn the past presence of a pacemaker was regarded as a contraindication for MR scanning , 14. NevIn MR conditional PM only deactivation (ODO-mode) or asynchronous pacing   are avaiIn conclusion the high value of adenosine stress CMR in known or suspected CAD is well established but it is still unknown whether the method is safe and feasible in PM patients with SND or AV block who are programmed to the restricted pacing modes required by MRI conditional devices during performance of CMR. We investigate for the first time feasibility and safety of CMR in clinical routine in PM patients.We retrospectively analyzed MR scans of 24 consecutive patients with MR conditional PM who underwent routine adenosine stress CMR for the evaluation of known or suspected CAD including cine imaging, adenosine stress perfusion and late gadolinium enhancement after informed consent was obtained from March 2014 to April 2015. The study complied with the Declaration of Helsinki and was approved by the local Institutional Review Board .CMR was performed more than six weeks after PM implantation in all individuals according to ESC guidelines . Prior tDevices were set to MR safe mode according to manufacturer’s instructions immediately prior to the scan and reprogrammed immediately thereafter. Programming was performed according to a predefined protocol: To avoid interference of intrinsic rhythm with PM-stimulation in patients with SND and resting heart rate HR > 45 bpm no pacing (ODO)-mode was engaged during the scan - also when atrial fibrillation (AF) was present at the time of the scan. In individuals with SND and HR ≤ 45 bpm the pacemaker was set to asynchronous atrial stimulation . All patients with intermittent or permanent second or third degree AV block were continuously paced in asynchronous mode irrespective of their actual rhythm and HR to avoid possible asystole or bradycardia due to worsening AV conduction induced by adenosine. Pacing rate was set 10 bpm above spontaneous heart rate with a minimum of 60 bpm. VOO mode at 60 bpm was chosen in AV block with sinus rate > 45 bpm to avoid competitive atrial stimulation, DOO mode at 60 bpm in AV block with sinus bradycardia ≤ 45 bpm. Patients in AF at the time of the scan were paced VOO at 60 bpm if resting heart rate was ≤ 45 bpm. Table Patients were monitored during the scan with continuous electrocardiographic and visual supervision by a cardiologist present in the scanner room. Voice contact was maintained with the patient at all times of the scan. Advanced cardiac life support protocol was in effect. In the scanner the patient was placed on a carry sheet; medical staff was trained for rapid removal of the patient from the scanner room in the event of cardiopulmonary compromise. Thus immediate treatment of severe arrhythmia and reactivation of PM stimulation within seconds in non-paced patients was guaranteed. Atropine, adrenaline and theophylline injections were prepared ready for use in case of bradycardia. Two separate cubital venous cannulas were used for adenosine and gadolinium contrast agent respectively.CMR was performed with a 1.5 T wide bore system  using a 4-channel body array and an 8-channel spine coil. Maximum gradient field was 33 mT/m (Z-Engine) with a slew rate of 100 T/m/s. Maximum specific absorption rates were limited to 2.0 W/kg.Our standard protocol meets the Society of Cardiovascular Magnetic Resonance (SCMR) standards for CMR . Cine stn = 18; 75 %) and second or third degree AV-block . No patient was PM dependent (HR <30 bpm). Impulse generator/lead models were Advisa  and Ensura  MRI SureScan/CapSureFix 5076 Novus , CapSureSense 4074 (ventricular) ; Entovis DR-T/Safio S 53 , Safio S60 (ventricular) , n = 1, 4.2 %. For detailed baseline characteristics see Table Twenty-four CMR examinations were analyzed. Patients had a mean age of 72.1 ± 11.0 years. 11 (45.8 %) had known CAD, 7 (29.1 %) previous MI. All other patients had intermediate pretest probability of CAD . Echocardent HR <0 bpm. ImThere were no adenosine induced adverse events.n = 14) or normofrequent AF (n = 3) at the time of the scan the pacemaker stimulation was deactivated (ODO). Adenosine administration accelerated mean HR by 12.3 ± 8.3 bpm (p = 0.001). AV-conduction was not significantly influenced by adenosine; no higher degree AV block occurred. When sinus rate was <45 bpm (n = 1) AOO pacing at 60 bpm led to permanent capture, no acceleration of HR under adenosine was noticed.In 17 patients with SND and normal AV-conduction (n = 5) that were paced asynchronously no arrhythmia was detected; permanent ventricular capture was seen on ECG monitoring during the scan. One patient with intermittent second degree AV block but with normal AV conduction at the time of CMR was paced 10 bpm above spontaneous HR. When sinus rate was <45 bpm (n = 1) D00 pacing at 60 bpm was engaged and did not lead to competitive atrial stimulation. No competitive ventricular stimulation was observed. Adenosine did not induce tachycardia.In patients with second or third degree AV block and sinus rate >45 bpm , LV hypertrophy in 7 (29.2 %) patients. Minor valve dysfunction was found in 3 (12.5 %) patients, aortic aneurysm > 45 mm in 2 (8.3 %) patients. LGE with subendocardial or transmural distribution pattern corresponding to post MI scarring was present in 7 (29.2 %) patients and was not obscured by PM artifacts caused by generator or leads. Postinflammatory myocardial scarring was seen in one patient. Adenosine induced perfusion deficit was visible in two patients. One patient consecutively underwent percutaneous coronary intervention with stent implantation in the right coronary artery; the second patient was scheduled for bypass surgery.See Fig. The present study shows no complications of adenosine stress CMR related to the presence of a PM or the underlying cardiac conduction disorder. The device remained intact; no arrhythmia was induced by adenosine in this highly selected entity of patients.Apart from influence of the MR field on device function, the most important safety issue in adenosine stress CMR is the MR conditional pacing mode itself. Only asynchronous pacing without sensing or deactivation can be programmed in this mode to avoid tracking of electromagnetic impulses and inhibition by electromagnetic interference . Thus twThis issue is complicated by the effect of adenosine on HR during stress perfusion: The negative dromotropic effect of the substance on the cardiac conduction system may result in bradycardia or asystole in patients with paused PM stimulation , 31. On The present data suggests that in SND with normal resting HR and preserved AV conduction paused PM stimulation (ODO mode) is suitable for adenosine stress perfusion. Apart from one patient with constant HR we found a significant increase in HR i.e. no negative dromotropic effect of adenosine in SND with an adenosine dosage of 140ug/kg/min limited to three minutes. Thus the direct sympatho-excitatory effect of adenosine overrides cardiac inhibition comparable to patients without SND. In AF we also found predominance of the sympatho-excitatory reflex with positive chronotropy. Choosing asynchronous pacing would have been problematic in SND because adenosine accelerated HR by up to 29 bpm. Pacing far above baseline HR for a longer time could cause discomfort or even circulatory compromise in PM patients adapted to relative bradycardia .We propose asynchronous pacing in AV block because the risk of asystole under adenosine is high , persistIn the present study no proarrhythmia was observed under individually adapted pacing modes; nevertheless arrhythmia is the main safety issue. Calculating the risk of arrhythmia one has to take into account that severe brady- or tachycardia has been described almost exclusively for bolus administration of adenosine; malignant reentrant tachycardia due to accessory pathways is predominant . In contWhile several publications have noted rather minimal artifact and the ability to produce diagnostic scans, others have noted compromised CMR images because of artifact . In thisThe present data on lead integrity are in line with previous studies on MR conditional PM , 23 showThis study is limited by the small sample size and the lack of a control group. Adverse effects may only appear in a larger cohort of patients. No intermediate or long-term follow up data was provided. Moreover the diagnostic value of CMR was not evaluated invasively in patients without perfusion deficit.Our data suggest adenosine stress CMR in patients with MR conditional PM to be feasible and safe for the workup of CAD. We propose individualized pacing modes to reduce the risk of proarrhythmia that have to be further evaluated. Adenosine induced sympathetic stimulation overrides inhibitory effects on the conduction system leading to positive chronotropy only in patients with intact AV conduction but not in higher degree AV block. We encourage further research to determine the diagnostic value of adenosine stress CMR in PM patients and to establish guidelines on pacemaker programming for adenosine stress in clinical routine.


The cerebrospinal fluid pressure (CSFP) is a major determinant of central retinal vein pressure and thus of retinal capillary pressure. We tested the hypothesis whether prevalence and severity of diabetic retinopathy are associated with CSFP.2]+0.16 Diastolic Blood Pressure[mmHg]–0.18xAge[Years]−1.91.The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6±9.8 years. A detailed ophthalmic examination was performed including fundus photography for the assessment of diabetic retinopathy according. Based on a previous study with lumbar cerebrospinal fluid pressure (CSFP) measurements, CSFP was calculated as CSFP[mmHg] = 0.44xBody Mass Index[kg/mP<0.001; regression coefficient B:0.25; odds ratio (OR):1.28; 95% confidence interval (CI):1.15,1.43), higher blood concentration of glucose , longer known duration of diabetes mellitus , higher systolic blood pressure , lower diastolic blood pressure , and higher CSFP . Severity of diabetic retinopathy was significantly associated with higher HbA1c value , higher blood concentration of glucose , longer known duration of diabetes mellitus , lower level of education , lower diastolic blood pressure , higher systolic blood pressure , and higher CSFP .In binary regression analysis, presence of diabetic retinopathy was significantly associated with higher levels of HbA1c (Higher prevalence and severity of diabetic retinopathy were associated with higher estimated CSFP after adjusting for systemic parameters. Higher CSFP through a higher retinal vein pressure may lead to more marked retinal venous congestion and vascular leakage in diabetic retinae. Features of diabetic retinopathy are retinal microaneurysms, retinal hemorrhages, retinal edema, retinal vein dilatation, and lipid deposition in the deep retinal layers The Medical Ethics Committee of the Beijing Tongren Hospital approved the study protocol and all participants gave informed written consent.The Beijing Eye Study 2011 is a population-based cross-sectional study in Northern China For all study participants, an interview was performed with standardized questions on the level of education, quality of life, known major systemic diseases, and other parameters. Fasting blood samples were taken for measurement of blood lipids, glucose and glycosylated hemoglobin HbA1c. Body height and weight and the circumference of the waist and hip were measured. The blood pressure was measured with the participant sitting for at least 5 minutes. The study participants had refrained from smoking and drinking of coffee, tea, or alcohol for at least 3 hours. In addition, any exercise was not performed for the last 30 minutes prior to the blood pressure measurements. A standardized mercury sphygmomanometer was used, and the cuff size was chosen according to the measured circumference of the upper arm Using the fundus photographs , diabetic retinopathy was assessed in a masked manner. The diagnosis for each individual was based on the grading of the worse eye per subject. The grading was performed according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) criteria P>0.10). Performing a multivariate analysis in the training group with the lumbar CSFP measurements as dependent variable and age, body mass index and blood pressure as independent variables revealed, that CSFP was best described by the formula of CSFP [mmHg] = 0.44 × Body Mass Index [kg/m2] +0.16 × Diastolic Blood Pressure [mmHg] –0.18 × Age [Years]−1.91. The association between higher CSFP and younger age, higher body mass index and higher blood pressure had also been found in other previous investigations P = 0.29) from the calculated CSFP (13.3±3.2 mm Hg). The Durbin-Watson value was 2.08. Durbin-Watson values falling into the acceptable range of 1.5 to 2.5 indicate a non-significant autocorrelation for the residuals in the multiple regression models. The intra-class correlation coefficient was 0.71. The Bland-Altman analysis revealed that 40 out of 42 measurements were within the 95% limits of agreement.For the calculation of a formula to estimate the CSFP, we used the lumbar CSFP measurements obtained in a previous pilot study P-values. In a fourth step of the analysis, we performed a multivariable analysis of the associations between the severity of diabetic retinopathy. We presented 95% confidence intervals (CI). All P-values were 2-sided and were considered statistically significant when the values were less than 0.05.Inclusion criteria for the present study were the availability of data on the estimated CSFP and diabetic retinopathy. Statistical analysis was performed using a commercially available statistical software package . In a first step, we examined the mean values (presented as mean ± standard deviation). Frequencies were presented as mean ± standard error. In a second step, we performed a univariate analysis of associations between the prevalence of diabetic retinopathy and systemic parameters and ocular parameters. In a third step, we carried out a binary regression analysis, with the presence of diabetic retinopathy as dependent parameter and all those parameters as independent variables which were significantly associated with diabetic retinopathy in univariate analysis. We then dropped in a step-wise manner all those variables from the list of independent parameters, which were no longer significantly associated with the presence of diabetic retinopathy, starting with the parameters with the highest P<0.001) younger and did not differ significantly in refractive error (P = 0.10) nor axial length (P = 0.81).Out of the 3468 subjects (6936 eyes) included into the study, data of CSFP and diabetic retinopathy were available for 3355 (96.7%) subjects (6705 (96.7%) eyes) with a mean age of 64.4±9.7 years , a mean refractive error of −0.22±2.11 diopters  and a mean axial length of 23.3±1.1 mm . The subjects participating in the study as compared to the non-participating subjects (n = 113)  were significantly ) of 98 subjects ). Diabetic retinopathy was of the mild type in 70 (43%) eyes, moderate type in 50 (31%) eyes, severe type in 20 (12%) eyes, and proliferative or status after retinal laser coagulation in 23 (14%) eyes.P<0.001), higher levels of glycosylated hemoglobin HbA1c (P<0.001), higher blood concentration of glucose (P<0.001), higher systolic blood pressure (P<0.001), longer known duration of diabetes mellitus (P<0.001), urban region of habitation (P = 0.001), lower level of education (P = 0.003), and higher CSFP (P = 0.01); and with the ocular parameters of higher intraocular pressure (P = 0.03) and shorter ocular axial length (P<0.001) (P = 0.69), gender (P = 0.85), blood concentrations of high-density lipoproteins (P = 0.36), low-density lipoproteins (P = 0.73) and triglycerides (P = 0.39), ever smoking (P = 0.62), and consumption of alcohol (P = 0.07).In univariate analysis, prevalence of diabetic retinopathy was significantly associated with the systemic parameters of higher body mass index (P<0.001) . The preP<0.001), higher blood concentration of glucose (P<0.001), longer known duration of diabetes mellitus (P<0.001), higher systolic blood pressure (P<0.001), lower diastolic blood pressure (P<0.001), and higher CSFP (P = 0.002) (P = 0.93) associated with diabetic retinopathy. In a similar manner, if age was added to the model, it was neither significantly (P = 0.93) associated with diabetic retinopathy.The binary regression analysis included the presence of diabetic retinopathy as dependent parameter and all those parameters as independent variables which were significantly associated with diabetic retinopathy in the univariate analysis. We then dropped step-by-step those independent parameters which were no longer significantly associated with diabetic retinopathy. After dropping intraocular pressure, presence of glaucoma, level of education, region of habitation, and axial length, presence of diabetic retinopathy remained to be significantly associated with higher levels of HbA1c (= 0.002)  If body P<0.001), higher blood concentration of glucose (P<0.001), longer known duration of diabetes mellitus (P<0.001), higher systolic blood pressure (P<0.001), rural region of habitation (P = 0.007), lower level of education (P = 0.003), and higher CSFP (P = 0.005) (P = 0.03), and shorter ocular axial length (P<0.001) (P = 0.86), blood concentrations of cholesterol (P = 0.64), high-density lipoproteins (P = 0.44), low-density lipoproteins (P = 0.71) and triglycerides (P = 0.52), ever smoking (P = 0.26), and consumption of alcohol (P = 0.07), and presence of glaucomatous optic neuropathy (P = 0.11).The severity of diabetic retinopathy was significantly associated  with the systemic parameters of higher levels of glycosylated hemoglobin HbA1c (= 0.005) ; and witP<0.001) . The sevP<0.001), higher blood concentration of glucose (P<0.001), longer known duration of diabetes mellitus (P<0.001), lower level of education (P = 0.001), lower diastolic blood pressure (P = 0.002), higher systolic blood pressure (P = 0.006), and higher CSFP (P = 0.006)  .P = 0.002) associated with higher CSFP after adjusting for higher levels of HbA1c, higher blood concentration of glucose, longer known duration of diabetes mellitus, higher systolic blood pressure and lower diastolic blood pressure. Correspondingly, the severity of diabetic retinopathy was significantly associated with higher CSFP (P = 0.006) after adjusting for higher levels of HbA1c, higher blood concentration of glucose, longer known duration of diabetes mellitus, lower level of education, higher systolic blood pressure and lower diastolic blood pressure.In our population-based study, presence of diabetic retinopathy was significantly (The findings of our study agree with a multitude of previous investigations that increased blood pressure, elevated HbA1c levels and a long duration of diabetes mellitus were major risk factors for the presence and severity of diabetic retinopathy The blood pressure in the central retinal vein inside of the eye is at least as high as the CSFP, since the central retinal vein, after leaving the eye, passes through the optic nerve and the orbital cerebrospinal fluid space. An elevated CSFP is therefore associated with an elevated intraocular retinal vein pressure as shown in previous ophthalmodynamometric studies Besides diabetic retinopathy, retinal vein occlusions are another hemorrhagic retinopathy and are characterized by retinal hemorrhages, retinal edema, lipid exudation and venous dilatation. Previous ophthalmodynamometric studies have revealed a markedly elevated retinal vein pressure in eyes with retinal vein occlusions The results of our study agree with clinical observations and studies that increased brain pressure can be associated with retinal hemorrhages. In the case of an acute subarachnoidal hemorrhage with a marked increase in intracranial pressure, retinal hemorrhages and an intravitreal bleeding can develop as part of Terson’s syndrome The findings of our study suggested that an altered CSFP could lead to an increased prevalence and severity of diabetic retinopathy with retinal hemorrhages and macular edema. While retinal capillary pressure is likely to play a role, previous studies have also suggested a role for ocular perfusion pressure which incorporates intraocular pressure. In a previous investigation, Quigely and Cohen combined the Ohm, Poiseuille, and Murray laws and found that the myopic arteriolar tree would produce a 16% greater pressure attenuation than that of emmetropic controls with a linear relationship between mean pressure attenuation index and axial length If the association between higher CSFP and presence and severity of diabetic retinopathy is further clarified in future studies, one may address the question whether lowering of CSFP by drugs such as systemic carbonic anhydrase inhibitors may have a therapeutically positive effect on diabetic retinopathy.Potential limitations of our study should be mentioned. First, the whole study depended on the estimation of CSFP being derived from a multivariate formula incorporating body mass index, diastolic blood pressure, and age. The result of this formula was then termed CSFP and it correlated with the presence and severity of diabetic retinopathy in multivariate analyses. Although the estimated CSFP was primarily just the result of a mathematical equation, the calculated CSFP values correlated well with invasively measured CSFP values in the independent test group of the pilot study. Nonetheless, the unknown general validity of the equation to estimate the CSFP may be the most important limiting factor of our study. Second, some of the components of the formula to estimate the CSFP were by themselves associated with diabetic retinopathy. It has therefore remained unclear whether diabetic retinopathy was correlated with CSFP or with the individual components that were used to calculate CSFP. In the multivariate analysis, the presence of diabetic retinopathy was significantly associated with higher CSFP after adjusting for systolic and diastolic blood pressure, while diabetic retinopathy was not associated with age or body mass index in the model. Since the three parameters of age, blood pressure and body mass index influence CSFP and since body mass index and blood pressure were also associated with diabetic retinopathy in univariate analysis, it was not possible to distinguish between a direct effect of CSFP on the prevalence of diabetic retinopathy and a secondary effect by the underlying basic parameters. Such a question may be addressed in a study comparing patients who have diabetic retinopathy and who have elevated or normal CSFP as measured by direct lumbar puncture. Such a design is however not possible to implement in a population-based investigation. Third, as for any population-based study, the rate of non-participation or non-availability of examination results can matter. In our study, the participation rate was 78.8% what may be acceptable. Fourth, blood pressure, although measured under standardized conditions, was determined only once, so that the question arises how representative this single measurement was for the subject’s blood pressure in general.In conclusion, higher prevalence and severity of diabetic retinopathy were associated with higher estimated CSFP after adjusting for systemic parameters. Higher CSFP through a higher central retinal vein pressure may lead to more marked retinal venous congestion and vascular leakage in diabetic retinae. Future studies may address whether lowering of a slightly elevated CSFP may be helpful for the treatment of diabetic retinopathy.


To investigate the usefulness of Fibroblast Growth Factor 23 (FGF-23) and vitamin D as possible biomarkers of pre-clinical atherosclerosis, assessed as arterial stiffness (AS), in a group of subjects with type 1 diabetes (T1DM) and no previous cardiovascular events.1c, estimated glomerular filtration rate (eGFR) and lipid profile; 2) microvascular complications; 3) blood concentrations of FGF-23 and mineral metabolism parameters  and 25-hydroxy-vitamin D (25(OH)D)); 4) AS, assessed as aortic pulse wave velocity (aPWV); and 5) low-grade inflammation  and endothelial dysfunction (ED) markers .68 T1DM patients and 68 age- and sex-matched controls were evaluated for 1) age, sex, diabetes duration, physical activity, smoking, alcohol intake, BMI, blood pressure, fasting plasma glucose, HbAPatients with T1DM had higher aPWV compared with controls (p<0.001), but they did not present differences in 25(OH)D (70.3(50.4–86.2)nmol/L vs. 70.7(59.7–83.0)nmol/L; p = 0.462) and in FGF-23 plasma concentrations (70.1(38.4–151.9)RU/mL vs. 77.6(51.8–113.9)RU/mL; p = 0.329). In T1DM patients, higher concentrations of FGF-23 were positively associated with aPWV after adjusting for eGFR and classical cardiovascular risk factors , other mineral metabolism parameters , microvascular complications, low-grade inflammation and ED markers . Lower 25(OH)D concentrations were also associated with higher aPWV after adjusting for all the above-mentioned factors .We conclude that both FGF-23 plasma concentrations (positively) and 25(OH)D serum concentrations (negatively) are associated with AS in patients with T1DM and no previous cardiovascular events. Cardiovascular disease is the major cause of mortality in type 1 diabetes mellitus (T1DM) . TherefoExisting evidence suggests that an abnormal mineral metabolism, and particularly vitamin D deficiency, may promote atherosclerosis. Recently, low blood concentrations of vitamin D have been associated with an increased risk of excess all-cause and cardiovascular mortality in the general population , as wellFGF-23 is a circulating peptide hormone secreted by bone cells, with three main physiological actions. First, it induces phosphaturia through a reduction in the reabsorption of phosphate at the proximal tubules. Second, it lowers circulating 1,25-dihydroxy-vitamin D concentrations through a decrease in the activation and an increase in the degradation of 25-hydroxy-vitamin D (25(OH)D). Third, FGF-23 suppresses the transcription of the parathyroid hormone (PTH) gene and PTH secretion . It actsRecently, we demonstrated that patients with T1DM have an increased inflammatory tone associated with arterial stiffness (AS) before clinical atherosclerotic manifestation . The incConsequently, we hypothesize that the FGF-23/vitamin D axis may be unbalanced in patients with T1DM with early stages of cardiovascular disease. We investigated blood concentrations of FGF-23 and 25(OH)D and their potential relationships with AS and classical cardiovascular risk factors in a group of patients with T1DM and no previous cardiovascular events.Sixty-eight patients with T1DM, aged 18–65 years and 68 age- and sex-matched controls were included in the study. Patients with T1DM were consecutively recruited from our outpatient clinic. The control group was recruited from hospital staff members and their relatives and friends. Exclusion criteria included: i) preexisting CKD with renal failure, ii) any other acute/chronic condition associated with an inflammatory response , iii) use of anti-inflammatory drugs in the previous 6 months and IV) presence of previous cardiovascular events. The study protocol was approved by our hospital ethics committee  and conducted in accordance with the Declaration of Helsinki. All subjects gave their written informed consent before participating in the study.1c, creatinine, lipid profile and mineral metabolism parameters D) were determined. In addition, aliquots of plasma and serum were stored at -80°C until processing. From these aliquots, FGF-23, high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6) and soluble fractions of tumor necrosis factor α receptors 1 and 2 , soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin were determined.All subjects underwent standardized anamnesis and physical examination. The following information was recorded using a predefined standardized form: age, sex, diabetes duration, physical activity  , smoking1c was determined by high-performance liquid chromatography . Total serum cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol were measured using standard enzymatic methods. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation on the basis of serum creatinine, age, sex and race [HbAand race . Serum 2and race ,19.AS is an early sign of atherosclerosis  and pred® system , NSW, Australia). Those aPWV recordings not satisfying the automatic quality controls specified by the SphygmoCor® software were rejected. The mean of two aPWV measurements was taken for each subject for all calculations. Data were available for all the participants included in the study.The aPWV measurements were performed in accordance with the recommendations of a recent consensus on measuring AS . The met2test for comparisons of proportions, and the unpaired t-test or the Mann-Whitney U test for comparisons of normally and non-normally distributed quantitative variables, as needed. Pearson’s or Spearman’s correlation coefficients were calculated to analyze the relationship between normally and non-normally distributed variables, as appropriate. To assess the likely association between FGF-23 and AS adjusting for potential confounders , several multiple linear regression models were employed, always treating aPWV as the dependent variable. All variables associated in the univariate analyses (p<0.20) and those variables known or likely to be associated with AS (based on previous literature) were included in those regression models as independent variables. Non-normally distributed variables were used after performing a log10-transformation. As low-grade inflammation and endothelial dysfunction (ED) markers were measured only once, their possible association (if any) with aPWV and FGF-23 was likely to be underestimated. To address this issue, a Z-score was calculated for each of these markers in each subject, as previously described  / SD) [All data were tested for normality using the Shapiro-Wilk test. Data are presented as percentage, mean (SD) for normally distributed variables, or median (interquartile range) for non-normally distributed variables. The analyses were performed in the whole population after excluding the presence of sex interaction (p for interaction FGF23*sex for aPWV = 0.960). Differences between groups (patients with T1DM vs. controls) were analyzed using the χn) / SD) ,19. SubsWe evaluated 68 patients with T1DM and 68 age- and sex-matched controls (n = 136). The main clinical and analytical characteristics of the study population are shown in 1c, aPWV, and general scores of low-grade inflammation and ED than controls. Additionally, patients with T1DM presented lower concentrations of LDL-cholesterol, probably due to the higher number of individuals on statins in this group. Patients with T1DM presented lower calcium concentrations compared with controls . By contrast, serum concentrations of 25(OH)D were negatively associated with aPWV  . In the In this study we highlight FGF-23 as a potential biomarker associated with increased AS in patients with T1DM without previous cardiovascular events. Furthermore, serum vitamin D concentrations were inversely associated with AS in these patients.FGF-23 has been revealed as a potential useful biomarker not only for cardiovascular disease in high-risk populations, such as CDK patients –10, but The mechanisms underlying FGF-23 bioactivity in vivo are unclear although some authors have suggested that FGF-23 may directly contribute to glomerular damage and enhanced proteinuria, as the link between FGF-23 and poor cardiovascular outcomes ,24,25. Iin vitro, inducing left ventricular hypertrophy in mice with normal kidney function [Several hypotheses have been proposed to explain the link between FGF-23 and cardiovascular disease. FGF-23 could indirectly modify cardiovascular risk by regulating essential parameters of mineral metabolism, such as serum phosphate, calcium, PTH and vitamin D . Howeverfunction . Additiofunction . It is kfunction . Moreovefunction –33. Thisfunction . Thus, tth percentile) independently predicted all-cause mortality in a prospective study with 220 patients with T1DM [per se.Vitamin D deficiency has also been associated with increased cardiovascular disease ,4 and haith T1DM . Howeverith T1DM ,41. In oWe are aware that the cross-sectional design of the present study cannot preclude causality or temporal ordering of the association among AS, FGF-23 and vitamin D concentrations. In addition, the variation in AS attributed to FGF-23 levels, despite being significant remains a low percentage of this clinical condition. Thus, the observational design does not allow us to ensure complete control of all the potential (unknown) confounding factors, especially those related to mineral metabolism . Finally, the lack of associations among AS, FGF-23 and vitamin D in the controls could be because the dispersion of aPWV and FGF-23 concentrations data, which was much lower in controls than in patients with T1DM.In conclusion, the current study shows for the first time that both higher FGF-23 plasma and lower vitamin D serum concentrations are associated with AS in patients with T1DM and no previous cardiovascular events. Prospective studies are warranted to ascertain the potential pathogenic role of FGF-23 and vitamin D in the development of AS and cardiovascular disease in patients with T1DM.


The objective of this study was to test the effect of removal of a ureteral obstruction  from anesthetized patients on the perfusion index (PI), as measured by a pulse oximeter, and on the estimated glomerular filtration rate (eGFR).This prospective study enrolled 113 patients with unilateral ureteral obstructions (kidney stones) who were scheduled for ureteroscopy (URS) laser lithotripsy. One urologist graded patient hydronephrosis before surgery. A pulse oximeter was affixed to each patient's index finger ipsilateral to the intravenous catheter, and a non-invasive blood pressure cuff was placed on the contralateral side. Ipsilateral double J stents and Foley catheters were inserted and left indwelling for 24 h. PI and mean arterial pressure (MAP) were determined at baseline, 5 min after anesthesia, and 10 min after surgery; eGFR was determined at admission, 1 day after surgery, and 14 days after surgery.Patients with different grades of hydronephrosis had similar age, eGFR, PI, mean arterial pressure (MAP), and heart rate (HR). PI increased significantly in each hydronephrosis group after ureteral stone disintegration. None of the groups had significant post-URS changes in eGFR, although eGFR increased in the grade I hydronephrosis group after 14 days. The percent change of PI correlates significantly with the percent change of MAP, but not with that of eGFR.Our results demonstrate that release of a ureteral obstruction leads to a concurrent increase of PI during anesthesia. Measurement of PI may be a valuable tool to monitor the successful release of ureteral obstructions and changes of microcirculation during surgery. There were also increases in eGFR after 14 days, but not immediately after surgery. Modern anesthetic practice places increasing emphasis on changes in microcirculation following the initiation of newly developed devices, and this has led to improved organ perfusion and reduced post-operative morbidity et al.Hydronephrosis can alter tubuloglomerular feedback and may lead to hypertension In the present study, we used the oximeter probe to test the hypothesis that release of a ureteral obstruction  improves renal hemodynamics and microcirculation, and that these are promptly indicated by increases in the PI. We also examined the effect of removal of ureteral obstructions on the post-operative estimated glomerular filtration rate (eGFR).2), peripheral arterial disease, usage of vasoactive agents, and contraindications to intravenous anesthesia. Although endothelial dysfunction may interfere the amplitude and velocity of changes in PI, we observed changes in PI for more than 5 min after stone disintegration, so this delayed effect can be ignored. There were 33 women and 80 men, the mean age was 53.7 years (range: 20–79 years), and American Society of Anesthesiologists Scores (ASA Scores) were between I and III. The grades of pre-operative hydronephrosis were classified according to Goertz JK and Lotterman S: grade I was defined as enlargement of the calyces with preservation of the renal papillae, grade II as rounding of the calyces with obliteration of the renal papillae, and grade III as calyceal ballooning with cortical thinning This prospective study was approved by the National Taiwan University Hospital Ethics Committee (201205117RIC).  One hundWe obtained written informed consent from patients for enrollment at the pre-anesthesia visit on the day before surgery. No medications were given to patients before entering the operating room (OR). A urologist graded the severity of hydronephrosis by renal echography at the out-patient department (OPD) visit. After arrival at the OR, each patient was placed in a supine position and fitted with a non-invasive blood pressure cuff, a 3-lead electrocardiogram, and a pulse oximeter probe  that was attached to the index finger on the ipsilateral side of intravenous catheter. After the signal stabilized, an average of five consecutive readings was recorded (baseline). After reaching a steady depth of anesthesia, the PI was recorded at 5-minintervals (pre-URS). A 6F/7.5F semi-rigid URS  was then introduced into the ureter retrogradely along with a safety guide wire to locate the ureteral stone. Then, the stone was disintegrated by use of a Holmium:YAG laser . After stone disintegration, readings were defined as post-URS. Ureteral patency was re-examined by URS assure that there was no ureteral injury caused by laser lithotripsy. All procedures involved insertion of a 28F ureteral double J stent into the operated side. The success rate was 100% and the 16F Foley catheter remained in place for one day.PI was calculated by measurement of the constant amount of light absorbed by non-pulsatile blood and other tissue (DC) and the variable amount of light absorbed by pulsating arterial inflow(AC)and use of the following equation: PI = (AC/DC)×100%. Anesthesia was administered as target-controlled infusion of propofol, and the blood concentration target was 5 µg/mL. Fentanyl was given at a concentration of 1 µg/kg body weight. Entropy values were maintained between 40 and 60 with adjustment of the target concentration of propofol by 0.5 µg/mL to achieve a steady state of sedation. The ambient temperature was 22°C and intravenous fluids (37°C) were infused at a rate of 500 mL/h.Serum creatinine (SCr) was measured three times in all patients: at baseline (upon admission), one day after URS laser lithotripsy, and 14 days after URS laser lithotripsy. The eGFR was calculated as: 186×(Serum Cr)−1.154×(age)−0.203××(1.210 if African- American) p-value less than 0.05 was considered statistically significant.Statistical analysis employed SPSS ver. 19, and data are presented as means ±SDs. The effect of sex and ASA score for patients with different hydronephrosis grades were examined by chi-square tests. Numerical data that had normal distributions and patient data were analyzed by one-way analysis of variance (ANOVA). Changes of variables in each hydronephrosis group were analyzed by repeated measure ANOVA. If there was a significant difference, a post-hoc Turkey HSD test was used to test for differences between groups. Pearson's correlation coefficient (γ) was used to assess the correlation between clinical variables or baseline parameters and the percent change in mean arterial pressure (MAP), PI, and eGFR. The interquartile range (IQR) was plotted relative to PI and MAP over different time periods. A p = 0.008).p<0.05 for all). In addition, Turkey HSD tests of the PI values indicated significant differences between baseline and pre-URS values, and between pre-URS and post-URS values .The MAP also declined significantly in all 3 hydronephrosis groups , but the difference between pre-URS and post-URS values were not significant when compared with post hoc test. The increase of eGFR was significant only in patients with grade I hydronephrosis (p<0.05), and the Turkey HSD test indicated significant differences only between pre-URS values and values at 14 days after surgery (p<0.05).p<0.05). The change ratios of PI, MAP, and eGFR were also not significantly different in patients with different grades of hydronephrosis (one-way ANOVA). However, the change ratio of PI was significantly and inversely correlated with the change ratio of MAP .Calculation of the PI by pulse oximetry provides a measure of changes in peripheral perfusion in the finger. In particular, the PI can predict postoperative shivering via the vasculature to each visceral organ. Any change in this system, including cardiac disease (pump dysfunction), vascular disease (circuit impairment), or renal obstruction(outflow stasis), may affect hemodynamic integrity and result in microcirculatory change In the present study, anesthesia and surgery of patients with renal calculi increased the measured PI in all hydronephrosis groups. Propofol relaxes vessel tone and decreases sympathetic reactions, resulting in an increase of the PI Devarajan p<0.05). This may be because changes in microcirculation mainly affected the distal arterioles (which is innervated by the sympathetic system) and the smooth muscle tone in arterioles, and these preceded the observed change in MAP We reported the impact of changes in peripheral microcirculation induced by restoration of ureteral patency and urine flow as the percent change of PI . The pervia PI following removal of ureteral obstructions. An animal study of the physiology of changes in hydronephrosis and relief of obstructive uropathy should be established to further examine the mechanisms of this effect.There can be great individual variations in PI, and several factors may interfere with measurement of PI In conclusion, our results showed that measurement of PI by a pulse oximeter allows monitoring of changes in peripheral microcirculation during endoscopic surgery for unilateral ureteral obstruction, but that eGFR did not change immediately after stone destruction. Use of a pulse oximeter to measure PI is simple and non-invasive, and provides important information regarding microperfusion in surgical patients. Thus, this method may improve patient safety and help clinicians to make important and prompt decisions while in the operating room.S1 TxtIRB protocol.(DOCX)Click here for additional data file.S2 TxtIRB protocol in Chinese.(DOCX)Click here for additional data file.S3 TxtCONSORT diagram.(DOC)Click here for additional data file.S4 TxtSTORBE checklist for cross-sectional study.(DOC)Click here for additional data file.


Primary open angle glaucoma (POAG) is a multifactorial disease characterized by progressive retinal ganglion cell death and visual field loss. It is known that alterations in intraocular pressure (IOP), blood pressure (BP), and ocular perfusion pressure (OPP) can play a significant role in the pathogenesis of the disease. Impaired autoregulatory capacity of ocular blood vessels may render tissues vulnerable to OPP changes and potentially harmful tissue ischemia-reperfusion damage. Vascular risk factors should be considered more important in a subgroup of patients with POAG, and especially in patients with normal tension glaucoma (NTG) with evidence of unphysiological BP response. For example, reduction of BP during the nighttime has an influence on OPP, and increased circadian OPP fluctuation, which might stand for unstable ocular blood flow, has been found to be the consistent risk factor for NTG development and progression. Central visual field may be affected more severely than peripheral visual field in NTG patients with higher 24-hour fluctuation of OPP. This review will discuss the current understanding of allegedly major systemic and ocular hemodynamic risk factors for glaucoma including systemic hypertension, arterial stiffness, antihypertensive medication, exaggerated nocturnal hypotension, OPP, and autonomic dysregulation.  Glaucoma is the leading cause of irreversible blindness worldwide, affecting more than 60 million people worldwide . The disPrimary open angle glaucoma (POAG) and normal tension glaucoma (NTG) share similar risk factors for the pathogenesis, which can be largely classified under mechanical and vascular categories. Mechanical risk factors include increased IOP, thinner lamina cribrosa (LC), larger LC displacement, anatomical variations of LC, or translaminar pressure dynamics –10.However, alteration of systemic blood pressure (BP) or ocular blood flow (OBF) also seems to be involved in the disease process . SeveralThe understanding of the relationship between these risk factors and glaucoma has not been established well. For example, systemic high BP may increase OPP theoretically, as BP is a major mathematical contributor in calculating OPP. However, it is inappropriate to regard high OPP which resulted from systemic hypertension as decreasing the risk of POAG and NTG for all age groups. Based on the current studies, systemic hypertension has different effect on the development of POAG in different age groups.This review article will summarize the present knowledge on several systemic and ocular hemodynamic risk factors in the pathogenesis of POAG and NTG and try to discuss the relationship among risk factors. The detailed topics will include systemic hypertension, arterial stiffness, antihypertensive medication, exaggerated nocturnal hypotension, mean ocular perfusion pressure (MOPP), and autonomic dysregulation. In the latter part of the paper, vascular pathogenesis theory based on the role of unstable OPP and autonomic dysregulation of the vessels will be highlighted.Systemic hypertension causes target organ damage (TOD) that involves vasculature, heart, brain, and kidneys. Complex biochemical, hormonal and hemodynamic mechanisms are involved in the pathogenesis of TOD. Common to all these processes is an increased bioavailability of reactive oxygen species (ROS) .It is well known that systemic hypertension accelerates atherosclerotic change that induces structural modifications of the arterial wall and reduction of vessel wall compliance. At its initial stage of hypertension, the blood flow may increase as BP increases. However, as irreversible vessel wall damage and endothelial hypertrophy progress, blood flow finally decreases. Hypertension more significantly compromises the vessel function in older people. For example, older subjects with hypertension are at much higher the risk of cardiovascular complications  and haveHowever, the role of systemic hypertension in the change of the optic nerve system related to glaucoma has not been elucidated very clearly. In meta-analyses, systemic hypertension increases the risk of developing POAG , 20. TheArterial stiffness, a loss of arterial elasticity, is one of the major signs of vascular aging . IncreasP < 0.002). In the arterial waveform analysis, POAG was associated with a lower brachial form factor than NTG (P < 0.001) and higher subendocardial viability ratio (P < 0.008) , (2) MOPP = 2/3 × MAP – IOP, and (3) circadian MOPP fluctuation = peak MOPP − trough MOPP. Unstable OBF may be a risk factor for open-angle glaucoma. BP, IOP, or vascular dysregulation may render the ocular perfusion pressure unstable and cause ischemia-reperfusion damage to the ganglion cells by oxygen free radicals and nitric oxide species. Diurnal variability of MOPP was associated with the development of POAG. Sehi et al. demonstrated that relative diurnal change in IOP did not differ between patients with untreated POAG and age-matched normal subjects. They also found that the percentage decrease in diurnal MOPP was significantly larger in patients with untreated POAG than in normal subjects, suggesting that relative diurnal change in MOPP may be a risk factor for POAG .Choi et al. found that marked circadian MOPP fluctuation was associated with nocturnal BP reduction. In the series of 132 NTG patients who had 24-hour ambulatory BP and IOP monitoring, they found out that MOPP significantly decreases at night and circadian MOPP fluctuation increases in BP over-dipper group. Increased circadian MOPP fluctuation was proportional to advanced structural and functional damage measured by Humphrey VF perimetry and scanning laser polarimetry in NTG patients at initial evaluation, implying the parameter as a possible risk factor for the development of NTG . Their sCircadian MOPP fluctuation seems to be related with VF progression in NTG eyes. In cohort studies using Kaplan-Meyer survival analysis, the group with highest circadian MOPP fluctuation showed a greater cumulative probability of central VF progression within 10 degrees than the group with lowest circadian MOPP fluctuation, by both linear regression analysis and modified Anderson criteria , 85. In The possible reason why central macular area seems more vulnerable to circadian MOPP fluctuation may be the different vascular support system between macular and peripapillary area. Macula is supplied only by the single-layered perifoveal capillary arcade. In contrast, peripapillary area has double-layered capillary system which consists of radial peripapillary capillaries in retinal nerve fiber layer and capillaries in ganglion cell layer . Thus, wVascular dysregulation refers to the regulation of blood flow that is not adapted to the needs of the respective tissue. In normal healthy eyes, the retinal blood flow is autoregulated and is independent of OPP within a certain range . However primary vascular dysregulation. In subjects with PVD, retinal vessels are stiffer and more irregular, and both neurovascular coupling and autoregulation capacity are reduced while retinal venous pressure is often increased [Insufficient or improper adaption of BF, despite anatomically healthy vessels and the absence of a causative disease, is termedncreased . The comncreased . Despitencreased . The OBFncreased .Various risk factors have been investigated in systemic and ocular hemodynamic risk factors for glaucoma. Every risk factor is complexly linked to each other. IOP-related mechanical stress, BP-related vascular stress, and disturbed autoregulation are complexly linked to each other in the development and progression of open-angle glaucoma . Daily r


Hypertension is one the most common causes of chronic kidney disease (CKD). One of the major concerns in hypertensive patients is early detection of renal disorders. In the past, serum creatinine (Scr) concentration was used as a marker of kidney function, but it proffers a late reflection of reduced glomerular filtration rate. Cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) have been recently proven to be useful for quantification of CKD. Therefore, we compared the diagnostic value of NGAL with cystatin C and creatinine to evaluate kidney function in hypertensive patients. 2. In this study, 42 hypertensive patients and 30 healthy volunteers were recruited. Serum cystatin C (Scys C) and plasma NGAL were measured using ELISA method. Creatinine, urea, hemoglobin, fibrinogen, and C-reactive protein were measured according to the routine methods. Estimated glomerular filtration rate (eGFR) was considered as the gold standard method (cut-off value of < 78 ml/min/1.73 m2. The sensitivity and specificity for NGAL were 96% and 100%, for cystatin C were 92% and 60% and for creatinine were 76% and 47%, respectively. In the patient group, plasma NGAL, cystatin C, and creatinine were all significantly correlated with eGFR, and plasma NGAL correlated best with eGFR. Receiver-operating characteristics analysis indicated that plasma NGAL was a better indicator than creatinine and cystatin C for predicting a GFR < 78 ml/min/1.73 m Plasma NGAL demonstrated a higher diagnostic value to detect kidney impairment in the early stages of CKD as compared to Scys C and Scr in hypertensive patients. Besides, Scr level is affected by factors, such as body mass, age, race, gender, inflammation as well as certain drugs such as cimetidin [et al. [Chronic kidney disease (CKD) is defined as either kidney damage or decreased kidney function (decreased eGFR [estimated glomerular filtration rate]) for at least three months . Hyperteimetidin .Studies imetidin . Cystatiimetidin , 6. Anotimetidin . Accordiimetidin -12. In aimetidin , 14, Mit [et al.  suggesteIn this cross-sectional study, 42 patients (10 men and 32 women) with high blood pressure  were reFor reduction of potential confounding factors, patients with chronic diseases, such as diabetes, liver and cardiovascular diseases, and elevated Scr and urea were excluded from the study. All patients were informed about the aim and procedure of the study and gave their informed consent. Healthy volunteers (n = 30) with the mean age of 54.73 ± 6.85 years were selected as the control group. Blood samples were collected in the morning before any food intake. Biochemical parameters including urea, Scr, hemoglobin, fibrinogen and C-reactive protein (CRP) were measured according to the standard methods in the routine clinical laboratory. eGFR (estimated creatinine clearance) were calculated using Cockcroft-Gault formula :2 after correction for body surface area according to the DuBois-DuBois formula [All clearances were expressed as ml/min/1.73 m formula : 2) = 0.007184 × height (cm)0.725 × weight (kg)0.425Body surface area  [○C until assay, and pNGAL was evaluated using commercially available ELISA kit . The intra- and inter-assay variances for pNGAL were 7.7% and 9.8% respectively. All measurements were made in a triplicate and in a blinded manner. pNGAL levels were expressed as nanograms per milliliter [ For pNGAL measurement, blood was placed into chilled vacutainer tubes containing potassium ethylenediaminetetracetate, and the plasma was promptly separated in a refrigerated centrifuge  , 20. Thelliliter . Scys wa Statistical analysis. Statistical analysis was performed using SPSS software (version18). Data were expressed as mean ± SD or percentage. t-test was used for comparison of the means between the two groups. Correlation between eGFR and other variables were assessed by Pearson's coefficient. The maximum efficiency, sensitivity, specificity, and positive- and negative-predictive values were also calculated. Receiver-operating characteristics analysis was used to calculate the area under the curve for pNGAL, Scys, and Scr to find the best NGAL, Scys, and Scr cut-off values for identifying the patients at risk of CKD. The accuracy of detection of pNGAL, Scys, and Scr was calculated using chi-square test. All results were considered significant if P value was < 0.05.P < 0.05). This study was performed on 42 high blood pressure patients (10 men and 32 women) with the mean age of 54.33 ± 8.89 years and 30 healthy individuals (14 men and 16 women) with the mean age of 54.7 ± 6.8 years. As shown in P < 0.001), Scys , and Scr , but no correlation was observed between eGFR and urea , eGFR and fibrinogen , eGFR and hemoglobin , and GFR and CRP . Receiver-operating characteristics analysis (2. The sensitivity and specificity were 96% and 100% for pNGAL (≥32.2 ng/ml) compared with 76% and 47% for sCr (≥0.97 mg/dl) and 92% and 60% for Scys, respectively (≥980 ng/ml). The best cut-off values of pNGAL, Scys, and Scr for detection of eGFR < 78 were 32.2 ng/ml, 980 ng/ml, and 0.97 mg/dl, respectively.  In this study, using the Pearson's correlation coefficient, eGFR correlation with various parameters, including urea, fibrinogen, CRP, hemoglobin, pNGAL and Scys was assessed. From the above parameters, eGFR showed a significant inverse correlation with pNGAL (R = -0.593, analysis  indicate As shown in Distribution of the patients based on pNGAL levels and eGFR is given in  Distribution of the patients based on Scys levels and eGFR is given in Distribution of the patients based on Scr levels and eGFR is given in et al. [et al. [ Studies have shown that there is an increased risk for CKD among individuals with high blood pressure , 23 An eet al.  found a et al.  were in et al.  on subje [et al.  study no [et al. . 2 was superior to Scr and Scys. Based on the results from this study, the best cut-off value for pNGAL to predict early stages of CKD was found to be 32.2 ng/ml with the sensitivity of 96% and specificity of 100%. pNGAL cut-off value in the current investigation is much lower than a previous investigation [Receiver-operating characteristics curves indicated that the diagnostic potential of pNGAL to detect patients with a GFR less than 78 ml/min/1.73 mtigation , most li2 [In accordance to a previous study, our results indicate the diagnostic superiority of Scys to Scr for predicting eGFR < 78 ml/min/1 m2 . Further2 . It is s2 . In conc


The comparison of changes in SBP and DBP to SR in ethnic groups compared in identical studies showed no statistically significant differences between the groups.The purpose of the meta-analysis of randomized trials was to analyze the significance of ethnicity on the effect of sodium reduction (SR) on blood pressure (BP) by estimating the effect of SR on BP in Asians, Blacks and Whites under conditions, which were adjusted with respect to baseline BP, baseline sodium intake and quantity of SR. Relevant studies were retrieved from a pool of 167 RCTs published in the period 1973–2010 and identified in a previous Cochrane review. 9 Asian, 9 Black, and 74 White populations standardized with respect to the range of baseline blood pressure, the range of baseline sodium, duration of SR (at least 7 days) and baseline sodium intake (at maximum 250 mmol) intake were included. In the cross-sectional analysis, there was no difference in change in SBP to SR between the ethnic groups, but there was a small difference in SR induced change in DBP between Blacks and Whites ( The effect of sodium reduction (SR) on blood pressure (BP) is smaller in persons with normal blood pressure than in hypertensive persons  than in White (5.5 mmHg) and Black hypertensive persons (6.4 mmHg)  range of these study groups were used to define the baseline SBP range of the white comparator study groups.The following factors were analyzed across the defined ethnic groups to evaluate the comparability of the groups: Age, baseline SBP, baseline diastolic BP (DBP), baseline sodium intake and the quantity of sodium reduction.In this re-analysis featuring improved control for blood pressure and the extent of salt intake and salt reduction the individual study data were integrated in meta-analyses separately for Asians, Blacks, and Whites, and the integrated summary data for each of the groups were then compared versus each other. As well the separate meta-analyses as the comparisons of the summary data for each ethnic group were performed by means of the inverse variance method (continuous data) in Review Manager (RevMan) [Computer program], version 5.1. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2008.A supplementary meta-regression analysis of Ethnicity versus effect on blood pressure  adjusted for amount of sodium reduction, baseline blood pressure (SBP and DBP), age, and the duration of the sodium reduction intervention was performed by means of the multiple regression analysis package in Statview 5.0.The study groups were defined from 167 references  Table . There wIn another additional analysis we excluded 35 study populations of Whites with a high sodium reduction to adjust the quantity of sodium reduction in Blacks and Whites (Table The present study, which attempted to adjust for baseline blood pressure and the quantity of sodium reduction showed that Asians had a non-significant trend toward a higher BP response to SR than whites, but they were also older, had a non-significantly higher mean baseline BP and a significantly higher baseline sodium intake Table . Blacks Our results are in accordance with a recent co-operation between Cuban, Canadian, and American researchers, who compared Black and White Cubans living under similar socio-economic conditions and found that “skin color was unrelated to mean blood pressure or hypertensive status” (Ordúñez1 et al., The possibility that socioeconomic conditions has an important influence on BP may also be reflected in the BP development in the United States during the 20th century. Not only did BP fall markedly in each new 10–year birth cohort from 1887 to 1975, the slope of the BP increase with age of each of these cohorts also decreased (Goff et al., An IOM report from 2004 recommended that all African Americans eat less than 1500 mg of sodium, whereas whites could eat up to 2300 mg of sodium (Institute of Medicine, In conclusion, ethnic differences in blood pressure response to sodium reduction seem smaller than previously observed. When the effect of SR on BP was adjusted for baseline blood pressure and quantity of sodium reduction there was a small statistically significant ethnic difference in SBP response and DBP response depending on the statistical method used, but the comparisons of Asian, Black and White study populations from studies investigating ethnic groups in identical studies showed no statistical differences in effect of SR on SBP or DBP between the ethnic groups in accordance with the conclusion of the 2013 IOM report. Whether the small observed differences in the present study are due to socio-economic factors or genetic factors remains to be setteled. Public guidelines like the American Guidelines (U.S. Department of Agriculture and U.S. Department of Health and Human Services The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.