Evaluation of cystatin C for the detection of chronic kidney disease in cats

BackgroundSerum cystatin C (sCysC) and urinary cystatin C (uCysC) are potential biomarkers for early detection of chronic kidney disease (CKD) in cats. An in-depth clinical validation is required. ObjectivesTo evaluate CysC as a marker for CKD in cats and to compare assay performance of the turbidimetric assay (PETIA) with the previously validated nephelometric assay (PENIA). AnimalsNinety cats were included: 49 CKD and 41 healthy cats. MethodsSerum CysC and uCysC concentrations were prospectively evaluated in cats with CKD and healthy cats. Based on plasma exo-iohexol clearance test (PexICT), sCysC was evaluated to distinguish normal, borderline, and low GFR. Sensitivity and specificity to detect PexICT<1.7mL/min/kg were calculated. Serum CysC results of PENIA and PETIA were correlated with GFR. Statistical analysis was performed using general linear modeling. ResultsCats with CKD had significantly higher meanSD sCysC (1.4 +/- 0.5mg/L) (P<.001) and uCysC/urinary creatinine (uCr) (291 +/- 411mg/mol) (P<.001) compared to healthy cats (sCysC 1.0 +/- 0.3 and uCysC/uCr 0.32 +/- 0.97). UCysC was detected in 35/49 CKD cats. R-2 values between GFR and sCysC or sCr were 0.39 and 0.71, respectively (sCysC or sCr=+GFR+epsilon). Sensitivity and specificity were 22 and 100% for sCysC and 83 and 93% for sCr. Serum CysC could not distinguish healthy from CKD cats, nor normal from borderline or low GFR, in contrast with sCr. ConclusionSerum CysC is not a reliable marker of reduced GFR in cats and uCysC could not be detected in all CKD cats

52-week efficacy and safety of telbivudine with conditional tenofovir intensification at week 24 in HBeAg-positive chronic Hepatitis B

Background and Aims: The Roadmap concept is a therapeutic framework in chronic hepatitis B for the intensification of nucleoside analogue monotherapy based on early virologic response. The efficacy and safety of this approach applied to telbivudine treatment has not been investigated. Methods: A multinational, phase IV, single-arm open-label study (ClinicalTrials.gov ID NCT00651209) was undertaken in HBeAg-positive, nucleoside-naive adult patients with chronic hepatitis B. Patients received telbivudine (600 mg once-daily) for 24 weeks, after which those with undetectable serum HBV DNA (<300 copies/mL) continued to receive telbivudine alone while those with detectable DNA received telbivudine plus tenofovir (300 mg once-daily). Outcomes were assessed at Week 52. Results: 105 patients commenced telbivudine monotherapy, of whom 100 were included in the efficacy analysis. Fifty-five (55%) had undetectable HBV DNA at Week 24 and continued telbivudine monotherapy; 45 (45%) received tenofovir intensification. At Week 52, the overall proportion of undetectable HBV DNA was 93% (93/100) by last-observation-carried-forward analysis (100% monotherapy group, 84% intensification group) and no virologic breakthroughs had occurred. ALT normalization occurred in 77% (87% monotherapy, 64% intensification), HBeAg clearance in 43% (65% monotherapy, 16% intensification), and HBeAg seroconversion in 39% (62% monotherapy, 11% intensification). Six patients had HBsAg clearance. Myalgia was more common in the monotherapy group (19% versus 7%). No decrease in the mean glomerular filtration rate occurred in either treatment group at Week 52. Conclusions: Telbivudine therapy with tenofovir intensification at Week 24, where indicated by the Roadmap strategy, appears effective and well tolerated for the treatment of chronic hepatitis B. Trial Registration: ClinicalTrials.gov NCT0065120

Heart rate variability and target organ damage in hypertensive patients

Background: We evaluated the association between linear standard Heart Rate Variability (HRV) measures and vascular, renal and cardiac target organ damage (TOD). Methods: A retrospective analysis was performed including 200 patients registered in the Regione Campania network (aged 62.4 ± 12, male 64%). HRV analysis was performed by 24-h holter ECG. Renal damage was assessed by estimated glomerular filtration rate (eGFR), vascular damage by carotid intima-media thickness (IMT), and cardiac damage by left ventricular mass index. Results: Significantly lower values of the ratio of low to high frequency power (LF/HF) were found in the patients with moderate or severe eGFR (p-value < 0.001). Similarly, depressed values of indexes of the overall autonomic modulation on heart were found in patients with plaque compared to those with a normal IMT (p-value <0.05). These associations remained significant after adjustment for other factors known to contribute to the development of target organ damage, such as age. Moreover, depressed LF/HF was found also in patients with left ventricular hypertrophy but this association was not significant after adjustment for other factors. Conclusions: Depressed HRV appeared to be associated with vascular and renal TOD, suggesting the involvement of autonomic imbalance in the TOD. However, as the mechanisms by which abnormal autonomic balance may lead to TOD, and, particularly, to renal organ damage are not clearly known, further prospective studies with longitudinal design are needed to determine the association between HRV and the development of TOD

Prevalence, predictors and prognostic implications of PR interval prolongation in patients with heart failure

Aims: To determine the prevalence, incidence, predictors and prognostic implications of PR interval prolongation in patients referred with suspected heart failure. Methods and Results: Consecutive patients referred with suspected heart failure were prospectively enrolled. After excluding patients with implantable cardiac devices and atrial fibrillation, 1420 patients with heart failure and reduced ejection fraction (HeFREF) [age: median 71 (interquartile range IQR: 63-78) years; men: 71%; NT-ProBNP: 1319 (583-3378) ng/L], 1094 with heart failure and normal ejection fraction (HeFNEF) [age: 76 (70-82) years; men: 47%; NT-ProBNP: 547 (321-1171) ng/L], and 1150 without heart failure [age: 68 (60-75) years; men: 51%; NT-ProBNP: 86 (46-140) ng/L] were included. The prevalence of first degree heart block [heart-rate corrected PR interval (PRc) >200 ms] was higher in patients with heart failure (21% HeFREF, 20% HeFNEF, 9% without heart failure). In patients with HeFREF or HeFNEF, longer baseline PRc was associated with greater age, male sex, and longer QRS duration and, in those with HeFREF, treatment with amiodarone or digoxin. Patients with heart failure in the longest PRc quartile had worse survival compared to shorter PRc quartiles but PRc was not independently associated with survival in multivariable analysis. For patients without heart failure, shorter baseline PRc was independently associated with worse survival. Conclusion: PRc prolongation is common in patients with HeFREF or HeFNEF and associated with worse survival, although not an independent predictor of outcome. The results of clinical trials investigating the therapeutic potential of shortening the PR interval by pacing are awaited

25-Hydroxyvitamin D levels and chronic kidney disease in the AusDiab (Australian Diabetes, Obesity and Lifestyle) study

<p>Abstract</p> <p>Background</p> <p>Low 25-hydroxy vitamin D (25(OH)D) levels have been associated with an increased risk of albuminuria, however an association with glomerular filtration rate (GFR) is not clear. We explored the relationship between 25(OH)D levels and prevalent chronic kidney disease (CKD), albuminuria and impaired GFR, in a national, population-based cohort of Australian adults (AusDiab Study).</p> <p>Methods</p> <p>10,732 adults ≥25 years of age participating in the baseline survey of the AusDiab study (1999–2000) were included. The GFR was estimated using an enzymatic creatinine assay and the CKD-EPI equation, with CKD defined as eGFR <60 ml/min/1.73 m². Albuminuria was defined as a spot urine albumin to creatinine ratio (ACR) of ≥2.5 mg/mmol for men and ≥3.5 for women. Serum 25(OH)D levels of <50 nmol/L were considered vitamin D deficient. The associations between 25(OH)D level, albuminuria and impaired eGFR were estimated using multivariate regression models.</p> <p>Results</p> <p>30.7% of the study population had a 25(OH)D level <50 nmol/L (95% CI 25.6-35.8). 25(OH)D deficiency was significantly associated with an impaired eGFR in the univariate model (OR 1.52, 95% CI 1.07-2.17), but not in the multivariate model (OR 0.95, 95% CI 0.67-1.35). 25(OH)D deficiency was significantly associated with albuminuria in the univariate (OR 2.05, 95% CI 1.58-2.67) and multivariate models (OR 1.54, 95% CI 1.14-2.07).</p> <p>Conclusions</p> <p>Vitamin D deficiency is common in this population, and 25(OH)D levels of <50 nmol/L were independently associated with albuminuria, but not with impaired eGFR. These associations warrant further exploration in prospective and interventional studies.</p

Human keratinocytes are vanilloid resistant

BACKGROUND: Use of capsaicin or resiniferatoxin (RTX) as analgesics is an attractive therapeutic option. RTX opens the cation channel inflammatory pain/vanilloid receptor type 1 (TRPV1) permanently and selectively removes nociceptive neurons by Ca(2+)-cytotoxicity. Paradoxically, not only nociceptors, but non-neuronal cells, including keratinocytes express full length TRPV1 mRNA, while patient dogs and experimental animals that underwent topical treatment or anatomically targeted molecular surgery have shown neither obvious behavioral, nor pathological side effects. METHODS: To address this paradox, we assessed the vanilloid sensitivity of the HaCaT human keratinocyte cell line and primary keratinocytes from skin biopsies. RESULTS: Although both cell types express TRPV1 mRNA, neither responded to vanilloids with Ca(2+)-cytotoxicity. Only ectopic overproduction of TRPV1 rendered HaCaT cells sensitive to low doses (1-50 nM) of vanilloids. The TRPV1-mediated and non-receptor specific Ca(2+)-cytotoxicity ([RTX]>15 microM) could clearly be distinguished, thus keratinocytes were indeed resistant to vanilloid-induced, TRPV1-mediated Ca(2+)-entry. Having a wider therapeutic window than capsaicin, RTX was effective in subnanomolar range, but even micromolar concentrations could not kill human keratinocytes. Keratinocytes showed orders of magnitudes lower TRPV1 mRNA level than sensory ganglions, the bona fide therapeutic targets in human pain management. In addition to TRPV1, TRPV1b, a dominant negative splice variant was also noted in keratinocytes. CONCLUSION: TRPV1B expression, together with low TRPV1 expression, may explain the vanilloid paradox: even genuinely TRPV1 mRNA positive cells can be spared with therapeutic (up to micromolar) doses of RTX. This additional safety information might be useful for planning future human clinical trials

Plant ecology meets animal cognition: impacts of animal memory on seed dispersal

We propose that an understanding of animal learning and memory is critical to predicting the impacts of animals on plant populations through processes such as seed dispersal, pollination and herbivory. Focussing on endozoochory, we review the evidence that animal memory plays a role in seed dispersal, and present a model which allows us to explore the fundamental consequences of memory for this process. We demonstrate that decision-making by animals based on their previous experiences has the potential to determine which plants are visited, which fruits are selected to be eaten from the plant and where seeds are subsequently deposited, as well as being an important determinant of animal survival. Collectively, these results suggest that the impact of animal learning and memory on seed dispersal is likely to be extremely important, although to date our understanding of these processes suffers from a conspicuous lack of empirical support. This is partly because of the difficulty of conducting appropriate experiments but is also the result of limited interaction between plant ecologists and those who work on animal cognition

Acute and chronic kidney disease in elderly patients with hip fracture: prevalence, risk factors and outcome with development and validation of a risk prediction model for acute kidney injury

Background Hip fracture is a common injury in older people with a high rate of postoperative morbidity and mortality. This patient group is also at high risk of acute kidney injury (AKI) and chronic kidney disease (CKD), but little is known of the impact of kidney disease on outcome following hip fracture. Methods An observational cohort of consecutive patients with hip fracture in a large UK secondary care hospital. Predictive modelling of outcomes using development and validation datasets. Inclusion: all patients admitted with hip fracture with sufficient serum creatinine measurements to define acute kidney injury. Main outcome measures – development of acute kidney injury during admission; mortality (in hospital, 30-365 day and to follow-up); length of hospital stay. Results Data were available for 2848 / 2959 consecutive admissions from 2007-2011; 776 (27.2%) male. Acute kidney injury occurs in 24%; development of acute kidney injury is independently associated with male sex (OR 1.48 (1.21 to 1.80), premorbid chronic kidney disease stage 3B or worse (OR 1.52 (1.19 to 1.93)), age (OR 3.4 (2.29 to 5.2) for >85 years) and greater than one major co-morbidities (OR 1.61 (1.34 to 1.93)). Acute kidney injury of any stage is associated with an increased hazard of death, and increased length of stay (Acute kidney injury: 19.1 (IQR 13 to 31) days; no acute kidney injury 15 (11 to 23) days). A simplified predictive model containing Age, CKD stage (3B-5), two or more comorbidities, and male sex had an area under the ROC curve of 0.63 (0.60 to 0.67). Conclusions Acute kidney injury following hip fracture is common and associated with worse outcome and greater hospital length of stay. With the number of people experiencing hip fracture predicted to rise, recognition of risk factors and optimal perioperative management of acute kidney injury will become even more important

Reproductive health and burn-out among female physicians: nationwide, representative study from Hungary

BACKGROUND: There is a worldwide rising tendency of women deciding to become physicians; hence, one of the most remarkable fields of investigation is the wellbeing of female doctors. The aim of this study was to describe female physicians' reproductive health in Hungary and to explore the potential correlation between their reproductive disorders and burnout symptoms. Up to our present knowledge, there have not been any studies investigating the correlation between reproductive disorders and burnout of female physicians; therefore, our study represents a unique approach. METHODS: Data in this representative cross-sectional epidemiological study were obtained from online questionnaires completed by 3039 female physicians. Participants in a representative nationwide survey (Hungarostudy, 2013) served as controls (n = 1069). Differences between physicians and the control group were disclosed by chi-square test. Correlations between certain factors of reproductive health and the three dimensions of burnout were detected by Pearson correlations and X2 test. Binary logistic regression analysis was used to determine the association between burnout and reproductive health. RESULTS: Female physicians were more often characterised by time-to-pregnancy interval longer than one year (18.4% vs. 9.8%), were bearing more high-risk pregnancies (26.3% vs.16.3%), and were more likely to be undergoing infertility therapy (8.5% vs. 3.4%) and experiencing miscarriage (20.8% vs. 14.6%) during their reproductive years, compared with the general female population. With the exception of miscarriages, the difference remained significant in all comparisons with the professional control group. Both high-risk pregnancies and miscarriages of doctors were associated with depersonalisation (p = 0.028 and p = 0.012 respectively) and personal accomplishment (p = 0.016 and p = 0.008 respectively) dimensions of burnout. Results of the multivariate analysis showed that, beside traditional risk factors, depersonalisation acted as an important explanatory factor in case of high-risk pregnancies (OR = 1.086). CONCLUSIONS: There is a circulatory causality between burnout and the development of reproductive disorders. Burnout is an important risk factor for high-risk pregnancies and miscarriages, and it has a negative effect on the outcome of pregnancies. At the same time, women suffering from reproductive disorders are more likely to develop burnout syndrome. Improvement of working conditions and prevention of burnout in female doctors are equally important tasks

Ergocalciferol and Microcirculatory Function in Chronic Kidney Disease and Concomitant Vitamin D Deficiency: An Exploratory, Double Blind, Randomised Controlled Trial

Vitamin D deficiency and endothelial dysfunction are non-traditional risk factors for cardiovascular events in chronic kidney disease. Previous studies in chronic kidney disease have failed to demonstrate a beneficial effect of vitamin D on arterial stiffness, left ventricular mass and inflammation but none have assessed the effect of vitamin D on microcirculatory endothelial function.We conducted a randomised controlled trial of 38 patients with non diabetic chronic kidney disease stage 3-4 and concomitant vitamin D deficiency (<16 ng/dl) who received oral ergocalciferol (50,000 IU weekly for one month followed by 50,000 IU monthly) or placebo over 6 months. The primary outcome was change in microcirculatory function measured by laser Doppler flowmetry after iontophoresis of acetylcholine. Secondary endpoints were tissue advanced glycation end products, sublingual functional capillary density and flow index as well as macrovascular parameters. Parallel in vitro experiments were conducted to determine the effect of ergocalciferol on cultured human endothelial cells.Twenty patients received ergocalciferol and 18 patients received placebo. After 6 months, there was a significant improvement in the ergocalciferol group in both endothelium dependent microcirculatory vasodilatation after iontophoresis of acetylcholine (p = 0.03) and a reduction in tissue advanced glycation end products (p = 0.03). There were no changes in sublingual microcirculatory parameters. Pulse pressure (p = 0.01) but not aortic pulse wave velocity was reduced. There were no significant changes in bone mineral parameters, blood pressure or left ventricular mass index suggesting that ergocalciferol improved endothelial function independently of these parameters. In parallel experiments, expression of endothelial nitric oxide synthase and activity were increased in human endothelial cells in a dose dependent manner.Ergocalciferol improved microcirculatory endothelial function in patients with chronic kidney disease and concomitant vitamin D deficiency. This process may be mediated through enhanced expression and activity of endothelial nitric oxide synthase.Clinical trials.gov NCT00882401