Cohort profile: Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT)

Background: The Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events (CanPREDDICT) is a large, prospective, pan-Canadian, cohort study designed to improve our understanding of determinants of renal and cardiovascular (CV) disease progression in patients with chronic kidney disease (CKD). The primary objective is to clarify the associations between traditional and newer biomarkers in the prediction of specific renal and CV events, and of death in patients with CKD managed by nephrologists. This information could then be used to better understand biological variation in outcomes, to develop clinical prediction models and to inform enrolment into interventional studies which may lead to novel treatments. Methods/Designs: Commenced in 2008, 2546 patients have been enrolled with eGFR between 15 and 45 ml/min 1.73m2 from a representative sample in 25 rural, urban, academic and non academic centres across Canada. Patients are to be followed for an initial 3 years at 6 monthly intervals, and subsequently annually. Traditional biomarkers include eGFR, urine albumin creatinine ratio (uACR), hemoglobin (Hgb), phosphate and albumin. Newer biomarkers of interest were selected on the basis of biological relevance to important processes, commercial availability and assay reproducibility. They include asymmetric dimethylarginine (ADMA), N-terminal pro-brain natriuretic peptide (NT-pro-BNP), troponin I, cystatin C, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6) and transforming growth factor beta 1 (TGFβ1). Blood and urine samples are collected at baseline, and every 6 monthly, and stored at −80°C. Outcomes of interest include renal replacement therapy, CV events and death, the latter two of which are adjudicated by an independent panel. Discussion: The baseline distribution of newer biomarkers does not appear to track to markers of kidney function and therefore may offer some discriminatory value in predicting future outcomes. The granularity of the data presented at baseline may foster additional questions. The value of the cohort as a unique resource to understand outcomes of patients under the care of nephrologists in a single payer healthcare system cannot be overstated. Systematic collection of demographic, laboratory and event data should lead to new insights. The mean age of the cohort was 68 years, 90% were Caucasian, 62% were male, and 48% had diabetes. Forty percent of the cohort had eGFR between 30–45 mL/min/1.73m2, 22% had eGFR values below 20 mL/min/1.73m2; 61% had uACR < 30. Serum albumin, hemoglobin, calcium and 25-hydroxyvitamin D (25(OH)D) levels were progressively lower in the lower eGFR strata, while parathyroid hormone (PTH) levels increased. Cystatin C, ADMA, NT-proBNP, hsCRP, troponin I and IL-6 were significantly higher in the lower GFR strata, whereas 25(OH)D and TGFβ1 values were lower at lower GFR. These distributions of each of the newer biomarkers by eGFR and uACR categories were variable

A New Distance to The Antennae Galaxies (NGC 4038/39) Based on the Type Ia Supernova 2007sr

Traditionally, the distance to NGC 4038/39 has been derived from the systemic recession velocity, yielding about 20 Mpc for H_0 = 72 km/s/Mpc. Recently, this widely adopted distance has been challenged based on photometry of the presumed tip of the red giant branch (TRGB), which seems to yield a shorter distance of 13.3+-1.0 Mpc and, with it, nearly 1 mag lower luminosities and smaller radii for objects in this prototypical merger. Here we present a new distance estimate based on observations of the Type Ia supernova (SN) 2007sr in the southern tail, made at Las Campanas Observatory as part of the Carnegie Supernova Project. The resulting distance of D(SN Ia) = 22.3+-2.8 Mpc [(m-M)_0 = 31.74+-0.27 mag] is in good agreement with a refined distance estimate based on the recession velocity and the large-scale flow model developed by Tonry and collaborators, D(flow) = 22.5+-2.8 Mpc. We point out three serious problems that a short distance of 13.3 Mpc would entail, and trace the claimed short distance to a likely misidentification of the TRGB. Reanalyzing Hubble Space Telescope (HST) data in the Archive with an improved method, we find a TRGB fainter by 0.9 mag and derive from it a preliminary new TRGB distance of D(TRGB) = 20.0+-1.6 Mpc. Finally, assessing our three distance estimates we recommend using a conservative, rounded value of D = 22+-3 Mpc as the best currently available distance to The Antennae.Comment: 8 pages, 5 figures, 1 table (emulateapj; uses amsmath package). Accepted for publication in The Astronomical Journal, Vol. 136. Figs. 1 & 2 degraded to reduce file size

The influence of chemical composition on the properties of Cepheid stars I - Period-Luminosity relation vs iron abundance

We have assessed the influence of the stellar iron content on the Cepheid Period-Luminosity (PL) relation by relating the V band residuals from the Freedman et al (2001) PL relation to [Fe/H] for 37 Galactic and Magellanic Clouds Cepheids. The iron abundances were measured from FEROS and UVES high-resolution and high-signal to noise optical spectra. Our data indicate that the stars become fainter as metallicity increases, until a plateau or turnover point is reached at about solar metallicity. Our data are incompatible with both no dependence of the PL relation on iron abundance, and with the linearly decreasing behavior often found in the literature (e.g. Kennicutt et al 1998, Sakai et al 2004). On the other hand, non-linear theoretical models of Fiorentino et al (2002) provide a fairly good description of the data.Comment: 5 pages, 2 figures. Accepted for pubblication in Astronomy & Astrophysics Letters (Table 1 will only appear in electronic form). Revised version (23.11.04) to fix typo in Table 1 (the V magnitudes for Galactic stars were wrong

Avoidance of Naked Singularities in Dilatonic Brane World Scenarios with a Gauss-Bonnet Term

We consider, in 5 dimensions, the low energy effective action induced by heterotic string theory including the leading stringy correction of order alpha'. In the presence of a single positive tension flat brane, and an infinite extra dimension, we present a particular class of solutions with finite 4-dimensional Planck scale and no naked singularity. A ``self-tuning'' mechanism for relaxing the cosmological constant on the brane, without a drastic fine tuning of parameters, is discussed in this context. Our solutions are distinct from the standard self-tuning solutions discussed in the context of vanishing quantum corrections in alpha', and become singular in this limit.Comment: 9 pages, 1 figure, discussion of self-tuning change

Scalar brane backgrounds in higher order curvature gravity

We investigate maximally symmetric brane world solutions with a scalar field. Five-dimensional bulk gravity is described by a general lagrangian which yields field equations containing no higher than second order derivatives. This includes the Gauss-Bonnet combination for the graviton. Stability and gravitational properties of such solutions are considered, and we particularily emphasise the modifications induced by the higher order terms. In particular it is shown that higher curvature corrections to Einstein theory can give rise to instabilities in brane world solutions. A method for analytically obtaining the general solution for such actions is outlined. Genericaly, the requirement of a finite volume element together with the absence of a naked singularity in the bulk imposes fine-tuning of the brane tension. A model with a moduli scalar field is analysed in detail and we address questions of instability and non-singular self-tuning solutions. In particular, we discuss a case with a normalisable zero mode but infinite volume element.Comment: published versio

BTN3A2 Expression in Epithelial Ovarian Cancer Is Associated with Higher Tumor Infiltrating T Cells and a Better Prognosis

BTN3A2/BT3.2 butyrophilin mRNA expression by tumoral cells was previously identified as a prognostic factor in a small cohort of high grade serous epithelial ovarian cancer (HG-EOC). Here, we evaluated the prognostic value of BT3.2 at the protein level in specimen from 199 HG-EOC patients. As the only known role of butyrophilin proteins is in immune regulation, we evaluated the association between BT3.2 expression and intratumoral infiltration of immune cells by immunohistochemistry with specific antibodies against BT3.2, CD3, CD4, CD8, CD20, CD68 and CD206. Epithelial BT3.2 expression was significantly associated with longer overall survival and lower risk of disease progression (HR = 0.651, p = 0.006 and HR = 0.642, p = 0.002, respectively) and significantly associated with a higher density of infiltrating T cells, particularly CD4+ cells (0.272, p<0.001). We also observed a strong association between the relative density of CD206+ cells, as evaluated by the ratio of intratumoral CD206+/CD68+ expression, and risk of disease progression (HR = 1.355 p = 0.044, respectively). In conclusion, BT3.2 protein is a potential prognostic biomarker for the identification of HG-EOC patients with better outcome. In contrast, high CD206+/CD68+ expression is associated with high risk of disease progression. While the role of BT3.2 is still unknown, our result suggest that BT3.2 expression by epithelial cells may modulates the intratumoral infiltration of immune cells

Aldo Keto Reductase 1B7 and Prostaglandin F2α Are Regulators of Adrenal Endocrine Functions

Prostaglandin F2α (PGF2α), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF2α synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF2α biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF2α but expressed different biosynthetic isozymes. In chromaffin cells, PGF2α secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF2α secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF2α release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF2α receptor was only detected in chromaffin cells, making medulla the primary target of PGF2α action. By comparing PGF2α-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF2α repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF2α may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Facteurs de risque vasculaire et insuffisance rénale

Les patients souffrant d’insuffisance rénale chronique (IRC) présentent un taux important de maladies cardiovasculaires (MCV). En effet, la prévalence des MCV est 10 à 30 fois plus élevée chez ces patients que dans la population générale. Cet excès est lié en partie à une prévalence accrue de facteurs de risque « classiques » tels que l’hypertension artérielle, le diabète et la dyslipidémie. Cependant, plusieurs autres facteurs de risque « non traditionnels » ont été identifiés au cours des dernières années et contribuent également à la prévalence accrue des MCV dans cette population. Les facteurs les plus étudiés et les plus influents en termes de risque cardiovasculaire sont l’inflammation et le stress oxydatif. Cet article présente, de façon critique, les données concernant l’impact de ces facteurs sur le développement de l’athérosclérose chez les sujets ayant une IRC, en mettant l’accent sur l’aspect épidémiologique et les recommandations thérapeutiques en matière d’insuffisance rénale.Patients with chronic kidney disease (CKD) have a substantially increased risk of cardiovascular disease (CVD) compared with the general population. The high prevalence of established traditional risk factors for atherosclerosis (diabetes, hypertension, dyslipidemia) in these patients undoubtedly contributes to the accelerated rate of vascular disease. In addition, several hypotheses have emerged to explain the high prevalence of CVD in patients with chronic renal failure. Growing evidence has been gathered over the last 15 years regarding the role of uremia-related risk factors such as inflammation and oxidant stress in the pathogenesis of atherosclerosis in subjects with renal failure. This paper will review current knowledge regarding the potential role of these non-traditional or uremia-related risk factors for atherosclerosis with special emphasis on prevalence, cardiac risk, and management in patients with CKD

The effects of exposure to psychological violence in the workplace on commitment and turnover intentions : The moderating role of social support and role stressors

Exposure to workplace violence has been identified as a serious and universal issue facing modern organizations. The present study focuses more specifically on exposure to psychological violence, and its association with turnover intentions as mediated by workplace affective commitment. In addition, we also explore the moderating role of various facets of job demands (role stressors) and resources (social support) on the aforementioned relations. Data collected from 1,228 university employees indicated that experiencing psychological violence at work was associated with lower levels of workplace affective commitment and higher levels of turnover intentions, and that the relation between psychological violence and turnover intentions was partially mediated by commitment. Furthermore, role stressors and social support were found to moderate the negative relation between exposure to psychological violence and workplace affective commitment, as well as between commitment and turnover intentions, but not the direct relation between psychological violence and turnover intentions. Theoretical and research implications for the literature on psychological violence and practical suggestions for minimizing its damaging consequences are proposed