C-Reactive protein and risk of ESRD: results from the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)

Background: To better understand a potential association of elevated C-reactive protein (CRP) level with progression of chronic kidney disease (CKD), we examined the relationship of CRP level with the development of end-stage renal disease (ESRD) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). Study Design Post hoc analysis of a randomized controlled trial. Setting & Participants: 4,038 patients with type 2 diabetes, CKD, and anemia in TREAT. Predictor: Baseline serum CRP concentrations. Outcomes: The primary outcome was development of ESRD; secondary outcomes included doubling of serum creatinine level, a composite of ESRD/serum creatinine doubling, and a composite of death or ESRD. Measurements: We fit unadjusted and adjusted Cox regression models to test the association of baseline CRP level with time to the development of the outcomes of interest. Results: Mean age of participants was 67 years, 43% were men, and 64% were white. Approximately half (48%) the patients had CRP levels > 3.0 mg/L; 668 patients developed ESRD, and 1,270 developed the composite outcome of death or ESRD. Compared with patients with baseline CRP levels ≤ 3.0 mg/L, those with moderately/markedly elevated CRP levels (≥6.9 mg/L; 24% of patients) had a higher adjusted risk for ESRD (HR, 1.32; 95% CI, 1.07-1.63) and the composite outcome of death or ESRD (HR, 1.41; 95% CI, 1.21-1.64). Although nonsignificant, similar trends were noted in competing-risk models. Limitations: Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Conclusions: Elevated baseline CRP levels are common in type 2 diabetic patients with anemia and CKD and are associated with the future development of ESRD and the composite of death or ESRD

Perturbation of the P-Body Component Mov10 Inhibits HIV-1 Infectivity

Exogenous retroviruses are obligate cellular parasites that co-opt a number of host proteins and functions to enable their replication and spread. Several host factors that restrict HIV and other retroviral infections have also recently been described. Here we demonstrate that Mov10, a protein associated with P-bodies that has a putative RNA-helicase domain, when overexpressed in cells can inhibit the production of infectious retroviruses. Interestingly, reducing the endogenous Mov10 levels in virus-producing cells through siRNA treatment also modestly suppresses HIV infectivity. The actions of Mov10 are not limited to HIV, however, as ectopic expression of Mov10 restricts the production of other lentiviruses as well as the gammaretrovirus, murine leukemia virus. We found that HIV produced in the presence of high levels of Mov10 is restricted at the pre-reverse transcription stage in target cells. Finally, we show that either helicase mutation or truncation of the C-terminal half of Mov10, where a putative RNA-helicase domain is located, maintained most of its HIV inhibition; whereas removing the N-terminal half of Mov10 completely abolished its activity on HIV. Together these results suggest that Mov10 could be required during the lentiviral lifecycle and that its perturbation disrupts generation of infectious viral particles. Because Mov10 is implicated as part of the P-body complex, these findings point to the potential role of cytoplasmic RNA processing machinery in infectious retroviral production

The limits of social class in explaining ethnic gaps in educational attainment

This paper reports an analysis of the educational attainment and progress between age 11 and age 14 of over 14,500 students from the nationally representative Longitudinal Study of Young People in England (LSYPE). The mean attainment gap in national tests at age 14 between White British and several ethnic minority groups were large, more than three times the size of the gender gap, but at the same time only about one-third of the size of the social class gap. Socio-economic variables could account for the attainment gaps for Black African, Pakistani and Bangladeshi students, but not for Black Caribbean students. Further controls for parental and student attitudes, expectations and behaviours indicated minority ethnic groups were on average more advantaged on these measures than White British students, but this was not reflected proportionately in their levels of attainment. Black Caribbean students were distinctive as the only group making less progress than White British students between age 11 and 14 and this could not be accounted for by any of the measured contextual variables. Possible explanations for the White British-Black Caribbean gap are considered

Observation of surface layering in a nonmetallic liquid

Oscillatory density profiles (layers) have previously been observed at the free surfaces of liquid metals, but not in other isotropic liquids. We have used x-ray reflectivity to study a molecular liquid, tetrakis(2-ethylhexoxy)silane. When cooled to T/Tc~0.25 (well above the freezing point for this liquid), density oscillations appear at the surface. Lateral order within the layers is liquid-like. Our results confirm theoretical predictions that a surface-layered state will appear even in dielectric liquids at sufficiently low temperatures, if not preempted by freezing.Comment: accepted for publication in Phys. Rev. Lett. 15 pages 4 figure

Human cyclin T1 expression ameliorates a T-cell-specific transcriptional limitation for HIV in transgenic rats, but is not sufficient for a spreading infection of prototypic R5 HIV-1 strains ex vivo

<p>Abstract</p> <p>Background</p> <p>Cells derived from native rodents have limits at distinct steps of HIV replication. Rat primary CD4 T-cells, but not macrophages, display a profound transcriptional deficit that is ameliorated by transient trans-complementation with the human Tat-interacting protein Cyclin T1 (hCycT1).</p> <p>Results</p> <p>Here, we generated transgenic rats that selectively express hCycT1 in CD4 T-cells and macrophages. hCycT1 expression in rat T-cells boosted early HIV gene expression to levels approaching those in infected primary human T-cells. hCycT1 expression was necessary, but not sufficient, to enhance HIV transcription in T-cells from individual transgenic animals, indicating that endogenous cellular factors are critical co-regulators of HIV gene expression in rats. T-cells from hCD4/hCCR5/hCycT1-transgenic rats did not support productive infection of prototypic wild-type R5 HIV-1 strains <it>ex vivo</it>, suggesting one or more significant limitation in the late phase of the replication cycle in this primary rodent cell type. Remarkably, we identify a replication-competent HIV-1 GFP reporter strain (R7/3 YU-2 Env) that displays characteristics of a spreading, primarily cell-to-cell-mediated infection in primary T-cells from hCD4/hCCR5-transgenic rats. Moreover, the replication of this recombinant HIV-1 strain was significantly enhanced by hCycT1 transgenesis. The viral determinants of this so far unique replicative ability are currently unknown.</p> <p>Conclusion</p> <p>Thus, hCycT1 expression is beneficial to <it>de novo </it>HIV infection in a transgenic rat model, but additional genetic manipulations of the host or virus are required to achieve full permissivity.</p

Effect of pre-partum supplementation of rumen protected methionine plus lysine and choline on the performance of crossbred cows

The study was conducted to determine rumen escape potential (REP) of commercial rumen protected methionine (RPM), lysine (RPL) and choline (RPC) products and to examine the effect of supplementing RPM plus RPL and RPC on the performance of preparturient crossbred cows. Crossbred cows (27; 2nd to 4th lactation) were randomly assigned to 3 groups of 9 animals each, on the basis of most probable production ability (MPPA). Cows in control group (T1), were fed basal diet as per NRC (2001). The cows in second group (T2), were supplemented with 5 g RPM and 20 g RPL, and those in third group (T3), were fed 54 g RPC per cow/day for 40 days pre-partum. In sacco study revealed that REP of RPM, RPL and RPC was 75.20, 54.97 and 72.89%, respectively. Supplementation of RPM plus RPL and RPC resulted in higher body condition score (BCS) in crossbred cows on the day of parturition. Nutrient intake was similar among the groups, except that duodenal supply of methionine and lysine was higher in T2 group. Plasma triglycerides, VLDL (very low density lipoproteins) and phosphatidylcholine levels were higher in T2 and T3 groups while vitamin E level was higher in T3 group, on the day of parturition, indicating better immune status. It was concluded that fortification of ration with RPM plus RPL and RPC resulted in improved body condition score, duodenal supply of methionine and lysine and better immune status in cows during prepartum period

Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism A Randomized Clinical Trial

Importance Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects. Objective To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet. Design, Setting, and Participants A randomized, double-blind, double-dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015. Interventions Etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily. Main Outcomes and Measures The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self-reported nausea or vomiting. Results The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was −10.5% (95% CI, −17.5% to −3.5%, P for noninferiority, <.001; P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to cinacalcet (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%). Conclusions and Relevance Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety

Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated-skeletal muscle insulin resistance

Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor κBα and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-α blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation