MZB1 is a GRP94 cochaperone that enables proper immunoglobulin heavy chain biosynthesis upon ER stress

MZB1 (pERp1) is a B-cell-specific and endoplasmic reticulum (ER)-localized protein implicated in antibody secretion and integrin-mediated cell adhesion. Here, we examine the role of MZB1 in vivo by conditional gene inactivation in the mouse germline and at different stages of B lymphopoiesis. Deletion of MZB1 impairs humoral immune responses and antibody secretion in plasma cells that naturally undergo ER stress. In addition, we found that experimental induction of ER stress by tunicamycin injections in mice results in a block of pro-B-cell to pre-B-cell differentiation specifically in Mzb1^−/− mice. A similar developmental block was observed in Mzb1^fl/flmb1^Cre mice, whereby a Cre recombinase-induced genotoxic stress unmasks a role for MZB1 in the surface expression of immunoglobulin µ heavy chains (µHCs). MZB1 associates directly with the substrate-specific chaperone GRP94 (also called HSP90B1 or gp96) in an ATP-sensitive manner and is required for the interaction of GRP94 with µHCs upon ER stress. Thus, MZB1 seems to act as a substrate-specific cochaperone of GRP94 that enables proper biosynthesis of µHCs under conditions of ER stress.     

Sleep changes following statin therapy: a systematic review and meta-analysis of randomized placebo-controlled polysomnographic trials

Introduction

Statin use might be associated with an increased risk of sleep disturbances including insomnia, but the evidence regarding sleep changes following statin therapy has not been conclusive. Therefore we assessed the impact of statin therapy on sleep changes through a systematic review and meta-analysis of available randomized controlled trials (RCTs).

Material and methods

We searched MEDLINE and SCOPUS up to October 1, 2014 to identify placebo-controlled RCTs investigating the effect of statin therapy on sleep changes. A meta-analysis was performed using either a fixed-effects or a random-effect model according to the I2 statistic. Effect size was expressed as weighted mean difference (WMD) and 95% confidence interval (CI).

Results

Overall, the impact of statin therapy on polysomnography (PSG) indices of sleep was reported in 5 trials comprising 9 treatment arms. Overall, statin therapy had no significant effect on total sleep duration (WMD: –7.75 min, 95% CI: –18.98, 3.48, p = 0.176), sleep efficiency (WMD: 0.09%, 95% CI: –2.27, 2.46, p = 0.940), entries to stage I (WMD: 0.36, 95% CI: –0.91, 1.63, p = 0.580), or latency to stage I (WMD: –1.92 min, 95% CI: –4.74, 0.89, p = 0.181). In contrast, statin therapy significantly reduced wake time (WMD: –4.43 min, 95% CI: –7.77, –0.88, p = 0.014) and number of awakenings (WMD: –0.40, 95% CI: –0.46, –0.33, p < 0.001). Meta-regression did not suggest any correlation between changes in wake time and awakening episodes with duration of treatment and LDL-lowering effect of statins.

Conclusions

The results indicated that statins have no significant adverse effect on sleep duration and efficiency, entry to stage I, or latency to stage I sleep, but significantly reduce wake time and number of awakenings.     

Hyperparathyroidism can be useful in the identification of primary aldosteronism due to aldosterone-producing adenoma

Type 1 diabetes triggers protein kinase C (PKC)-dependent NADPH oxidase activation in the renal medullary thick ascending limb (mTAL), resulting in accelerated superoxide production. As acute exposure to superoxide stimulates NaCl transport by the mTAL, we hypothesized that diabetes increases mTAL Na(+) transport through PKC-dependent and NADPH oxidase-dependent mechanisms. An O(2)-sensitive fluoroprobe was used to measure O(2) consumption by mTALs from rats with streptozotocin-induced diabetes and sham rats. In sham mTALs, total O(2) consumption was evident as a 0.34±0.03 U change in normalized relative fluorescence (ΔNRF)/min per mg protein. Ouabain (2 mmol/L) reduced O(2) consumption by 69±4% and 500 μmol/L furosemide reduced O(2) consumption by 58±8%. Total O(2) consumption was accelerated in mTAL from diabetic rats (0.74±0.07 ΔNRF/min/mg protein; P<0.05 versus sham), reflecting increases in ouabain- and furosemide-sensitive O(2) consumption. NADPH oxidase inhibition (100 μmol/L apocynin) reduced furosemide-sensitive O(2) consumption by mTAL from diabetic rats to values not different from sham. The PKC inhibitor calphostin C (1 μmol/L) or the PKCα/β inhibitor G?6976 (1 μmol/L) decreased furosemide-sensitive O(2) consumption in both groups, achieving values that did not differ between sham and diabetic. PKCβ inhibition had no effect in either group. Similar inhibitory patterns were evident with regard to ouabain-sensitive O(2) consumption. We conclude that NADPH oxidase and PKC (primarily PKCα) contribute to an increase in O(2) consumption by the mTAL during type 1 diabetes through effects on the ouabain-sensitive Na(+)-K(+)-ATPase and furosemide-sensitive Na(+)-K(+)-2Cl(-) cotransporter that are primarily responsible for active transport Na(+) reabsorption by this nephron segment.     

Effect of statins on platelet function in patients with hyperlipidemia

Introduction

It is generally assumed that cholesterol reduction by statins is the predominant therapeutic result underlying their beneficial effects in cardiovascular disease. However, the action of statins may be partially independent of their effects on plasma cholesterol levels, as they combine lipid lowering with positive effects on hemorheological conditions and endothelial function. We evaluated the impact of statin treatment on platelet adhesion to fibrinogen (spontaneous and ADP-activated), along with ADP, collagen or ristocetin-induced aggregation in type II hyperlipidemic patients.

Material and methods

The study group included 70 persons: 50 patients affected by type II hyperlipidemia without concomitant diseases and 20 healthy volunteers. The effects of 8-week statin treatment (atorvastatin 10 mg/day, simvastatin 20 mg/day, or pravastatin 20 mg/day) on platelet activation were evaluated.

Results

Regardless of the type of statin, a significant decrease in ADP-induced platelet aggregation was observed: for atorvastatin 50.6 ±12.8% vs. 41.1 ±15.8% (p < 0.05), for simvastatin 57.2 ±18.0% vs. 44.7 ±22.1% (p = 0.05), and for pravastatin 55.8 ±19.5% vs. 38.8 ±23.3% (p < 0.05). There was no significant effect of statins on collagen or ristocetin-induced platelet aggregation and adhesion.

Conclusions

Therapy with statins beneficially modifies ADP-induced platelet aggregation in patients with hyperlipidemia and does not affect spontaneous or ADP-induced platelet adhesion to fibrinogen and platelet aggregation induced by collagen or ristocetin.     

Microchimerism in twins

Introduction

The aim of this paper was to report the occurrence of peripheral blood chimerism in newborns from bigeminal pregnancies.

Material and methods

Cord blood collected from 50 pairs of twins constituted the biological material studied. Analyses included: DNA isolation, quantitative and qualitative assessment of DNA preparations, hybridization analysis of SLS type as well as of MLS type, and analysis of microsatellite sequences with regard to polymorphisms using polymerase chain reaction.

Results

The presence of additional fragments of DNA in peripheral blood lymphocytes was found in four out of fifty pairs of monozygotic twins (8%) at locus D7S21 (7p22, n = 3) and locus D12S11 (12q24.3, n = 1). In these cases, the presence of additional DNA fragments was also proved by analysis of microsatellite sequence polymorphisms at loci HUMPLA2A1 (pancreatic phospholipase A-2, 12q23), HUMCYARO (cytochrome P450, 15q21.1) and HUMvWF (von Willebrand factor, 12p13).

Conclusions

The results of our study confirm the occurrence of chimerism in twins and constitutes the starting point for further studies aimed at determining the clinical significance of chimerism in twins both for women and fetuses.     

Reproductive outcome is optimized by genomic embryo screening,vitrification, and subsequent transfer into a prepared synchronous endometrium

Purpose

The aim of this study is to compare implantation and live birth rates (LBR) between fresh euploid embryo transfers versus cryo-all cycles with a subsequent embryo transfer into a prepared endometrium.

Material and Methods

This is a retrospective cohort study. Patients who underwent an IVF cycle with PGS with trophectoderm biopsy from January 2011 to July 2015 were included. Patients were divided into three groups: “Fresh Only,” “Frozen Embryo Transfer ('FET) Only,” and “Fresh ET then FET.” For “Fresh Only” group (n = 345), PGS results were received within 24 h. For “FET Only” group (n = 514), results were expected after 24 h, and embryos were cryopreserved after biopsy; only FET was performed in this group (no fresh transfer). For “FET with a previous fresh ET” (n = 139) group, patients underwent a fresh ET with a subsequent FET, in which the same cohort of embryos was utilized. The main outcome measures were pregnancy rate (PR), clinical PR, implantation rate (IR), LBR, and early pregnancy loss rate.

Results

IRs were statistically higher in the “FET Only” group when compared to the “Fresh Only” group (59.5 vs. 50.6 %, p < 0.01) and the “FET with a previous fresh ET” (59.5 vs. 50.6 %, p < 0.05). LBR was statistically significant in the “FET Only” group when compared to the “Fresh Only” group (57.6 vs. 46.5 %, p < 0.005) but not when compared to “FET with a previous fresh ET” group (57.6 vs. 47.7 %, p = 0.07).

Conclusions

This analysis suggests euploid embryos to be more likely to implant and achieve a LBR in a synthetic FET cycle than in a fresh cycle.

     

A Translational Randomized Trial of Perioperative Arginine Immunonutrition on Natural Killer Cell Function in Colorectal Cancer Surgery Patients

Annals of Surgical Oncology - Surgery results in severe impairment of natural killer (NK) cell cytotoxicity (NKC) and activity (NKA, cytokine secretion), and a dramatic drop in arginine levels....     

Acceptability of the nestorone®/ethinyl estradiol contraceptive vaginal ring: development of a model; implications for introduction

Objectives

Develop and test a theoretical acceptability model for the Nestorone®/ethinyl estradiol contraceptive vaginal ring (CVR); explore whether domains of use within the model predict satisfaction, method adherence and CVR continuation.

Study Design

Four domains of use were considered relative to outcome markers of acceptability, that is, method satisfaction, adherence and continuation. A questionnaire to evaluate subjects' experiences relative to the domains, their satisfaction (Likert scale) and adherence to instructions for use was developed and administered to 1036 women enrolled in a 13-cycle Phase 3 trial. Method continuation was documented from the trial database. Stepwise logistic regression (LR) analysis was conducted and odds ratios (ORs) calculated to assess associations of satisfaction with questions from the four domains. Fisher's Exact Test was used to determine the association of satisfaction with outcome measures.

Results

A final acceptability model was developed based on the following determinants of CVR satisfaction: ease of use, side effects, expulsions/feeling the CVR and sexual activity including physical effects during intercourse. Satisfaction was high (89%) and related to higher method adherence [OR, 2.6 (1.3, 5.2)] and continuation [OR, 5.5 (3.5, 8.4)]. According to the LR analysis, attributes of CVR use representing items from the four domains — finding it easy to remove, not complaining of side effects, not feeling the CVR while wearing it and experiencing no change or an increase in sexual pleasure and/or frequency — were associated with higher odds of satisfaction.

Conclusion

Hypothesized domains of CVR use were related to satisfaction, which was associated with adherence and continuation. Results provide a scientific basis for introduction and future research.

Implications Statement

Acceptability research is important when introducing a new method of contraception and determining whether it can be a successful option in meeting the reproductive health needs of women and men. This study was designed to test a conceptual model of acceptability and identify factors associated with successful use of a new contraceptive delivery modality. Original research was conducted for this publication.