Influence of exercise and menstrual cycle phase on plasma homocyst(e)ine levels in young women--a prospective study.

Plasma total homocysteine (tHcy) has been identified as an independent risk factor for cardiovascular diseases (CVD). The difference in tHcy between the sexes has most often been related to the sex hormones, but also to a higher muscle mass in men. The purpose of this study was to assess the effects of acute exercise, brief exhaustive training, and menstrual cycle phase on circulating plasma tHcy concentrations. Fifteen untrained eumenorrheic women (mean age [+/-SD]: 18.7+/-0.4 yr, body fat: 25.8+/-3.4%, VO2max: 43.8+/-2.3 ml x kg(-1) x min(-1)) volunteered for the present study, which covered two menstrual cycles. During the second cycle the subjects participated in two exhaustive 5-day training programs on a cycle ergometer: one in the follicular (FPh) and one in the luteal phase (LPh). Pre- and posttraining plasma tHcy and total estrogen (E) responses were determined in blood samples obtained immediately before, during and immediately after incremental exercise to exhaustion. tHcy levels showed a large between-subject variation, but differences between FPh and LPh levels were consistent (P=0.063). Mean tHcy levels at rest were 9.44+/-1.65 micromol/L and 8.93+/-1.71 micromol/L during the FPh and LPh, respectively. Brief exhaustive training did not elicit any changes in plasma tHcy concentrations, although posttraining LPh E levels were lower (P<0.01). Overall, the differences between FPh and LPh values for tHcy and E were attenuated by training. Acute exercise increased plasma tHcy concentrations (P<0.001). At exhaustion, tHcy levels increased by 17% and 16% during the FPh and LPh, respectively. This was also significantly above tHcy levels at submaximal exercise (P=0.044). After a short period of training tHcy levels did not increase as much during acute exercise as they did before training; however, the increments were still significant (P=0.048). In conclusion, acute exercise in women produces significant increases in plasma tHcy concentrations, whereas brief exhaustive training does not significantly alter plasma tHcy levels. Our findings also suggest that plasma tHcy concentrations are menstrual cycle phase-dependent and that there is a close association between estrogen status and tHcy levels.     

FcγR interaction is not required for effective anti-PD-L1 immunotherapy but can add additional benefit depending on the tumor model

Immunomodulatory antibodies blocking interactions of coinhibitory receptors to their ligands such as CTLA-4, PD1 and PD-L1 on immune cells have shown impressive therapeutic efficacy in clinical studies. The therapeutic effect of these antibodies is mainly mediated by reactivating antitumor T cell immune responses. Detailed analysis of anti-CTLA4 antibody therapy revealed that an optimal therapeutic efficacy also requires binding to Fc receptors for IgG, FcγR, mediating depletion of intratumoral regulatory T cells. Here, we investigated the role of Fc binding in anti-PD-L1 antibody therapy in the MC38 C57BL/6 and CT26 BALB/c colon adenocarcinoma tumor models. In the MC38 tumor model, all IgG subclasses anti-PD-L1 showed similar therapeutic efficacy when compared to each other in either wild-type mice or in mice deficient for all FcγR. In contrast, in the CT26 tumor model, anti-PD-L1 mIgG2a, the IgG subclass with the highest affinity for activating FcγR, showed stronger therapeutic efficacy than other IgG subclasses. This was associated with a reduction of a myeloid cell subset with high expression of PD-L1 in the tumor microenvironment. This subclass preference for mIgG2a was lost in C57BL/6 × BALB/c F1 mice, indicating that the genetic background of the host may determine the additional clinical benefit of the high affinity antibody subclasses. Based on these data, we conclude that FcγR are not crucial for anti-PD-L1 antibody therapy but might play a role in some tumor models.     

The role of p-glycoprotein in psychiatric disorders: a reliable guard of the brain?

A major component in the protection of the brain against blood-borne toxic influences is the multispecific efflux pump P-glycoprotein. This pump, a 170 kD protein, located at the luminal side of the capillary endothelial cells, has a large capacity and is capable of extruding a wide array of structurally divergent substrates. The brain uptake of the majority of antidepressants and antipsychotics, as well as many other psychotropic drugs and endogenous compounds is hampered by the activity of P-glycoprotein. In this review we discuss the current state of knowledge concerning the role of Pglycoprotein on pharmacokinetics of psychiatric drugs and the impact of modulation of P-glycoprotein on major psychiatric disorders. Relevant issues in reference to the function of P-glycoprotein and other efflux pumps in the blood-brain barrier related to mood disorders and schizophrenia are addressed, such as a possible role of P-glycoprotein as a susceptibility factor in depressive disorders and psychotic disorders.     

Smooth muscle homeostasis in human atherosclerotic plaques through interleukin 15 signalling

Interleukin (IL)-15 is a cytokine that has a broad tissue distribution and is important in maintaining homeostasis of cells and stability of tissues. When II-15 is also expressed by vascular smooth muscle cells (SMC), which are the dominant type of cells in most atherosclerotic plaques, it could be important in maintaining plaque tissue integrity and hence resistance of plaques towards development of clinically relevant complications such as plaque rupture and thrombosis. In this study, IL-15 and IL-15Rα in vitro expression by coronary artery SMC was investigated using RT -PCR and FACS analysis. Immunohistochemistry was used to study in situ expression of IL-15 and IL-15R by SMC of human carotid artery atherosclerotic plaques. Multiplex ligand-dependent probe amplification (MLPA) was used to investigate the mRNA expression of 40 pro- and anti inflammatory genes after stimulating coronary SMC with IL-15. We found that atherosclerotic SMC express both IL-15 and its receptor IL-15R, and TNF-γ and TNF-α enhance IL-15R expression in cultured SMC. MLPA studies on SMC revealed enhanced expression of PDGF beta mRNA after IL15 stimulation. In conclusion, our data suggest that IL-15 may contribute to atherosclerotic plaque integrity by stimulation of smooth muscle cells, probably in a PDGF dependent fashion.     

Safety and efficacy of dual‐axis rotational coronary angiography vs. standard coronary angiography

Objective: To determine the safety and efficacy of dual‐axis rotational coronary angiography (DARCA) by directly comparing it to standard coronary angiography (SA). Background: Standard coronary angiography (SA) requires numerous fixed static images of the coronary tree and has multiple well‐documented limitations. Dual‐axis rotational coronary angiography (DARCA) is a new rotational acquisition technique that entails simultaneous LAO/RAO and cranial/caudal gantry movement. This technological advancement obtains numerous unique images of the left or right coronary tree with a single coronary injection. We sought to assess the safety and efficacy of DARCA as well as determine DARCA's adequacy for CAD screening and assessment. Methods: Thirty patients underwent SA following by DARCA. Contrast volume, radiation dose (DAP) and procedural time were recorded for each method to assess safety. For DARCA acquisitions, blood pressure (BP), heart rate (HR), symptoms and any arrhythmias were recorded. All angiograms were reviewed for CAD screening adequacy by two independent invasive cardiologists. Results: Compared to SA, use of DARCA was associated with a 51% reduction in contrast, 35% less radiation exposure, and 18% shorter procedural time. Both independent reviewers noted DARCA to be at least equivalent to SA with respect to the ability to screen for CAD. Conclusion: DARCA represents a new angiographic technique which is equivalent in terms of image quality and is associated with less contrast use, radiation exposure, and procedural time than SA. © 2011 Wiley‐Liss, Inc.