Siponimod Modulates the Reaction of Microglial Cells to Pro-Inflammatory Stimulation

Siponimod (Mayzent^®), a sphingosine 1-phosphate receptor (S1PR) modulator which prevents lymphocyte egress from lymphoid tissues, is approved for the treatment of relapsing-remitting and active secondary progressive multiple sclerosis. It can cross the blood–brain barrier (BBB) and selectively binds to S1PR1 and S1PR5 expressed by several cell populations of the central nervous system (CNS) including microglia. In multiple sclerosis, microglia are a key CNS cell population moving back and forth in a continuum of beneficial and deleterious states. On the one hand, they can contribute to neurorepair by clearing myelin debris, which is a prerequisite for remyelination and neuroprotection. On the other hand, they also participate in autoimmune inflammation and axonal degeneration by producing pro-inflammatory cytokines and molecules. In this study, we demonstrate that siponimod can modulate the microglial reaction to lipopolysaccharide-induced pro-inflammatory activation.     

Aspirin Inhibits the Inflammatory Response of Protease-Activated Receptor 1 in Pregnancy Neutrophils: Implications for Treating Women with Preeclampsia

Neutrophils expressing cyclooxygenase-2 (COX-2) extensively infiltrate maternal blood vessels in preeclampsia, associated with vascular inflammation. Because pregnancy neutrophils also express protease-activated receptor 1 (PAR-1, F2R thrombin receptor), which they do not in non-pregnant subjects, they can be activated by proteases. We tested the hypothesis that aspirin at a dose sufficient to inhibit COX-2 would reduce inflammatory responses in preeclampsia neutrophils. Neutrophils were isolated from normal pregnant and preeclamptic women at approximately 30 weeks’ gestation. Normal pregnancy neutrophils were treated with elastase, a protease elevated in preeclampsia, or elastase plus aspirin to inhibit COX-2, or elastase plus pinane thromboxane, a biologically active structural analog of thromboxane and a thromboxane synthase inhibitor. Preeclamptic pregnancy neutrophils were treated with the same doses of aspirin or pinane thromboxane. Confocal microscopy with immunofluorescence staining was used to determine the cellular localization of the p65 subunit of nuclear factor-kappa B (NF-κB) and media concentrations of thromboxane were measured to evaluate the inflammatory response. In untreated neutrophils of normal pregnant women, p65 was localized to the cytosol. Upon stimulation with elastase, p65 translocated from the cytosol to the nucleus coincident with increased thromboxane production. When neutrophils were co-treated with aspirin or pinane thromboxane, elastase was not able to cause nuclear translocation of p65 or increase thromboxane. In untreated neutrophils of preeclamptic women, the p65 subunit was present in the nucleus and thromboxane production was elevated, but when preeclamptic neutrophils were treated with aspirin or pinane thromboxane, p65 was cleared from the nucleus and returned to the cytosol along with decreased thromboxane production. These findings suggest that COX-2 is a downstream mediator of PAR-1 and demonstrate that PAR-1- mediated inflammation can be inhibited by aspirin. Given the extensive and ubiquitous expression of PAR-1 and COX-2 in preeclamptic women, consideration should be given to treating women with preeclampsia using a dose of aspirin sufficient to inhibit COX-2.     

Post-tonsillectomy bacteraemia in children

It has been postulated that the bacteraemia rate following guillotine tonsillectomy is lower than that following dissection tonsillectomy due to intra-operative compression of tonsillar blood vessels by the guillotine. The aim of this study was to evaluate the incidence of bacteraemia following dissection and guillotine tonsillectomy. Sixty-four patients undergoing elective tonsillectomy for recurrent acute tonsillitis were randomly selected, 32 underwent dissection tonsillectomy and 32 guillotine tonsillectomy. Positive intra-operative blood cultures were obtained in 16 patients (25 per cent), nine (28.1 per cent) of the dissection group and seven (21.8 per cent) of the guillotine group. There was no significant difference between the two methods (Chi-squared test, p = 0.77).     

A structural analysis of secondary conditions experienced by people with physical disabilities.

Examined how secondary conditions experienced by people with a physical disability might group together and how these clusters might be related to various primary impairments. It was predicted that primary impairments would predict specific clusters of secondary conditions and that certain secondary conditions (e.g., depression) would be endorsed independently of primary impairments. A survey measuring 40 secondary conditions was completed by 594 adults (mean age 55.4 yrs) who experienced a mobility impairment. Results indicate that certain secondary conditions (e.g., depression) are evident across a wide variety of impairments. Results are discussed with respect to their implications for the treatment and prevention of secondary conditions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Electrochemical microscopy of polymer layers

Electrochemical imaging of holes in a polymer layer lying on a metal is demonstrated. Electrochemical imaging has been used to obtain high definition “pictures” of metal/insulator composite surfaces (under aqueous solutions), and porous materials, eg dentine and membranes, [1]. The principle of the method depends on scanning the surface of interest with a microelectrode (the “tip”) which either responds to changes in potential or changes in current as it is scanned [2]. We demonstrate here how the method can be used to image holes in a thin polymer coating on a metal surface.     

Effects of total replacement of atrial myosin light chain-2 with the ventricular isoform in atrial myocytes of transgenic mice

BACKGROUND: In contrast to their well-known and critical role in excitation-contraction coupling of vascular smooth muscle, the effects of the myosin light chains on cardiomyocyte mechanics are poorly understood. Accordingly, we designed the present experiment to define the cardiac chamber-specific functional effects of the ventricular isoform of the regulatory myosin light chain (MLC2v). METHODS AND RESULTS: Postnatal transgenic cardiac-specific overexpression of MLC2v was achieved by use of the alpha-myosin heavy chain promoter. Enzymatically disaggregated atrial and ventricular mouse myocytes were field-stimulated at multiple frequencies, and mechanical properties and calcium kinetics were studied by use of video edge detection and FURA 2-AM, respectively. MLC2v overexpression resulted in complete replacement of the atrial with the ventricular isoform of the regulatory myosin light chain at the steady-state mRNA and protein levels in the atria of transgenic mice. Mechanical properties of transgenic atrial myocytes were enhanced to the level of ventricular myocytes of control animals in association with modest decreases in the amplitude of the calcium transient. CONCLUSIONS: MLC2v modulates chamber-specific contractility by enhanced calcium sensitivity and/or improved cross-bridge cycling of the thin and thick filaments of the cardiomyocyte.