Matrix metalloproteinases and their pathological upregulation in multiple sclerosis: an overview

Matrix metalloproteinases (MMPs) are a family of extracellular proteases associated with extracellular matrix remodeling. They are involved in many physiological and reparative processes. MMPs can break down all extracellular constituents; therefore, their expression is very tightly regulated and their abnormal activity or over production has been linked to many diseases including multiple sclerosis (MS) which is a leading cause of non-traumatic disability in young adults in North America. Recently many studies, both in animals and humans, have been conducted to better elucidate the underlying causes, mechanisms and pathophysiology of MS. In this review, we discuss the potential role of pathological upregulation of MMPs in MS and future challenges which if properly addressed might help in development of potential cure for this disease.     

The cross‐pin retained implant supported restoration: a study of gasket placement and leakage

Background: Advantages of cross‐pin retained implant supported restorations (ISRs) include predictable retrieval and predictable retention. Unlike direct to fixture (DTF) or cement retained restorations, the prosthetic design of a cross‐pinned restoration retains gaps at the interfaces between the crown, abutment and cross‐pin screw. These spaces permit leakage into the suprastructure and gasket placement has been recommended to prevent this leakage. Methods: Five different gaskets were assessed for their ability to prevent leakage into a cross‐pinned ISR. The gaskets tested were: cement admixture on the cross‐pin screw; cement admixture on the inner surface of the coping and the cross‐pin screw; cement admixture on the inner surface of the coping only; cement admixture placed 1 mm from the margin of the coping and a filler placed in the abutment chimney. Results: Only gaskets which sealed both the cross‐pin screw interface and the abutment‐crown interface prevented leakage. A filler placed in the abutment chimney prevented leakage into this space but did not prevent fluid accumulating between the coping and abutment. Conservative placement of cement at the margin of the coping failed to prevent leakage. Conclusions: Cement gaskets may effectively prevent leakage into a cross‐pinned ISR. However, the use of a cement as a gasket has to be weighed against the issue of predictable retrieval, cement extrusion and incomplete seating.     

Identification,isolation, structural characterization,in silico toxicity prediction and in vitro cytotoxicity assay of simeprevir acidic and oxidative degradation products

Simeprevir is a new direct-acting antiviral drug used for the treatment of chronic hepatitis C. In this work, a simple, fast and economical chromatographic method was developed for the determination of simeprevir in the presence of its acidic and oxidative degradation products. The stress studies performed herein showed that simeprevir degraded under acidic and oxidative conditions but was stable under thermal and alkaline conditions. Chromatographic separation was achieved on a reversed-phase Eclipse XDB C₁₈ column (4.6 × 150 mm, 5 μm). The mobile phase consisted of methanol-0.05 M ammonium acetate (pH 4) (90 : 10, v/v) and was used at a flow rate of 1 mL min⁻¹. The column effluent was monitored at 237 nm. The calibration curve was linear over the concentration range of 0.1–20 μg mL⁻¹. The relative standard deviations for the intra-day and inter-day precision were less than 2%, and good percentage recoveries that met the acceptance criteria of the International Conference on Harmonization (ICH) guidelines were obtained. The robustness was assessed using the Plackett–Burman design. The simeprevir degradation products were isolated by flash chromatography and confirmed by ¹H NMR and LC-MS/MS techniques. The fully validated chromatographic method can be applied as a stability-indicating method for simeprevir and for routine analysis during quality control. Additionally, in silico toxicity prediction of the degradation products demonstrated a hepatotoxicity alert for DP 1, DP 2, DP 4 and DP 5 and a carcinogenicity alert for DP 3. In view of safety aspects, an in vitro cytotoxicity assay was carried out for simeprevir degradation products. They were found to be non-toxic in vitro at the tested concentrations.

Simeprevir is a new direct-acting antiviral drug used for the treatment of chronic hepatitis C.     

Evidence for Electrical Coupling in the SubCoeruleus (SubC) Nucleus

SubCoeruleus (SubC) neurons, which are thought to modulate rapid-eye-movement (REM) sleep, were recorded in brain stem slices from 7- to 20-day rats and found to manifest spikelets, indicative of electrical coupling. Spikelets occurred spontaneously or could be induced by superfusion of the cholinergic agonist carbachol. Whole cell recordings revealed that carbachol induced membrane oscillations and spikelets in the theta frequency range in SubC neurons in the presence of fast synaptic blockers. Electrical coupling in neurons is mediated by the gap junction protein connexin 36 (Cx 36). We found that Cx 36 gene expression and protein in the mesopontine tegmentum decreased during development. Cx 36 protein levels specifically in the SubC decreased in concert with the developmental decrease in REM sleep. The presence of electrical coupling in the SubC introduces a novel potential mechanism of action for the regulation of sleep-wake states.     

Thymoquinone protects rat liver after partial hepatectomy under ischaemia/reperfusion through oxidative stress and endoplasmic reticulum stress prevention

Ischaemia reperfusion (I/R) is associated with liver injury and impaired regeneration during partial hepatectomy (PH). The aim of this study was to investigate the effect of thymoquinone (TQ), the active compound of essential oil obtained from Nigella sativa seeds, on rat liver after PH. Male Wistar rats were divided equally into four groups (n = 6) receiving an oral administration of either vehicle solution (sham and PH groups) or TQ at 30 mg/kg (TQ and TQ + PH groups) for 10 consecutive days. Then, rats underwent PH (70%) with 60 minutes of ischaemia followed by 24 hours of reperfusion (PH and TQ + PH groups). Alanine aminotransferase (ALT) activity and histopathological damage were determined. Also, antioxidant parameters, liver regeneration index, hepatic adenosine triphosphate (ATP) content, endoplasmic reticulum (ER) stress and apoptosis were assessed. In response to PH under I/R, liver damage was significantly alleviated by TQ treatment as evidenced by the decrease in ALT activity (P < .01) and histological findings (P < .001). In parallel, TQ preconditioning increased hepatic antioxidant capacities. Moreover, TQ improved mitochondrial function (ATP, P < .05), attenuated ER stress parameters and repressed the expression of apoptotic effectors. Taken together, our results suggest that TQ preconditioning could be an effective strategy to reduce liver injury after PH under I/R. The protective effects were mediated by the increase of antioxidant capacities and the decrease of ER stress and apoptosis.     

Descriptive and Prospective Analysis of Young Adult Alcohol Use and Romantic Relationships: Disentangling between- and within-Person Associations Using Monthly Assessments

Background: Prior research on romantic relationships and alcohol use among young adults has not distinguished between differences in patterns of relationship status over extended periods of time and within-person changes in status that only occur for some individuals. Objectives: This study captured between-person differences in relationship patterns, assessed associations between relationship patterns and alcohol use, and examined within-person associations between alcohol use and relationship status changes. In addition, age and sex differences in between- and within-person associations were tested. Methods: We used multilevel modeling of monthly data collected over one year on alcohol use and romantic relationship status from a Seattle area community sample of 620 young adults (ages 18–24). Results: Participants were coded into six relationship pattern groups: (1) single-not-dating (16%), (2) stable-in-a-relationship (30%), (3) single-dating (10%), (4) ended-a-relationship (14%), (5) started-a-relationship (13%), and (6) ended-and-started-a-relationship (18%). Single-not-dating and stable-in-a-relationship groups reported the least drinking across the entire year; the single-dating, ended-a-relationship, and ended-and-started-a-relationship groups reported higher levels of drinking. Examining within-person changes in groups 3–6 revealed increases in drinking associated with months of dating among the single-dating group, months postbreakup among the ended-a-relationship group, and months of breaking up and starting a new relationship among the ended-and-started-a-relationship group. Few differences by age or sex were found for between- or within-person associations. Conclusions: The findings point to heterogeneity in patterns of relationship status over time, differences in relationship patterns associated with variations in drinking, and particular time points of elevated risk for young adults who experience changes in status.