The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals

The recent identification of the mitochondrial Ca(2+) uniporter gene (Mcu/Ccdc109a) has enabled us to address its role, and that of mitochondrial Ca(2+) uptake, in neuronal excitotoxicity. Here we show that exogenously expressed Mcu is mitochondrially localized and increases mitochondrial Ca(2+) levels following NMDA receptor activation, leading to increased mitochondrial membrane depolarization and excitotoxic cell death. Knockdown of endogenous Mcu expression reduces NMDA-induced increases in mitochondrial Ca(2+), resulting in lower levels of mitochondrial depolarization and resistance to excitotoxicity. Mcu is subject to dynamic regulation as part of an activity-dependent adaptive mechanism that limits mitochondrial Ca(2+) overload when cytoplasmic Ca(2+) levels are high. Specifically, synaptic activity transcriptionally represses Mcu, via a mechanism involving the nuclear Ca(2+) and CaM kinase-mediated induction of Npas4, resulting in the inhibition of NMDA receptor-induced mitochondrial Ca(2+) uptake and preventing excitotoxic death. This establishes Mcu and the pathways regulating its expression as important determinants of excitotoxicity, which may represent therapeutic targets for excitotoxic disorders

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

The effects of the Two-Week Rule on NHS colorectal cancer diagnostic services: a systematic literature review.

Contains fulltext : 49770.pdf ( ) (Open Access)BACKGROUND: The Two-Week Rule (TWR) was introduced to ensure that all patients with a suspected colorectal cancer (CRC) saw a hospital specialist within 14 days of an urgent GP referral. Guidelines were available to GPs to facilitate the appropriate TWR referral of patients exhibiting high-risk CRC symptoms. METHODS: We aimed to evaluate the TWR and its CRC detection rate on NHS CRC diagnostic services by performing a literature search and critically appraising the peer-reviewed studies. Only 12 studies were eligible for inclusion. Data was collected and overall results were given as weighted averages. RESULTS: The studies identified indicated that only 10.3% of patients referred by the TWR were eventually diagnosed with CRC. When examining the referral origin of all CRC patients diagnosed during the time of the studies, 24% had been referred using the TWR, 24.1% were referred as emergency cases, and 52.4% were referred using alternative routes. No evidence was found to indicate that the TWR had resulted in identifying CRC patients at an earlier, more treatable stage of their disease. CONCLUSION: The TWR referral system needs to be improved to increase the number of CRC patients referred using this fast track method as they present to their GP. The TWR and new NICE Guidelines for the referral of patients with suspected cancer should be independently evaluated

An Introduction to Internet-Based Data and Its Relevance to Forensic Mental Health Assessment

This opening chapter first discusses the prevalence and current state of Internet use in our society with a focus on social media, including data on who is more inclined to use social media and a brief review of extant literature on the relationship between social media and personality. Also reviewed is the use of social media by legal and mental health professionals more broadly. Branching from these disciplines, we then outline the relevance of Internet-based data to forensic mental health assessment and argue for the need to consider the unique aspects associated with the integration of Internet-based data sources in this context. We highlight existing legal and professional standards that have applicability to collateral information obtained from the Internet and introduce newly proposed guidelines specific to this data modality. The chapter ends with an overview of the content and structure of the remaining chapters