Mortality of patients with multiple sclerosis: a cohort study in UK primary care

We aimed to estimate rates, causes and risk factors of all-cause mortality in a large population-based cohort of multiple sclerosis (MS) patients compared with patients without MS. Using data from the UK General Practice Research Database, we identified MS cases diagnosed during 2001–2006 and validated using patients’ original records where possible. We also included MS cases during 1993–2000 identified and validated in an earlier study. Cases were matched to up to ten referents without MS by age, sex, index date (date of first MS diagnosis for cases and equivalent reference date for controls), general practice and length of medical history before first MS diagnosis. Patients were followed up to identify deaths; hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated using Cox-proportional regression. MS patients (N = 1,822) had a significantly increased risk of all-cause mortality compared with referents (N = 18,211); adjusted HR 1.7 (95 % CI 1.4–2.1). Compared with referents, female MS patients had a higher but not significantly different HR for death than males; adjusted HR 1.86 (95 % CI 1.46–2.38) vs. HR 1.31 (95 % CI 0.93–1.84), respectively. The most commonly recorded cause of death in MS patients was ‘MS’ (41 %), with a higher proportion recorded among younger patients. A significantly higher proportion of referents than MS patients had cancer recorded as cause of death (40 vs. 19 %). Patients with MS have a significant 1.7-fold increased risk of all-cause mortality compared with the general population. MS is the most commonly recorded cause of death among MS patients. Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7370-3) contains supplementary material, which is available to authorized users

Glutathione accelerates sodium channel inactivation in excised rat axonal membrane patches

The effects of glutathione were studied on the gating behaviour of sodium channels in membrane patches of rat axons. Depolarizing pulses from –120 to –40 mV elicited sodium currents of up to 500 pA, indicating the simultaneous activation of up to 250 sodium channels. Inactivation of these channels in the excised, inside-out configuration was fitted by two time constants ( h1=0.81 ms; h2= 5.03 ms) and open time histograms at 0 mV revealed a biexponential distribution of channel openings ( short=0.28 ms; long=3.68 ms). Both, the slow time constant of inactivation and the long lasting single channel openings disappeared after addition of the reducing agent glutathione (2–5 mM) to the bathing solution. Sodium channels of excised patches with glutathione present on the cytoplasmatic face of the membrane had inactivation kinetics similar to channels recorded in the cell-attached configuration. These observations indicate that redox processes may contribute to the gating of axonal sodium channels

Section on Prospects for Dark Matter Detection of the White Paper on the Status and Future of Ground-Based TeV Gamma-Ray Astronomy

This is a report on the findings of the dark matter science working group for the white paper on the status and future of TeV gamma-ray astronomy. The white paper was commissioned by the American Physical Society, and the full white paper can be found on astro-ph (arXiv:0810.0444). This detailed section discusses the prospects for dark matter detection with future gamma-ray experiments, and the complementarity of gamma-ray measurements with other indirect, direct or accelerator-based searches. We conclude that any comprehensive search for dark matter should include gamma-ray observations, both to identify the dark matter particle (through the charac- teristics of the gamma-ray spectrum) and to measure the distribution of dark matter in galactic halos.Comment: Report from the Dark Matter Science Working group of the APS commissioned White paper on ground-based TeV gamma ray astronomy (19 pages, 9 figures

What is Asset-Based Community Development and how might it improve the health of people with long-term conditions? A realist synthesis

Abstract Background Asset Based Community Development (ABCD) appears to be a promising way to supporting people with long-term health problems but there is currently a lack of evidence to support this approach. Methods Taking a realist approach, a review and concept-mapping exercise of ABCD approaches to improve health were conducted with a view to providing a better understanding about these approaches, how they work, and who they work for. Results 29 papers were deemed relevant and included in the review. The realist synthesis and concept mapping helped identify concepts most commonly associated with ABCD but found no papers focussed on LTCs and thus no evidence that this approach improves health outcomes for people with LTCs. Conclusions Whilst there is a lack of clarity about how to implement ABCD or how to evaluate it, this paper offers a clearer theoretical framework about the essential ingredients needed to activate ABCD

Effect of superficial treatment with new natural antioxidant on salmon (Salmo salar) lipid oxidation

Lipid oxidation is one of the main factors responsible for the quality loss in refrigerated and frozen stored fish products. The aim of the study was to evaluate the effect of superficial treatment of Atlantic salmon (Salmo salar) with dihydroquercetin (DHQ) solutions on the hydrolytic and oxidative changes in fish lipids during refrigerated storage. It was found that treatment with DHQ solution (1.0 g l−1) reduced approximately twice the free fatty acids content of chilled stored salmon. After 11 days of storage at 1 °С, the contents of hydroperoxides (HPO) and 2-thiobarbituric acid reactive substances (TBARS) of these samples decreased with 45.00 and 0.91 mg MDA/kg, respectively. The share of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA) in control and experimental samples did not differ significantly (P>0.05). Results obtained show that the superficial treatment of salmon with DHQ solution (1.0 g l−1) delayed the hydrolytic and oxidative changes in fish lipids significantly, thus preserving the salmon freshness up to 11 days of storage at 1 °С

Small molecule induced reactivation of mutant p53 in cancer cells

The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 μM and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53