The multiple roles of myelin protein genes during the development of the oligodendrocyte

It has become clear that the products of several of the earliest identified myelin protein genes perform functions that extend beyond the myelin sheath. Interestingly, these myelin proteins, which comprise proteolipid protein, 2′,3′-cyclic nucleotide 3′-phosphodiesterase and the classic and golli MBPs (myelin basic proteins), play important roles during different stages of oligodendroglial development. These non-myelin-related functions are varied and include roles in the regulation of process outgrowth, migration, RNA transport, oligodendrocyte survival and ion channel modulation. However, despite the wide variety of cellular functions performed by the different myelin genes, the route by which they achieve these many functions seems to converge upon a common mechanism involving Ca2+ regulation, cytoskeletal rearrangements and signal transduction. In the present review, the newly emerging functions of these myelin proteins will be described, and these will then be discussed in the context of their contribution to oligodendroglial development

WldS Reduces Paraquat-Induced Cytotoxicity via SIRT1 in Non-Neuronal Cells by Attenuating the Depletion of NAD

WldS is a fusion protein with NAD synthesis activity, and has been reported to protect axonal and synaptic compartments of neurons from various mechanical, genetic and chemical insults. However, whether WldS can protect non-neuronal cells against toxic chemicals is largely unknown. Here we found that WldS significantly reduced the cytotoxicity of bipyridylium herbicides paraquat and diquat in mouse embryonic fibroblasts, but had no effect on the cytotoxicity induced by chromium (VI), hydrogen peroxide, etoposide, tunicamycin or brefeldin A. WldS also slowed down the death of mice induced by intraperitoneal injection of paraquat. Further studies demonstrated that WldS markedly attenuated mitochondrial injury including disruption of mitochondrial membrane potential, structural damage and decline of ATP induced by paraquat. Disruption of the NAD synthesis activity of WldS by an H112A or F116S point mutation resulted in loss of its protective function against paraquat-induced cell death. Furthermore, WldS delayed the decrease of intracellular NAD levels induced by paraquat. Similarly, treatment with NAD or its precursor nicotinamide mononucleotide attenuated paraquat-induced cytotoxicity and decline of ATP and NAD levels. In addition, we showed that SIRT1 was required for both exogenous NAD and WldS-mediated cellular protection against paraquat. These findings suggest that NAD and SIRT1 mediate the protective function of WldS against the cytotoxicity induced by paraquat, which provides new clues for the mechanisms underlying the protective function of WldS in both neuronal and non-neuronal cells, and implies that attenuation of NAD depletion may be effective to alleviate paraquat poisoning

Barriers to Pharmacy-Based Syringe Purchase Among Injection Drug Users in Tijuana, Mexico: A Mixed Methods Study

Injection drug users (IDUs) may be denied purchase of sterile syringes even where purchase without a prescription is legal. This study examined barriers to over-the-counter (OTC) syringe purchase among IDUs in Tijuana, Mexico. A quantitative survey and subsequent focus groups were used to quantify barriers to purchase, identify their correlates and provide in-depth exploration of syringe purchase experiences. Of 627 IDUs, 81% purchased a syringe in the past 6 months and 16% were refused or overcharged. Factors independently associated with refusal/overcharging were homelessness, receptive syringe sharing, >5 uses per syringe, and number of lifetime abscesses. Few pharmacies sold syringes to IDUs, who adapted by limiting purchase attempts to pharmacies known to sell syringes consistently. Failed purchases occurred when drug withdrawal required purchase at unusual times or locations, often following release from jail. IDUs reported syringe sharing, syringe reuse, and searching through unsecured medical waste for syringes in response to failed purchase attempts. Interventions to expand OTC syringe sales to IDUs, particularly near detention facilities, will facilitate safer injection practices

Polymorphisms of the XRCC1, XRCC3 and XPD genes and risk of colorectal adenoma and carcinoma, in a Norwegian cohort: a case control study

BACKGROUND: Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of developing cancer. For colorectal cancer the importance of mutations in mismatch repair genes has been extensively documented. Less is known about other DNA repair pathways in colorectal carcinogenesis. In this study we have focused on the XRCC1, XRCC3 and XPD genes, involved in base excision repair, homologous recombinational repair and nucleotide excision repair, respectively. METHODS: We used a case-control study design (157 carcinomas, 983 adenomas and 399 controls) to test the association between five polymorphisms in these DNA repair genes (XRCC1 Arg(194)Trp, Arg(280)His, Arg(399)Gln, XRCC3 Thr(241)Met and XPD Lys(751)Gln), and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression model adjusting for age, gender, cigarette smoking and alcohol consumption. RESULTS: The XRCC1 280His allele was associated with an increased risk of adenomas (OR 2.30, 95% CI 1.19–4.46). The XRCC1 399Gln allele was associated with a reduction of risk of high-risk adenomas (OR 0.62, 95% CI 0.41–0.96). Carriers of the variant XPD 751Gln allele had an increased risk of low-risk adenomas (OR 1.40, 95% CI 1.03–1.89), while no association was found with risk of carcinomas. CONCLUSION: Our results suggest an increased risk for advanced colorectal neoplasia in individuals with the XRCC1 Arg(280)His polymorphism and a reduced risk associated with the XRCC1 Arg(399)Gln polymorphism. Interestingly, individuals with the XPD Lys(751)Gln polymorphism had an increased risk of low-risk adenomas. This may suggest a role in regression of adenomas

Ecology and Transmission of Buruli Ulcer Disease: A Systematic Review

Buruli ulcer is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis. Cases have been reported from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific. Large lesions often result in scarring, contractual deformities, amputations, and disabilities, and in Africa, most cases of the disease occur in children between the ages of 4–15 years. This environmental mycobacterium, Mycobacterium ulcerans, is found in communities associated with rivers, swamps, wetlands, and human-linked changes in the aquatic environment, particularly those created as a result of environmental disturbance such as deforestation, dam construction, and agriculture. Buruli ulcer disease is often referred to as the “mysterious disease” because the mode of transmission remains unclear, although several hypotheses have been proposed. The above review reveals that various routes of transmission may occur, varying amongst epidemiological setting and geographic region, and that there may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods. We discuss traditional and non-traditional methods for indicting the roles of living agents as biologically significant reservoirs and/or vectors of pathogens, and suggest an intellectual framework for establishing criteria for transmission. The application of these criteria to the transmission of M. ulcerans presents a significant challenge

Why medical students choose psychiatry - a 20 country cross-sectional survey

BACKGROUND: Recruitment to psychiatry is insufficient to meet projected mental health service needs world-wide. We report on the career plans of final year medical students from 20 countries, investigating factors identified from the literature which influence psychiatric career choice. METHODS: Cross sectional electronic or paper survey. Subjects were final year medical students at 46 medical schools in participating countries. We assessed students' career intentions, motivations, medical school teaching and exposure to psychiatry. We assessed students' attitudes and personality factors. The main outcome measure was likelihood of specializing in psychiatry. Multilevel logistic regression was used to examine the joint effect of factors upon the main outcome. RESULTS: 2198 of 9135 (24%) of students responded (range 4 to 91%) across the countries. Internationally 4.5% of students definitely considered psychiatry as a career (range 1 to 12%). 19% of students (range 0 to 33%) were "quite likely", and 25% were "definitely not" considering psychiatry. Female gender, experience of mental/physical illness, media portrayal of doctors, and positive attitudes to psychiatry, but not personality factors, were associated with choosing psychiatry. Quality of psychiatric placement (correlation coefficient = 0.22, p < 0.001) and number of placements (correlation coefficient =0.21, p < 0.001) were associated with higher ATP scores. During medical school, experience of psychiatric enrichment activities (special studies modules and university psychiatry clubs), experience of acutely unwell patients and perceived clinical responsibility were all associated with choice of psychiatry.Multilevel logistic regression revealed six factors associated with students choosing psychiatry: importance of own vocation, odds ratio (OR) 3.01, 95% CI 1.61 to 5.91, p < 0.001); interest in psychiatry before medical school, OR 10.8 (5.38 to 21.8, p < 0.001); undertaking a psychiatry special study module, OR 1.45 (1.05 to 2.01, p = 0.03) or elective OR 4.28 (2.87- 6.38, p < 0.001); membership of a university psychiatry club, OR 3.25 (2.87 to 6.38, p < 0.001); and exposure to didactic teaching, OR 0.54 (0.40 to 0.72, p < 0.001). CONCLUSIONS: We report factors relevant to medical student selection and psychiatry teaching which affect career choice. Addressing these factors may improve recruitment to psychiatry internationally

A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.

NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld(S) prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld(S) protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies