A questionnaire for multinational case-control studies of environmental risk factors in multiple sclerosis (EnvIMS-Q).

OBJECTIVES: The increasing incidence of multiple sclerosis (MS) worldwide, especially in women, points to the crucial role of environmental and lifestyle risk factors in determining the disease occurrence. An international multicentre case-control study of Environmental Risk Factors In Multiple Sclerosis (EnvIMS) has been launched in Norway, Sweden, Italy, Serbia and Canada, aimed to examine MS environmental risk factors in a large study population and disclose reciprocal interactions. To ensure equivalent methodology in detecting age-related past exposures in individuals with and without MS across the study sites, a new questionnaire (EnvIMS-Q) is presented. MATERIALS AND METHODS: EnvIMS-Q builds on previously developed guidelines for epidemiological studies in MS and is a 6-page self-administered postal questionnaire. Participants are de-identified through the use of a numerical code. Its content is identical for cases and controls including 'core' and population-specific questions as proxies for vitamin D exposure (sun exposure, dietary habits and supplementation), childhood infections (including infectious mononucleosis) and cigarette smoking. Information on possible confounders or effect modifiers is also obtained. EnvIMS-Q was initially drafted in English and subsequently translated into Italian, Serbian, Norwegian, Swedish and French-Canadian. EnvIMS-Q has been tested for acceptability, feasibility and reliability. RESULTS AND CONCLUSIONS: EnvIMS-Q has shown cross-cultural feasibility, acceptability and reliability in both patients with MS and healthy subjects from all sites. EnvIMS-Q is an efficient tool to ensure proper assessment of age-specific exposure to environmental factors in large multinational population-based case-control studies of MS risk factors.

Month of birth as a risk factor for multiple sclerosis: an update.

BACKGROUND: Several studies have indicated month of birth as a risk factor for multiple sclerosis (MS) susceptibility and disease progression. METHODS: We performed a systematic search on PubMed and Medline up to May 2012 using the search string 'multiple sclerosis' and 'month of birth' or 'season of birth'. In addition, congress abstracts and the reference lists of the publications identified were examined for further citations of relevance. RESULTS: A total of fifteen published studies and two congress abstracts were found on the effect of month or season of birth on MS risk (sixteen in the northern and one in the southern hemisphere). Most studies in the northern hemisphere detected an excess of MS births in spring and a decrease in autumn. In the southern hemisphere, a reverse pattern was detected, with an excess in November and a decrease in April. Only three studies did not report any month of birth effect, all in low-risk areas for MS. Five studies have analysed a possible effect on disease course by month of birth. Of these, two studies reported an association between month of birth and age at onset of relapsing-remitting MS, with a younger disease onset for those born in the winter months. No consistent findings have been detected on the association between month of birth and disease progression. DISCUSSION: The month of birth effect is consistently found to influence the risk of MS, and the effect seems to be most prominent in high-risk areas of the disease, especially in areas with low sunlight exposure. There seems to be little or no month of birth effects in areas with high sunlight exposure. These findings indicate a possible role for vitamin D concentrations during pregnancy or early life of the newborn. A possible effect of vitamin D supplementation needs to be further investigated.

Multiple sclerosis, a cause of secondary osteoporosis? What is the evidence and what are the clinical implications?

BACKGROUND: Both women and men with multiple sclerosis (MS) are at increased risk of developing osteoporosis. METHODS: A non-systematic review of the prevalence,pathogenesis and treatment of osteoporosis in patients with multiple sclerosis. RESULTS: MS and osteoporosis share aetiological risk factors such as smoking and hypovitaminosis D, as well as pathogenetic players such as osteopontin and osteoprotegerin. Recently, low bone mineral density (BMD) values have been measured shortly after diagnosis of clinically isolated syndrome and MS and in fully ambulatory persons with MS below 50 years of age. Studies consistently show that BMD at the femoral neck decreases with increasing MS-related disability. Osteoporosis-related fractures cause increased morbidity and mortality and add to the burden of having MS. CONCLUSION: We argue that MS, like a number of other chronic diseases, is a cause of secondary osteoporosis. Therefore, bone health assessment should be a part of the integral management of persons with MS. We suggest that BMD be measured shortly after diagnosis, that BMD measurements be repeated depending on BMD values and individual osteoporosis risk profile, and that serum 25-hydroxyvitamin D be monitored. All persons with MS should receive bone health advice.

Environmental risk factors in multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) likely results from an interaction between genetic and exogenous factors. While genetics shapes the overall population MS susceptibility, observed epidemiological patterns strongly suggest a role for the environment in disease initiation and modulation. RESULTS: Findings from studies on seasonality in MS patients' birth, disease onset and exacerbations, as well as apparent temporal trends in incidence and gender ratio support an influential effect of viruses, metabolic and lifestyle factors on MS risk. Epstein-Barr virus, vitamin D status, and smoking are factors that may explain such epidemiological patterns. CONCLUSIONS: Further epidemiological investigations are encouraged and opportunities to use data from existing cohort studies as well as the design of new studies should be pursued. In particular, the development of new large multicentre population-based case-control studies which incorporate the study of the role of environment and genetics, including epigenetic mechanisms, in determining MS risk is proposed.

Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle.

BACKGROUND: A relationship between the latitude related distribution of multiple sclerosis (MS) and exposure to sunlight has long been considered. Higher sun exposure during early life has been associated with decreased risk of MS. OBJECTIVE: Since Norway is an exception to the latitude gradient of MS prevalence, we tested here whether sunlight exposure or vitamin D-related dietary factors in childhood and adolescence are associated with the risk of MS. METHODS: Retrospective recall questionnaire data from 152 MS patients and 402 population controls born at and living at latitudes 66-71 degrees N were analysed by means of conditional logistic regression analysis accounting for the matching variables age, sex, and place of birth. RESULTS: Increased outdoor activities during summer in early life were associated with a decreased risk of MS, most pronounced at ages 16-20 years (odds ratio (OR) 0.55, 95% CI 0.39-0.78, p = 0.001, adjusted for intake of fish and cod-liver oil). A protective effect of supplementation with cod-liver oil was suggested in the subgroup that reported low summer outdoor activities (OR 0.57, 95% CI 0.31-1.05, p = 0.072). Consumption of fish three or more times a week was also associated with reduced risk of MS (OR 0.55, 95% CI 0.33-0.93, p = 0.024). CONCLUSION: Summer outdoor activities in childhood and adolescence are associated with a reduced risk of MS even north of the Arctic Circle. Supplemental cod-liver oil may be protective when sun exposure is less, suggesting that both climate and diet may interact to influence MS risk at a population level.

Low frequency of the disease-associated DRB1*15-DQB1*06 haplotype may contribute to the low prevalence of multiple sclerosis in Sami.

This study confirms a low frequency of multiple sclerosis (MS) among Sami. Only 12 Sami with a diagnosis of MS were identified in the Norwegian Sami population, which represents a significantly lower prevalence of MS in Sami (30/10(5)) compared with other Norwegians (73-164/10(5)). The clinical characteristics as well as the results of human leukocyte antigen (HLA)-DRB1 and -DQB1 typing of the Sami MS patients are reported, showing that three (27%) of the Sami MS patients carried the MS-associated HLA-DRB1*15-DQB1*06 haplotype. Interestingly, the DRB1*15-DQB1*06 haplotype had a significantly reduced frequency among Sami controls (0.086) compared with non-Sami Norwegian controls (0.163) (P(corrected) = 0.015). The low frequency of the disease-associated DRB1*15-DQB1*06 haplotype in the Sami population may contribute to the low prevalence of MS in Sami, in addition to other yet unidentified genetic and environmental factors.

Denervation enhances spontaneous inflammatory myopathy in SJL mice.

We studied the effect of denervation on the spontaneous inflammatory myopathy that occurs in SJL mice. Cryosections from innervated and denervated calf muscles were assessed for severity of inflammation, relative proportions of mononuclear cell subsets, and major histocompatibility complex (MHC) class I expression. A significant increase in mononuclear cell infiltrates occurred in the denervated muscle. Denervation also changed the composition of mononuclear cell infiltrates towards a higher percentage of CD8(+) T cells (19% versus 11%). MHC class I expression was enhanced in denervated muscle compared with innervated muscle. Our findings indicate that inflammation in muscle may be enhanced by denervation.

Human leukocyte antigen class I in polymyositis: leukocyte infiltrates, regeneration, and impulse block.

In polymyositis (PM), T-cell mediated myocytotoxicity is directed against strongly human leukocyte antigen class I positive (HLA-I+) muscle fibers. Fiber regeneration probably is partly responsible for this HLA-I up-regulation. We have evaluated regeneration, denervation/impulse blockade, and focal leukocyte infiltrates as possible HLA-I inducing factors in PM. Distinctive patterns of HLA-I, nerve cell adhesion molecule (NCAM), and vimentin expression accompany denervation and regeneration. Regenerating fibers also have centralized nuclei. Using semiquantitative methods, we examined strongly HLA-I+ fibers in PM muscle biopsies for these markers. Sarcoplasmic HLA-I levels were related to the presence of leukocyte infiltrates and invasion of fibers. Strongly HLA-I+ fibers were frequently invaded, and regeneration-associated changes were usually observed at sites of fiber damage. Sarcoplasmic HLA-I levels were stable along intact fibers, also adjacent to leukocyte infiltrates. A majority of the strongly HLA-I+ fibers were nonregenerating (NCAM+ only). Though other mechanisms cannot be excluded, this suggests that impulse blockade or denervation may contribute to extra HLA-I up-regulation in these fibers.

Cerebral cortex ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.

Hyperammonemia has been suggested to induce enhanced cerebral cortex ammonia uptake, subsequent glutamine synthesis and accumulation, and finally net glutamine release into the blood stream, but this has never been confirmed in liver insufficiency models. Therefore, cerebral cortex ammonia- and glutamine-related metabolism was studied during liver insufficiency-induced hyperammonemia by measuring plasma flow and venous-arterial concentration differences of ammonia and amino acids across the cerebral cortex (enabling estimation of net metabolite exchange), 1 day after portacaval shunting and 2, 4, and 6 h after hepatic artery ligation (or in controls). The intra-organ effects were investigated by measuring cerebral cortex tissue ammonia and amino acids 6 h after liver ischemia induction or in controls. Arterial ammonia and glutamine increased in portacaval-shunted rats versus controls, and further increased during liver ischemia. Cerebral cortex net ammonia uptake, observed in portacaval-shunted rats, increased progressively during liver ischemia, but net glutamine release was only observed after 6 h of liver ischemia. Cerebral cortex tissue glutamine, gamma-aminobutyric acid, most other amino acids, and ammonia levels were increased during liver ischemia. Glutamate was equally decreased in portacaval-shunted and liver-ischemia rats. The observed net cerebral cortex ammonia uptake, cerebral cortex tissue ammonia and glutamine accumulation, and finally glutamine release into the blood suggest that the rat cerebral cortex initially contributes to net ammonia removal from the blood during liver insufficiency-induced hyperammonemia by augmenting tissue glutamine and ammonia pools, and later by net glutamine release into the blood. The changes in cerebral cortex glutamate and gamma-aminobutyric acid could be related to altered ammonia metabolism.

Altered glutamine metabolism in rat portal drained viscera and hindquarter during hyperammonemia.

In normal rats, muscle is the major glutamine releasing organ and gut is the major glutamine consuming organ. It has been suggested that enhanced muscle ammonia detoxification and gut ammonia production occurs during liver insufficiency-induced hyperammonemia. Therefore, ammonia and amino acid fluxes across portal-drained viscera and hindquarter, and muscle concentrations were measured in portacaval shunted and acute liver ischemia rats. Arterial ammonia and most amino acids were increased after portacaval shunting and increased progressively during liver ischemia, but net hindquarter ammonia uptake was not observed. Net hindquarter glutamine efflux was increased during portacaval shunting, but it decreased during liver ischemia, while muscle glutamine concentrations increased. The comparable net portal drained viscera glutamine uptake in normal and portacaval shunted rats changed during liver ischemia from net uptake to release, coinciding with release of most other amino acids. These results cast doubt on the ammonia detoxifying role of muscle during acute liver ischemia-induced hyperammonemia in the rat. The portal drained viscera glutamine release during severe hyperammonemia could be due to intestinal damage.

No acute effect of cigarette smoking on bleeding time of habitual smokers.

To study the influence of cigarette smoking on blood platelet function, bleeding time was measured in two groups of 14 habitual smokers before and after a 20-minute period during which the subjects either smoked two cigarettes (experimental group) or rested (control group). The second bleeding time appeared to be slightly shortened upon cigarette-smoking (-0.1 min) and was found to be prolonged in the control group (+0.4 min). These changes did not differ significantly from each other (P = 0.38). Consequently, bleeding time of habitual smokers is not affected by smoking two cigarettes.