Accessing human selenoproteins through chemical protein synthesis.

The human body contains 25 selenoproteins, which contain in their sequence the twenty-first encoded amino acid, selenocysteine. About a dozen of these proteins remain functionally uncharacterized or poorly studied. Challenges in accessing these selenoproteins using traditional recombinant expressions have prevented biological characterization thus far. Chemical protein synthesis has the potential to overcome these hurdles. Here we report the first total chemical syntheses of two human selenoproteins, selenoprotein M (SELM) and selenoprotein W (SELW). The synthesis of the more challenging protein SELM was enabled using recent advances in the field of selenocysteine chemistry. This approach allows the preparation of selenoproteins in milligram quantities and in homogenous form, which should open new horizons for future studies to pursue a fuller biological understanding of their role in health and disease.

Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial.

We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL(S447X) gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPL(S447X) gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a ≥40% reduction in fasting median plasma triglyceride (TG) at 3-12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 10(11) gc kg(-1), and cohort 3 (n=8) received 1 × 10(12) gc kg(-1). Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a ≥40% reduction in fasting TG between 3 and 12 weeks. TG subsequently returned to baseline, although sustained LPL(S447X) expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG.

Dietary sodium intake deleteriously affects blood pressure in a normotensive population.

Western dietary pattern, and particularly high dietary sodium intake (DSI), is recognized for its detrimental impact on blood pressure (BP). This paper examined the association of DSI with BP in Nunavik Inuit (Québec), a population known to have an optimal BP on average. In a population-based study, we recruited 421 normotensive participants aged 18-74 years from 14 coastal villages, situated north of the 55th parallel. BP, biochemistry and anthropometry were obtained. DSI was assessed by a 24-h dietary recall. Mean (s.e.) DSI was higher in men than in women (2358 (101) vs. 1702 (100) mg/d, P<0.0001). Similar gender difference was found in systolic BP (118 (0.7) vs. 111 (0.6) mm Hg; P<0.0001). After adjustment for confounders, we found a positive association between BP and DSI (all P<0.05). In a normotensive population, BP shows a linear relationship with DSI. Our results emphasize the potent deleterious impact of DSI on BP.

Seroprevalence of seven zoonotic infections in Nunavik, Quebec (Canada).

In Nunavik, common practices and food habits such as consumption of raw meat and untreated water place the Inuit at risk for contracting zoonotic diseases. The aim of this study was to determine the seroprevalence of seven zoonotic infections among the permanent residents of Nunavik. The study was conducted in the fall 2004 as part of the Nunavik Health Survey. Blood samples from adults aged 18-74 years (n = 917) were collected and analysed for the presence of antibodies against Trichinella spp., Toxocara canis, Echinococcus granulosus, Brucella spp., Coxiella burnetii, Leptospira spp. and Francisella tularensis. Information on sociodemographic characteristics, traditional activities, drinking water supply and nutrition was gathered using english/inuktitut bilingual questionnaires. The chi-squared test was used to evaluate associations between seropositivity and other measured variables. Statistically significant variables were included in a multivariate logistic regression model to control for confounding factors. Estimated seroprevalences were 8.3% for E. granulosus, 3.9% for T. canis, 5.9% for Leptospira spp. and 18.9% for F. tularensis. Seroprevalence was ≤ 1% for Trichinella spiralis, Brucella spp. and C. burnetii. For most infections, seropositivity tended to increase with age. In multivariate analyses, seroprevalence was positively (i.e. directly) associated with age and residence in the Ungava coast area for F. tularensis; age and residence in the Hudson coast area for T. canis; female gender, lower level of schooling and frequent cleaning of water reservoirs for E. granulosus. No risk factor for Leptospira spp. infection was identified. No associations were detected with regards to food habits or environmental exposures. A small but significant portion of the Nunavik population has serologic evidence of exposure to at least one of the pathogenic microorganisms investigated. Further studies are needed to better understand the mechanisms for transmission of zoonotic infections and their potential reservoirs in Nunavik.

Is marine mammal fat or fish intake most strongly associated with omega-3 blood levels among the Nunavik Inuit?

Here we determined the relationship between red blood cell (RBC) omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFAs) and usual dietary marine food product intake among 630 Nunavik Inuit adults. Marine food product intake was determined by a food frequency questionnaire (FFQ) and fatty acids were quantified in RBC membranes. Multiple linear regression was undertaken to determine the relationship between marine food product intake and RBC n-3 LC-PUFAs (dependent variable). Mean RBC n-3 LC-PUFA level was 9.16 ± 0.11% [SEM]. The highest correlations noted with RBC n-3 LC-PUFAs were for marine mammal fat (r(s)=0.41, P<0.0001) and fish (r(s)=0.35, P<0.0001). Age, total marine mammal fat and fish intakes were the variables that contributed the most to predicted RBC n-3 LC-PUFAs and explained 34%, 15% and 5%, respectively, of its variances. Our study indicates that marine mammal fat intake is more important than fish in accounting for RBC n-3 LC-PUFA levels among the Nunavik Inuit.

Cardiovascular burden and related risk factors among Nunavik (Quebec) Inuit: insights from baseline findings in the circumpolar Inuit health in transition cohort study.

BACKGROUND: The Inuit are commonly portrayed to be somehow protected from cardiovascular diseases (CVDs) through their traditional lifestyle and diet. However, actual sociocultural transition and related major, modifiable risk factors have scarcely been quantified in the Inuit population. Such knowledge is extremely valuable in terms of public health intervention. METHODS: A total of 887 Inuit residents from Nunavik, Quebec, participated in a cohort study. The estimates presented were derived from anthropometric and biological measurements gathered at the time of recruitment and enhanced by information collected in the medical file of each participant. All estimates were corrected for a complex sampling strategy and bootstrapped to ensure the representativeness of the general Nunavik population. RESULTS: Overall, 19% of Inuit had a disease of the circulatory system according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision. Among all disorders, peripheral circulatory system disease was the most prevalent (9%). Prevalences of ischemic heart disease and cerebrovascular disease were of similar magnitude (2.5%). No significant difference in disease prevalence was noted between sexes. The major modifiable CVD risk factors were smoking (84%), obesity (49%) [corrected] (body mass index of greater than 30 kgm2) and elevated blood pressure (13085 mmHg or greater) (18%). Prevalences were globally higher among women. CONCLUSION: The current belief that the Inuit are protected from CVD is seriously questioned by the results of the present study. Considering the extremely high prevalence of CVD risk factors, a population-based intervention reinforced for women is urgently needed to reduce their risk.

Seroprevalence of Toxoplasma gondii among Nunavik Inuit (Canada).

As a result of their intimate contact with the land and their nutritional habits, the Inuit of Nunavik are considered to be at risk from zoonotic infections. To better understand the risk factors for Toxoplasma gondii infection, a serosurvey was conducted in Nunavik, Québec, in September 2004. A representative sample of the Inuit adult population of Nunavik participated in this cross-sectional study (n = 917). Antibodies (IgG) against T. gondii were detected by immunoassay. Information on sociodemographic characteristics, traditional activities, domestic environment and nutrition was gathered by questionnaire and explored as variables explanatory of seropositive results. Associations found to be statistically significant in univariate analyses were assessed by multivariable logistic regression to control for confounding factors. Almost two thirds (59.8%) of the Inuit of Nunavik were found to be seropositive for T. gondii. In multivariate analyses, risk factors for seropositivity were: increasing age, gender (women > men), lower level of education, consumption of potentially contaminated water (determined by an index of risk from waterborne infections), frequent cleaning of water reservoirs, and consumption of seal meat and feathered game. There was some variation in seroprevalence between the Ungava Bay coast (52.3%) and the Hudson Bay coast (65.6%), the two main regions of Nunavik, but this variation was not significant in the multivariable logistic regression model. This cross-sectional study demonstrated high T. gondii seroprevalence in the Inuit population and revealed that age, gender, schooling and community of residence all influence serostatus in this population. Variables related to drinking water and food choices may also influence the risk of infection. These results raise important questions about T. gondii transmission in Nunavik including possible links between terrestrial and marine cycles.

Monitoring of umbilical cord blood lead levels and sources assessment among the Inuit.

Analyses completed on samples collected between 1993 and 1996 showed that about 7% of 475 Inuit newborns from northern Quebec (Canada) had a cord blood lead concentration equal to or greater than 0.48 micromol/l, an intervention level adopted by many governmental agencies. A comparison between the cord blood lead isotope ratios of Inuit and southern Quebec newborns showed that lead sources for these populations were different. Our investigation suggests that lead shots used for game hunting were an important source of lead exposure in the Inuit population. A cohort study conducted in three Inuit communities shows a significant decrease of cord blood lead concentrations after a public health intervention to reduce the use of lead shot. Lead shot ammunition can be a major and preventable source of human exposure to lead.

The value of mass screening for chlamydia control in high prevalence communities.

The social context and epidemiology of STIs in remote communities in Northern Canada was examined. These communities have a persistently high reported incidence of gonorrhoea and chlamydial infection. They remain in the hyperendemic phase of the N. gonorrhoeae and C. trachomatis epidemics. They are ethnically and culturally homogeneous and contain no readily identifiable core groups, making it impossible to distinguish between spread and maintenance networks. Mass screening of the adult population can reduce the reservoir of C. trachomatis infection under these circumstances. It is particularly important to target men in settings such as this where women are routinely screened in antenatal and family planning clinics.

[Epidemiological study of a tuberculosis case in a large manufacturing enterprise in Quebec]. / Enquête épidémiologique sur un cas de tuberculose dans une grande entreprise manufacturière québécoise.

OBJECTIVES: To determine the prevalence of tuberculosis infection related to a case of pulmonary and laryngeal tuberculosis in a workplace and to study PPD predictors. METHODS: The Mantoux skin test (PPD) was offered to all potentially infected contacts. Participants were asked to answer a questionnaire. RESULTS: Among 112 exposed employees, 92 (82.1%) were tested. At the 5 mm level, 65.2% of employees had positive tuberculin skin test (PPD). By controlling prior BCG and the degree of exposure, it showed a positive association between age and PPD (RC: 3.5; 95% CI: 1.25-10.03). When age and BCG were controlled, high exposure was statistically associated with PPD results (RC: 5.6; 95% CI: 1.25-24.68). CONCLUSION: The observed prevalence rate is probably related to the fact that the index case was very infectious and had contact in an enclosed area over a long period of time before withdrawal from work.