The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP.

The spinocerebellar ataxias (SCAs) are a class of incurable diseases characterized by degeneration of the cerebellum that results in movement disorder. Recently, a new heritable form of SCA, spinocerebellar ataxia type 48 (SCA48), was attributed to dominant mutations in STIP1 homology and U box-containing 1 (STUB1); however, little is known about how these mutations cause SCA48. STUB1 encodes for the protein C terminus of Hsc70 interacting protein (CHIP), an E3 ubiquitin ligase. CHIP is known to regulate proteostasis by recruiting chaperones via a N-terminal tetratricopeptide repeat domain and recruiting E2 ubiquitin-conjugating enzymes via a C-terminal U-box domain. These interactions allow CHIP to mediate the ubiquitination of chaperone-bound, misfolded proteins to promote their degradation via the proteasome. Here we have identified a novel, de novo mutation in STUB1 in a patient with SCA48 encoding for an A52G point mutation in the tetratricopeptide repeat domain of CHIP. Utilizing an array of biophysical, biochemical, and cellular assays, we demonstrate that the CHIPA52G point mutant retains E3-ligase activity but has decreased affinity for chaperones. We further show that this mutant decreases cellular fitness in response to certain cellular stressors and induces neurodegeneration in a transgenic Caenorhabditis elegans model of SCA48. Together, our data identify the A52G mutant as a cause of SCA48 and provide molecular insight into how mutations in STUB1 cause SCA48.

The hefty fetal phenotype hypothesis revisited: high birth weight, type 2 diabetes and gestational diabetes in a Saskatchewan cohort of First Nations and non-First Nations women.

Although low birth weight (LBW) increases the risk for type 2 diabetes (T2DM), the relationship between high birth weight (HBW) and T2DM is less definitive and largely confined to North American Indigenous populations. We re-examined the relationship between LBW (4000 g) and both T2DM and gestational diabetes (GDM) among First Nations and non-First Nations women in Saskatchewan. We analyzed new data for female subjects from a 2001 case-control study that led to our hefty fetal phenotype hypothesis. Using survival analysis techniques and a validated algorithm for identifying diabetes in health care administrative data, we followed a 1950-1984 birth cohort of 2003 women until March 31, 2013. Cox regression analysis determined the time to occurrence of first episode of GDM and diagnosis of T2DM by birth weight and ethnicity. First Nations women with HBW demonstrated a greater risk for developing both T2DM [hazard ratios (HR) 1.568; 95% confidence interval (CI) 1.188, 2.069] and GDM (HR 1.468; 95% CI 1.016, 2.121) than those with normal birth weight (NBW). Non-First Nations women with LBW had a greater risk of developing GDM than those with NBW (HR 1.585; 95% CI 1.001, 2.512). HBW is a risk factor for GDM and T2DM among First Nations women. This is likely due to exposure of these women to their own mothers' diabetic pregnancies or gestational impaired glucose tolerance. This inter-generational amplification of T2DM risk mediated through prenatal exposures appears to play a substantial role in the epidemic of T2DM among First Nations peoples.

Indoor mold levels and current asthma among school-aged children in Saskatchewan, Canada.

Current knowledge regarding the association between indoor mold exposures and asthma is still limited. The objective of this case-control study was to investigate the relationship between objectively measured indoor mold levels and current asthma among school-aged children. Parents completed a questionnaire survey of health history and home environmental conditions. Asthma cases had a history of doctor-diagnosed asthma or current wheeze without a cold in the past 12 months. Controls were age- and sex-matched to cases. Vacuumed dust samples were collected from the child's indoor play area and mattress. Samples were assessed for mold levels and quantified in colony-forming units (CFU). Sensitization to mold allergens was also determined by skin testing. Being a case was associated with family history of asthma, pet ownership, and mold allergy. Mold levels (CFU/m2 ) in the dust samples of children's mattress and play area floors were moderately correlated (r = 0.56; P < 0.05). High mold levels (≥30 000 CFU/m2 ) in dust samples from play [adjusted odds ratio (aOR) = 2.6; 95% CI: 1.03-6.43] and mattress (aOR) = 3.0; 95% CI: 1.11-8.00) areas were significantly associated with current asthma. In this study high levels of mold are a risk factor for asthma in children.

Agreement between questionnaire report of allergy-related outcomes in school-age children and objective measures of atopy: the Saskatchewan rural health study.

BACKGROUND AND OBJECTIVES: In population-based studies, questionnaires remain the most efficient tool to assess the presence of allergy and atopic conditions, but the quality of the information obtained needs to be validated. We sought to evaluate the agreement and predictive values of a questionnaire to assess atopy in rural children, an understudied population with regard to atopy and allergic disease. METHODS: A total of 480 schoolchildren (grades 1-8) from rural Saskatchewan completed a questionnaire report of allergy and atopic outcomes and participated in skin prick testing (SPT). SPT for 6 common allergens (local grasses, wheat dust, cat dander, house dust mite mixed, Alternaria, and Cladosporium) was completed. Subjects with at least one positive SPT (≥ 3 mm) compared to the negative control were considered to be atopic. We considered per cent concordance, Kappa, sensitivity, specificity, and the positive predictive value and negative predictive value (NPV, PPV) of reported allergies or allergic conditions in comparison with SPT as the gold standard. RESULTS: We found that 25.0% of children reported a history of any allergy and 19.4% were atopic based on SPT. The agreement between questionnaire report of allergic triggers and atopy measured by SPT was high (83.0-89.5%). The agreement between atopy and report of allergic conditions ranged from 67.1% to 79.6%. Individual allergic conditions demonstrated high specificity but low sensitivity. The questionnaire report of any allergy had a low PPV in detecting atopy (47.3%) and high NPV (86.3%). The PPV of reported allergic conditions was low (24.8-43.9%), but the NPV was again high (82.0-82.9%). CONCLUSIONS: We found that the standardized questionnaire report of allergy and atopic conditions was shown not to efficiently and reliably predict atopy. However, given the good specificity and the NPV, the questionnaire may be an efficient tool for epidemiological studies that involve the differential inclusion of subjects without atopy.

Prevalence and determinants of atopy and allergic diseases among school-age children in rural Saskatchewan, Canada.

BACKGROUND: There have been few investigations of farming-related activities or specific characteristics resulting in the associations between those exposures and atopic disease. OBJECTIVE: To study the associations between farm-associated exposures and atopic diseases. METHODS: As part of a longitudinal study of lung health in rural residents, a cross-sectional baseline study was conducted in rural Saskatchewan, Canada. This included an initial survey phase followed by a clinical testing phase. A subsample of 584 children (grades 1-8) completed skin prick testing to assess atopic status. Atopy was defined as a positive reaction to any of 6 allergens (local grasses, wheat dust, cat dander, house dust mite, Alternaria species, or Cladosporium species) of at least 3 mm compared with the negative control. RESULTS: Of those who completed clinical testing, the prevalence of atopy was 19.4%, that of hay fever was 8.8%, and that of eczema was 27.4%. Based on skin prick testing, sensitization was highest for cat dander (8.6%) followed by local grasses (8.2%) and house dust mite (5.1%). After adjustment for potential confounders, home location (farm vs non-farm) was not associated with atopic status. However, livestock farming was protective against atopy (adjusted odds ratio 0.38, 95% confidence interval 0.17-0.88). In contrast, current residence on a farm was associated with an increase in the likelihood of hay fever in these children (adjusted odds ratio 3.68, 95% confidence interval 1.29-10.45). Also, regular farming activities in the past year were associated with an increased risk of hay fever. CONCLUSION: In children, livestock exposure has a protective effect on skin prick test positivity, whereas farm living and activities increase the risk of hay fever.

Longitudinal trends in mental health among ethnic groups in Canada.

INTRODUCTION: Immigration continues to transform the ethnic composition of the Canadian population. We investigated whether longitudinal trends in mental distress vary between seven cultural and ethnic groups and whether mental distress within the same ethnic group varies by demographic (immigrant status, sex, age, marital status, place and length of residence), socio-economic (education, income), social support and lifestyle factors. METHOD: The study population consisted of 14 713 respondents 15 years and older from the first six cycles of the National Population Health Survey (NPHS); 20% reported themselves to be immigrant at Cycle 1, in 1994/1995. The logistic regression model was fitted by modifying a multivariate quasi-likelihood approach, and robust variance estimates were obtained by using balanced repeated replication techniques. RESULTS: Based on the multivariable model and self-reported data, we observed that female respondents were more likely to report moderate/high mental distress than male respondents; younger respondents more than older respondents; single respondents more than those in a relationship; urban-dwellers more than rural-dwellers; less educated respondents more than more educated respondents; current and former smokers more than non-smokers; and those living in a smoking household more than those living in non-smoking households. The relationship between ethnicity and mental distress was modified by immigrant status, sex, social involvement score and education. Confirming other research, we found an inverted U-shaped relationship between length of stay and mental distress: those who had lived in Canada for less than 2 years were less likely to report moderate/high mental distress, while those who had lived in Canada for 2 to 20 years were significantly more likely to report moderate/high mental distress than those who had lived in Canada for more than 20 years. CONCLUSION: There is a need to develop ethnicity-specific mental health programs targeting those with low education attainment and low social involvement. Policies and programs should also target women, the younger age group (15-24 years) and low-income adequacy groups.

Prevalence of High Epworth Sleepiness Scale scores in a rural population.

BACKGROUND: Increased daytime sleepiness is an important symptom of obstructive sleep apnea (OSA). OSA is frequently underdiagnosed, and the Epworth Sleepiness Scale (ESS) can be a useful tool in alerting physicians to a potential problem involving OSA. OBJECTIVE: To measure the prevalence and determinants of daytime sleepiness measured using the ESS in a rural community population. METHODS: A community survey was conducted to examine the risk factors associated with ESS in a rural population in 154 households comprising 283 adults. Questionnaire information was obtained regarding physical factors, social factors, general medical history, family medical history, ESS score, and self-reported height and weight. Multivariable binary logistic regression analysis based on the generalized estimating equations approach to account for clustering within households was used to predict the relationship between a binary ESS score outcome (normal or abnormal) and a set of explanatory variables. RESULTS: The population included 140 men (49.5%) and 143 women (50.5%) with an age range of 18 to 97 years (mean [± SD] 52.0±14.9 years). The data showed that 79.2% of the study participants had an ESS score in the normal range (0 to 10) and 20.8% had an ESS score >10, which is considered to be abnormal or high sleepiness. Multivariable regression analysis revealed that obesity was significantly associated with an abnormal or high sleepiness score on the ESS (OR 3.40 [95% CI 1.31 to 8.80). CONCLUSION: High levels of sleepiness in this population were common. Obesity was an important risk factor for high ESS score.

Statistical modelling of mental distress among rural and urban seniors.

The senior population is growing rapidly in Canada. Consequently, there will be an increased demand for health care services for seniors who have mental illness. Seniors are more likely to live in rural areas than younger people; therefore, it is important to identify the differences between rural and urban seniors in order to design and deliver mental health services. The main objective of this paper was to use the National Population Health Survey (NPHS) to examine the differences with regard to mental distress between rural and urban seniors (i.e. 55 years and older). The other objectives were to investigate the long-term association between smoking and mental health and the long-term association between unmet health care needs and the mental health of seniors in rural and urban areas. The mental distress measure was examined as a binary outcome. The analysis was conducted using a generalized estimating equation approach that accounted for the complexity of a multi-stage survey design. Rural seniors reported a higher proportion of mental distress [OR=1.16; 95% CI: 0.98, 1.37] with a borderline statistical significance than urban seniors. This finding was based on a final multivariate model to study the relationship between mental distress and location of residence(i.e. rural or urban) as well as between smoking and self-perceived unmet health care needs, adjusting for other important covariates and missing outcome values. A significant correlation was noted between smoking and mental health problems among seniors after adjusting for other covariates [OR = 1.26; 95% CI: 1.00, 1.60]. Participants who reported self-perceived unmet health care needs reported a higher proportion of mental distress [OR = 1.72; 95% CI: 1.38, 2.13] compared to those who were satisfied with their health care.