What is the comparative health status and associated risk factors for the Métis? A population-based study in Manitoba, Canada

<p>Abstract</p> <p>Background</p> <p>Métis are descendants of early 17^thcentury relationships between North American Indians and Europeans. This study's objectives were: (1) to compare the health status of the Métis people to all other residents of Manitoba, Canada; and (2) to analyze factors in predicting the likelihood of diabetes and related lower limb amputation.</p> <p>Methods</p> <p>Using de-identified administrative databases plus the Métis Population Database housed at the Manitoba Centre for Health Policy, age/sex-adjusted rates of mortality and disease were calculated for Métis (n = 73,016) and all other Manitobans (n = 1,104,672). Diseases included: hypertension, arthritis, diabetes, ischemic heart disease (age 19+); osteoporosis (age 50+); acute myocardial infarction (AMI) and stroke (age 40+); total respiratory morbidity (TRM, all ages). Using logistic regression, predictors of diabetes (2004/05-2006/07) and diabetes-related lower-limb amputations (2002/03-2006/07) were analyzed.</p> <p>Results</p> <p>Disease rates were higher for Métis compared to all others: premature mortality before age 75 (4.0 vs. 3.3 per 1000, p < .001); total mortality (9.7 vs. 8.4 per 1000, p < .001); injury mortality (0.58 vs. 0.51 per 1000, p < .03); Potential Years of Life Lost (64.6 vs. 54.6 per 1000, p < .001); all-cause 5-year mortality for people with diabetes (20.8% vs. 18.6%, p < .02); hypertension (27.9% vs. 24.8%, p < .001); arthritis (24.2% vs. 19.9%, p < .001), TRM (13.6% vs. 10.6%, p < .001); diabetes (11.8% vs. 8.8%, p < .001); diabetes-related lower limb amputation (24.1 vs. 16.2 per 1000, p < .001); ischemic heart disease (12.2% vs. 8.7%, p < .001); osteoporosis (12.2% vs. 12.3%, NS), dialysis initiation (0.46% vs. 0.34%, p < .001); AMI (5.4 vs. 4.3 per 1000, p < .001); stroke (3.6 vs. 2.9 per 1000, p < .001). Controlling for geography, age, sex, income, continuity of care and comorbidities, Métis were more likely to have diabetes (aOR = 1.29, 95% CI 1.25-1.34), but not diabetes-related lower limb amputation (aOR = 1.13, 95% CI 0.90-1.40, NS). Continuity of care was associated with decreased risk of amputation both provincially (aOR = 0.71, 95% CI 0.62-0.81) and for Métis alone (aOR = 0.62, 95% CI 0.40-0.96).</p> <p>Conclusion</p> <p>Despite universal healthcare, Métis' illness and mortality rates are mostly higher. Although elevated diabetes risk persists for the Métis even after adjusting for sociodemographic, healthcare and comorbidity variables, the risk of amputation for Métis appears more related to healthcare access rather than ethnicity.</p

Resolving the contributions of the membrane-bound and periplasmic nitrate reductase systems to nitric oxide and nitrous oxide production in Salmonella enterica serovar Typhimurium

The production of cytotoxic nitric oxide (NO) and conversion into the neuropharmacological agent and potent greenhouse gas nitrous oxide (N2O) is linked with anoxic nitrate catabolism by Salmonella enterica serovar Typhimurium. Salmonella can synthesize two types of nitrate reductase: a membrane-bound form (Nar) and a periplasmic form (Nap). Nitrate catabolism was studied under nitrate-rich and nitrate-limited conditions in chemostat cultures following transition from oxic to anoxic conditions. Intracellular NO production was reported qualitatively by assessing transcription of the NO-regulated genes encoding flavohaemoglobin (Hmp), flavorubredoxin (NorV) and hybrid cluster protein (Hcp). A more quantitative analysis of the extent of NO formation was gained by measuring production of N2O, the end-product of anoxic NO-detoxification. Under nitrate-rich conditions, the nar, nap, hmp, norV and hcp genes were all induced following transition from the oxic to anoxic state, and 20% of nitrate consumed in steady-state was released as N2O when nitrite had accumulated to millimolar levels. The kinetics of nitrate consumption, nitrite accumulation and N2O production were similar to those of wild-type in nitrate-sufficient cultures of a nap mutant. In contrast, in a narG mutant, the steady-state rate of N2O production was ~30-fold lower than that of the wild-type. Under nitrate-limited conditions, nap, but not nar, was up-regulated following transition from oxic to anoxic metabolism and very little N2O production was observed. Thus a combination of nitrate-sufficiency, nitrite accumulation and an active Nar-type nitrate reductase leads to NO and thence N2O production, and this can account for up to 20% of the nitrate catabolized

Heritable breast cancer in twins

Known major mutations such as BRCA1/2 and TP53 only cause a small proportion of heritable breast cancers. Co-dominant genes of lower penetrance that regulate hormones have been thought responsible for most others. Incident breast cancer cases in the identical (monozygotic) twins of representative cases reflect the entire range of pertinent alleles, whether acting singly or in combination. Having reported the rate in twins and other relatives of cases to be high and nearly constant over age, we now examine the descriptive and histological characteristics of the concordant and discordant breast cancers occurring in 2310 affected pairs of monozygotic and fraternal (dizygotic) twins in relation to conventional expectations and hypotheses. Like other first-degree relatives, dizygotic co-twins of breast cancer cases are at higher than usual risk (standardised incidence ratio (SIR)=1.7, CI=1.1–2.6), but the additional cases among monozygotic co-twins of cases are much more numerous, both before and after menopause (SIR=4.4, CI=3.6–5.6), than the 100% genetic identity would predict. Monozygotic co-twin diagnoses following early proband cancers also occur more rapidly than expected (within 5 years, SIR=20.0, CI=7.5–53.3). Cases in concordant pairs represent heritable disease and are significantly more likely to be oestrogen receptor-positive than those of comparable age from discordant pairs. The increase in risk to the monozygotic co-twins of cases cannot be attributed to the common environment, to factors that cumulate with age, or to any aggregate of single autosomal dominant mutations. The genotype more plausibly consists of multiple co-existing susceptibility alleles acting through heightened susceptibility to hormones and/or defective tumour suppression. The resultant class of disease accounts for a larger proportion of all breast cancers than previously thought, with a rather high overall penetrance. Some of the biological characteristics differ from those of breast cancer generally

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.Peer reviewe

Imaging Multidrug Resistance P-glycoprotein Transport Function Using MicroPET with Technetium-94m-Sestamibi

The best characterized mechanism of multidrug resistance (MDR) in cancer involves the MDR1 efflux transporter P-glycoprotein (Pgp). The positron-emitting radiotracer hexakis (2-methoxyisobutylisonitrile)- 94m Tc ( 94m Tc-MIBI) was synthesized and validated in cell transport studies as a substrate for MDR1 Pgp. In vivo small-scale PET imaging and biodistribution studies of mdr1a/1b (−/−) gene deleted and wild-type mice demonstrated the use of 94m Tc-MIBI to detect Pgp function. The reversal effect of a Pgp modulator was shown in tissue distribution studies of KB 3–1 (Pgp-) and KB 8–5 (Pgp+) tumor-bearing nude mice. The current 94m Tc-MIBI experiments parallel previous studies employing 99m Tc-MIBI, showing essentially identical performance of the two technetium radiotracers and providing biological validation of 94m Tc-MIBI for PET imaging of multidrug resistance

Rate of Total Hip Replacement after Legg Calve Perthes Disease in a Canadian Province

Legg Calve Perthes disease is a pediatric hip condition that leads to early hip degeneration. The efficacy of operative and nonoperative treatment is not well defined in the literature. Using the rate of total hip arthroplasty as a surrogate measure for symptomatic hip degeneration, the rate of total hip arthroplasty was compared in Legg Calve Perthes disease patients with and without previous surgical intervention in the province of Manitoba, Canada. A retrospective review was conducted using de-identified, individual-level administrative records of health services for the entire population of Manitoba. Codes for Legg Calve Perthes disease, femoral osteotomies, pelvic osteotomies, adductor tenotomies, and total hip arthroplasty were searched from 1984 to 2018. The rate of total hip arthroplasty in patients with Legg Calve Perthes disease was determined for two groups: (1) patients with earlier surgical intervention and (2) patients with no previous surgical intervention. Of the 202 patients included in the study, 180 had no prior surgery and 22 had prior surgery. The rate of total hip arthroplasty between the previous operative and nonoperative groups was found to be 32% and 40%, respectively (p = 0.458). There was no significant difference in rates of total hip arthroplasty in the operative and nonoperative groups. Further prospective studies are required to elucidate the differences in outcomes between operative and nonoperative treatment groups in patients with Legg Calve Perthes disease