Juvenile dermatomyositis (JDM) is a chronic inflammatory myopathy and vasculopathy driven by genetic and environmental influences. Here, we investigated the genetic underpinnings of an analogous, ...spontaneous disease of dogs also termed dermatomyositis (DMS). As in JDM, we observed a significant association with a haplotype of the major histocompatibility complex (MHC) (DLA-DRB1*002:01/-DQA1*009:01/-DQB1*001:01), particularly in homozygosity (P-val = 0.0001). However, the high incidence of the haplotype among healthy dogs indicated that additional genetic risk factors are likely involved in disease progression. We conducted genome-wide association studies in two modern breeds having common ancestry and detected strong associations with novel loci on canine chromosomes 10 (P-val = 2.3X10-12) and 31 (P-val = 3.95X10-8). Through whole genome resequencing, we identified primary candidate polymorphisms in conserved regions of PAN2 (encoding p.Arg492Cys) and MAP3K7CL (c.383_392ACTCCACAAA>GACT) on chromosomes 10 and 31, respectively. Analyses of these polymorphisms and the MHC haplotypes revealed that nine of 27 genotypic combinations confer high or moderate probability of disease and explain 93% of cases studied. The pattern of disease risk across PAN2 and MAP3K7CL genotypes provided clear evidence for a significant epistatic foundation for this disease, a risk further impacted by MHC haplotypes. We also observed a genotype-phenotype correlation wherein an earlier age of onset is correlated with an increased number of risk alleles at PAN2 and MAP3K7CL. High frequencies of multiple genetic risk factors are unique to affected breeds and likely arose coincident with artificial selection for desirable phenotypes. Described herein is the first three-locus association with a complex canine disease and two novel loci that provide targets for exploration in JDM and related immunological dysfunction.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We developed comprehensive models to determine risk of Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors.
We used pooled data from 3288 patients ...with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett’s and EAC consortium as well as the United Kingdom’s BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis.
Individuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89–2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07–2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%.
We used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use.
Storm surge associated with Hurricane Katrina and the breach of levees protecting New Orleans, Louisiana allowed floodwaters from Lake Pontchartrain to inundate 80% of the city. Environmental samples ...were collected during September 16−18, 2005 to determine immediate human and wildlife health hazards from pathogens and toxicants in the floodwaters. Baseline information on potential long-term environmental damage resulting from contaminants in water and sediments pumped into Lake Pontchartrain was also collected. Concentrations of aldrin, arsenic, lead, and seven semivolatile organic compounds in sediments/soils exceeded one or more United States Environmental Protection Agency (USEPA) thresholds for human health soil screening levels and high priority bright line screening levels. High numbers of Aeromonas spp., pathogenic Vibrio spp., and other coliform bacteria were found in floodwater samples. Alligator and snake tissues did not contain excessive toxicant concentrations. Initial findings suggest numerous environmental contaminants are present in New Orleans and support the need for further evaluation of the extent of those threats.
Background
Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been ...identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog.
Hypothesis/Objective
Clinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies.
Animals
Four GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs.
Methods
Complete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database.
Results
Clinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds.
Conclusions and Clinical Importance
We confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness.
Background
Unhealthy alcohol use among persons living with HIV (PLWH) is linked to significant morbidity, and use of alcohol services may differ by HIV status. Our objective was to compare unhealthy ...alcohol use screening and treatment by HIV status in primary care.
Methods
Cohort study of adult (≥18 years) PLWH and HIV‐uninfected participants frequency matched 20:1 to PLWH by age, sex, and race/ethnicity who were enrolled in a large integrated healthcare system in the United States, with information ascertained from an electronic health record. Outcomes included unhealthy alcohol screening, prevalence, provider‐delivered brief interventions, and addiction specialty care visits. Other predictors included age, sex, race/ethnicity, neighborhood deprivation index, depression, smoking, substance use disorders, Charlson comorbidity index, prior outpatient visits, insurance type, and medical facility. Cox proportional hazards models were used to compute hazard ratios (HR) for the outcomes of time to unhealthy alcohol use screening and time to first addiction specialty visit. Poisson regression with robust standard errors was used to compute prevalence ratios (PR) for other outcomes.
Results
11,235 PLWH and 227,320 HIV‐uninfected participants were included. By 4.5 years after baseline, most participants were screened for unhealthy alcohol use (85% of PLWH and 93% of HIV‐uninfected), but with a lower rate among PLWH (adjusted HR 0.84, 95% CI 0.82 to 0.85). PLWH were less likely, compared with HIV‐uninfected participants, to report unhealthy drinking among those screened (adjusted PR 0.74, 95% CI 0.69 to 0.79), and among those who screened positive, less likely to receive brief interventions (adjusted PR 0.82, 95% CI 0.75 to 0.90), but more likely (adjusted HR 1.7, 95% CI 1.2 to 2.4) to have an addiction specialty visit within 1 year.
Conclusions
Unhealthy alcohol use was lower in PLWH, but the treatment approach by HIV status differed. PLWH reporting unhealthy alcohol use received less brief interventions and more addiction specialty care than HIV‐uninfected participants.
Unhealthy alcohol use can adversely impact people living with HIV (PLWH), but it is unknown if treatment varies by HIV status. We studied alcohol
interventions among 11,235 PLWH and 227,320 HIV‐uninfected participants enrolled in a US‐based healthcare system. PLWH reporting unhealthy alcohol
use were 18% less likely to have brief interventions in primary care compared with HIV‐uninfected, but 70% more likely to have an addiction specialty care visit. These results have important implications for integrating alcohol interventions in HIV care.
We determined whether environmentally relevant concentrations of ammonium perchlorate alter development and metamorphosis in Xenopus laevis. Eggs and larvae were exposed to varying concentrations of ...ammonium perchlorate or control medium for 70 d. Most treatment‐related mortality was observed within 5 d after exposure and was due in large part to reduced hatching success. The 5‐ and 70‐d median lethal concentrations (LC50s) were 510 ± 36 mg ammonium perchlorate/L and 223 ± 13 mg ammonium perchlorate/L, respectively. Ammonium perchlorate did not cause any concentration‐related developmental abnormalities at concentrations below the 70‐d LC50. Ammonium perchlorate inhibited metamorphosis in a concentration‐dependent manner as evident from effects on forelimb emergence, tail resorption, and hindlimb growth. These effects were observed after exposure to ammonium perchlorate concentrations in the parts‐per‐billion range, at or below concentrations reported in surface waters contaminated with ammonium perchlorate. Ammonium perchlorate significantly inhibited tail resorption after a 14‐d exposure in the U.S. Environmental Protection Agency (U.S. EPA) Endocrine Disruptor Screening and Testing Committee (EDSTAC) Tier I frog metamorphosis assay for thyroid disruption in amphibians. We believe that ammonium perchlorate may pose a threat to normal development and growth in natural amphibian populations.
The perchlorate anion—an oxidizer found in rockets, missiles, some ammunition, flares, airbags, and fireworks—occurs as a contaminant in ground and surface water in many parts of the United States. ...Its toxic effects include inhibition of thyroid hormone synthesis. To investigate its chronic toxicity, mosquitofish (
Gambusia holbrooki) adults and fry were exposed to aqueous sodium perchlorate at 1, 10, and 100
mg/L, and growth and reproductive performance (fecundity, eggs/embryos mass, and gonadosomatic index GSI) were determined. Five-day acute toxicity tests were also performed. Perchlorate had a stimulatory effect on fecundity, GSI, and egg/embryo mass, at least for some treatments. The LC
50 of sodium perchlorate was 404
mg/L. Growth was enhanced at 1
mg/L but inhibited at 10
mg/L. These results suggest that, at environmentally relevant concentrations, perchlorate does not induce acutely toxic effects but may have mild stimulatory or hormetic effects on fitness parameters in this species.
There have been increasing human health and ecological concerns about ionic perchlorate (ClO4-) since it was detected in drinking water sources in 1997. Perchlorate is known to affect thyroid ...function, causing subsequent hormone disruption and potential perturbations of metabolic activities. According to current estimates, perchlorate is found in the surface of groundwater of 14 states, including Texas. Longhorn Army Ammunition Plant, located in east central Texas, was a facility historically associated with perchlorate-containing propellants and rocket motors. Subsequently, perchlorate contamination in ground and surface waters at the facility has been reported. Soil, sediment, water, vegetation, and animal tissue samples were collected from several locations within the plant for a preliminary site assessment of perchlorate contamination. Perchlorate concentrations ranged from 555-5,557,000 ppb in vegetation, 811-2038 ppb in aquatic insects, below detection limits (ND) to 207 ppb in fish, ND-580 ppb in frogs, and ND-2328 ppb in mammals. Consistent with our hypothesis, aquatic organisms inhabiting perchlorate-contaminated surface water bodies contained detectable concentrations of perchlorate. Additionally, terrestrial organisms were exposed through pathways not necessarily related to contaminated surface waters. Therefore, these data demonstrate that aquatic and terrestrial species are exposed to perchlorate in the environment. To our knowledge, this represents the first incidence of perchlorate exposure among wild animals reported in the scientific literature.
The effect of TNT (2,4,6-trinitrotoluene) and its metabolites, 2,4-dinitrotoluene (2,4-DNT), 2-amino-4,6-dinitrotoluene (2A-DNT), and 4-amino-2,6-dinitrotoluene (4A-DNT) on cricket (
Acheta ...domesticus) reproduction was evaluated. We previously used crickets to assess the toxicity of a nitramine explosive (RDX) and its metabolites. It is common to find that while much information on the environmental impact of the parent compound is available in the literature, such is often not the case for the degradation metabolites of the parent compound. In some instances, these metabolites are as toxic (or more so) as the parent compound and we hypothesized that this might be the case for TNT. The presence of TNT and its metabolites in sand (10 µg/g) did not adversely affect cricket egg production, but adversely affected hatching of cricket eggs as compared to controls. However, there were no differences in hatching success among TNT and metabolite treatment groups. Hatching success of cricket eggs in soil or following topical exposure decreased as concentrations of TNT and its metabolites increased. The relative toxicity of TNT and its metabolites in soil generally followed the trend of TNT
<
2A-DNT
<
4A-DNT
<
2,4-DNT. In addition, toxicity appeared to be higher in sand than in sandy loam soil or in the topical exposure test. After 45 days of exposure in sandy loam soil, the EC
20 (20% effect concentration), EC
50 (50% effect concentration), and EC
95 (95% effect concentration) were 14, 116, and 10,837 µg/g for TNT: 1.7, 32, and 16,711 µg/g for 2A-DNT: 1.9, 9, and 296 µg/g for 4A-DNT: and 0.4, 5.7, and 1437 µg/g for 2,4-DNT. Overall, results suggest that parent TNT and metabolites are toxic to cricket eggs at relatively high concentrations and these toxic effects are manifested as a decrease in hatching success.
Gluteofemoral obesity (determined by measurement of subcutaneous fat in the hip and thigh regions) could reduce risks of cardiovascular and diabetic disorders associated with abdominal obesity. We ...evaluated whether gluteofemoral obesity also reduces the risk of Barrett's esophagus (BE), a premalignant lesion associated with abdominal obesity.
We collected data from non-Hispanic white participants in 8 studies in the Barrett's and Esophageal Adenocarcinoma Consortium. We compared measures of hip circumference (as a proxy for gluteofemoral obesity) from cases of BE (n = 1559) separately with 2 control groups: 2557 population-based controls and 2064 individuals with gastroesophageal reflux disease (GERD controls). Study-specific odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using individual participant data and multivariable logistic regression and combined using a random-effects meta-analysis.
We found an inverse relationship between hip circumference and BE (OR per 5-cm increase, 0.88; 95% CI, 0.81-0.96), compared with population-based controls in a multivariable model that included waist circumference. This association was not observed in models that did not include waist circumference. Similar results were observed in analyses stratified by frequency of GERD symptoms. The inverse association with hip circumference was statistically significant only among men (vs population-based controls: OR, 0.85; 95% CI, 0.76-0.96 for men; OR, 0.93; 95% CI, 0.74-1.16 for women). For men, within each category of waist circumference, a larger hip circumference was associated with a decreased risk of BE. Increasing waist circumference was associated with an increased risk of BE in the mutually adjusted population-based and GERD control models.
Although abdominal obesity is associated with an increased risk of BE, there is an inverse association between gluteofemoral obesity and BE, particularly among men.
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