Childhood Adversity is Associated with Left Basal Ganglia Dysfunction During Reward Anticipation in Adulthood

Background: Childhood adversity increases the risk of psychopathology, but the neurobiological mechanisms underlying this vulnerability are not well-understood. In animal models, early adversity is associated with dysfunction in basal ganglia regions involved in reward processing, but this relationship has not been established in humans. Methods: Functional magnetic resonance imaging was used to examine basal ganglia responses to (a) cues signaling possible monetary rewards and losses, and (b) delivery of monetary gains and penalties, in 13 young adults who experienced maltreatment before age 14 and 31 non-maltreated controls. Results: Relative to controls, individuals exposed to childhood adversity reported elevated symptoms of anhedonia and depression, rated reward cues less positively, and displayed a weaker response to reward cues in the left globus pallidus. There were no group differences in right hemisphere basal ganglia response to reward cues, or in basal ganglia response to loss cues, no-incentive cues, gains, or penalties. Conclusions: Results indicate that childhood adversity in humans is associated with blunted subjective responses to reward-predicting cues as well as dysfunction in left basal ganglia regions implicated in reward-related learning and motivation. This dysfunction may serve as a diathesis that contributes to the multiple negative outcomes and psychopathologies associated with childhood adversity. The findings suggest that interventions that target motivation and goal-directed action may be useful for reducing the negative consequences of childhood adversity.Psycholog

The ACTN3 R577X Polymorphism across Three Groups of Elite Male European Athletes

The ACTN3 R577X polymorphism (rs1815739) is a strong candidate to influence elite athletic performance. Yet, controversy exists in the literature owing to between-studies differences in the ethnic background and sample size of the cohorts, the latter being usually low, which makes comparisons difficult. In this case:control genetic study we determined the association between elite athletic status and the ACTN3 R577X polymorphism within three cohorts of European Caucasian men, i.e. Spanish, Polish and Russian [633 cases (278 elite endurance and 355 power athletes), and 808 non-athletic controls]. The odds ratio (OR) of a power athlete harbouring the XX versus the RR genotype compared with sedentary controls was 0.54 [95% confidence interval (CI): 0.34–0.48; P = 0.006]. We also observed that the OR of an endurance athlete having the XX versus the RR genotype compared with power athletes was 1.88 (95%CI: 1.07–3.31; P = 0.028). In endurance athletes, the OR of a “world-class” competitor having the XX genotype versus the RR+RX genotype was 3.74 (95%CI: 1.08–12.94; P = 0.038) compared with those of a lower (“national”) competition level. No association (P>0.1) was noted between the ACTN3 R577X polymorphism and competition level (world-class versus national-level) in power athletes. Our data provide comprehensive support for the influence of the ACTN3 R577X polymorphism on elite athletic performance

Hypoparathyroidism-retardation-dysmorphism syndrome—Clinical insights from a large longitudinal cohort in a single medical center

BackgroundHypoparathyroidism, retardation, and dysmorphism (HRD) Syndrome is a rare disease composed of hypoparathyroidism, retardation of both growth and development, and distinctive dysmorphic features. Here, we describe the long-term morbidity and mortality in a large cohort of HRD patients and suggest recommendations for follow up and treatment.MethodsMedical records of 63 HRD syndrome patients who were followed at Soroka Medical Center during 1989–2019 were reviewed retrospectively. Information regarding demographics, medical complications, laboratory findings, and imaging studies was collected.ResultsThe mortality rate was 52%. The main causes of death were infectious diseases including pneumonia, septic shock, and meningitis. Multiple comorbidities were found including brain anomalies in 90% of examined patients (basal ganglia calcifications, tightening of corpus callosum, Chiari malformation, hydrocephalous, and brain atrophy), seizures in 62%, nephrocalcinosis and/or nephrolithiasis in 47%, multiple eye anomalies were recorded in 40%, bowel obstructions in 9.5%, and variable expression of both conductive and senso-neural hearing loss was documented in 9.5%.ConclusionHRD is a severe multisystem disease. Active surveillance is indicated to prevent and treat complications associated with this rare syndrome

Health promotion programs in prison: attendance and role in promoting physical activity and subjective health status

IntroductionMaintaining an inmate’s health can serve as a challenge due to unhealthy background, risky behavior, and long imprisonment. This study aimed to analyze the prevalence of participation in health promotion activities among Israeli inmates and its association with their physical activity levels and subjective health status.MethodsA cross-sectional study was designed to examine 522 inmates (429 males, 93 females). The data were collected by trained face-to-face interviewers and self-report questionnaires.ResultsMost of the participants (82.37%) did not meet the recommended physical activity level. Half of the participants reported that their physical activity levels decreased since they were in prison compared with 29.50% who reported that their physical activity levels increased. Physical activity and subjective health status were significantly higher among younger male inmates. Furthermore, participation in health-promoting activities was associated with higher levels of physical activity and subjective health status.DiscussionHealth promotion activities may play an important role in addressing the challenges of maintaining inmate health. Implications of the findings are further discussed

Gain-of-Function R225W Mutation in Human AMPKγ3 Causing Increased Glycogen and Decreased Triglyceride in Skeletal Muscle

BACKGROUND: AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is evolutionarily conserved from yeast to mammals and functions to maintain cellular and whole body energy homeostasis. Studies in experimental animals demonstrate that activation of AMPK in skeletal muscle protects against insulin resistance, type 2 diabetes and obesity. The regulatory gamma(3) subunit of AMPK is expressed exclusively in skeletal muscle; however, its importance in controlling overall AMPK activity is unknown. While evidence is emerging that gamma subunit mutations interfere specifically with AMP activation, there remains some controversy regarding the impact of gamma subunit mutations. Here we report the first gain-of-function mutation in the muscle-specific regulatory gamma(3) subunit in humans. METHODS AND FINDINGS: We sequenced the exons and splice junctions of the AMPK gamma(3) gene (PRKAG3) in 761 obese and 759 lean individuals, identifying 87 sequence variants including a novel R225W mutation in subjects from two unrelated families. The gamma(3) R225W mutation is homologous in location to the gamma(2)R302Q mutation in patients with Wolf-Parkinson-White syndrome and to the gamma(3)R225Q mutation originally linked to an increase in muscle glycogen content in purebred Hampshire Rendement Napole (RN-) pigs. We demonstrate in differentiated muscle satellite cells obtained from the vastus lateralis of R225W carriers that the mutation is associated with an approximate doubling of both basal and AMP-activated AMPK activities. Moreover, subjects bearing the R225W mutation exhibit a approximately 90% increase of skeletal muscle glycogen content and a approximately 30% decrease in intramuscular triglyceride (IMTG). CONCLUSIONS: We have identified for the first time a mutation in the skeletal muscle-specific regulatory gamma(3) subunit of AMPK in humans. The gamma(3)R225W mutation has significant functional effects as demonstrated by increases in basal and AMP-activated AMPK activities, increased muscle glycogen and decreased IMTG. Overall, these findings are consistent with an important regulatory role for AMPK gamma(3) in human muscle energy metabolism

Re-evaluating a vision-related quality of life questionnaire with item response theory (IRT) and differential item functioning (DIF) analyses

Background: For the Low Vision Quality Of Life questionnaire (LVQOL) it is unknown whether the psychometric properties are satisfactory when an item response theory (IRT) perspective is considered. This study evaluates some essential psychometric properties of the LVQOL questionnaire in an IRT model, and investigates differential item functioning (DIF). Methods: Cross-sectional data were used from an observational study among visually-impaired patients (n = 296). Calibration was performed for every dimension of the LVQOL in the graded response model. Item goodness-of-fit was assessed with the S-X2-test. DIF was assessed on relevant background variables (i.e. age, gender, visual acuity, eye condition, rehabilitation type and administration type) with likelihood-ratio tests for DIF. The magnitude of DIF was interpreted by assessing the largest difference in expected scores between subgroups. Measurement precision was assessed by presenting test information curves; reliability with the index of subject separation. Results: All items of the LVQOL dimensions fitted the model. There was significant DIF on several items. For two items the maximum difference between expected scores exceeded one point, and DIF was found on multiple relevant background variables. Item 1 ‘Vision in general’ from the “Adjustment” dimension and item 24 ‘Using tools’ from the “Reading and fine work” dimension were removed. Test information was highest for the “Reading and fine work” dimension. Indices for subject separation ranged from 0.83 to 0.94. Conclusions: The items of the LVQOL showed satisfactory item fit to the graded response model; however, two items were removed because of DIF. The adapted LVQOL with 21 items is DIF-free and therefore seems highly appropriate for use in heterogeneous populations of visually impaired patients. (aut.ref.

The case for strategic international alliances to harness nutritional genomics for public and personal health

Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene-nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient-genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countrie

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Refined histopathological predictors of BRCA1 and BRCA2 mutation status : a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Abstract Introduction The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management

Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred

Abstract Background The hypothalamic G-protein-coupled-receptor melanocortin-4 receptor (MC4R) is a key player in the central circuit regulating energy expenditure and appetite. Heterozygous loss-of-function MC4R mutations are the most common known genetic cause of monogenic human obesity, with more than 200 mutations described to date, affecting 2–3% of the population in various cohorts tested. Homozygous or compound heterozygous MC4R mutations are much less frequent, and only few families have been described in which heterozygotes and homozygotes of the same mutation are found. Methods We performed exome sequencing in a consanguineous Bedouin family with morbid obesity to identify the genetic cause of the disease. Clinical examination and biochemical assays were done to delineate the phenotype. Results We report the frequency of MC4R mutations in the large inbred Bedouin Israeli population. Furthermore, we describe consanguineous inbred Bedouin kindred with multiple individuals that are either homozygous or heterozygous carries of the same novel MC4R mutation (c.124G > T, p.E42*). All family members with the homozygous mutation exhibited morbid early-onset obesity, while heterozygote individuals had either a milder overweight phenotype or no discernable phenotype compared to wild type family members. While elder individuals homozygous or heterozygous for the MC4R mutation had abnormally high triglycerides, cholesterol, glucose and HbA1C levels, most did not. Conclusions MC4R mutation homozygotes exhibited morbid early-onset obesity, while heterozygotes had a significantly milder overweight phenotype. Whereas obesity due to MC4R mutations is evident as of early age – most notably in homozygotes, the metabolic consequences emerge only later in life