Ebi/AP-1 Suppresses Pro-Apoptotic Genes Expression and Permits Long-Term Survival of Drosophila Sensory Neurons

Sensory organs are constantly exposed to physical and chemical stresses that collectively threaten the survival of sensory neurons. Failure to protect stressed neurons leads to age-related loss of neurons and sensory dysfunction in organs in which the supply of new sensory neurons is limited, such as the human auditory system. Transducin β-like protein 1 (TBL1) is a candidate gene for ocular albinism with late-onset sensorineural deafness, a form of X-linked age-related hearing loss. TBL1 encodes an evolutionarily conserved F-box–like and WD40 repeats–containing subunit of the nuclear receptor co-repressor/silencing mediator for retinoid and thyroid hormone receptor and other transcriptional co-repressor complexes. Here we report that a Drosophila homologue of TBL1, Ebi, is required for maintenance of photoreceptor neurons. Loss of ebi function caused late-onset neuronal apoptosis in the retina and increased sensitivity to oxidative stress. Ebi formed a complex with activator protein 1 (AP-1) and was required for repression of Drosophila pro-apoptotic and anti-apoptotic genes expression. These results suggest that Ebi/AP-1 suppresses basal transcription levels of apoptotic genes and thereby protects sensory neurons from degeneration

Altered sensory-weighting mechanisms is observed in adolescents with idiopathic scoliosis

BACKGROUND: Scoliosis is the most common type of spinal deformity. In North American children, adolescent idiopathic scoliosis (AIS) makes up about 90% of all cases of scoliosis. While its prevalence is about 2% to 3% in children aged between 10 to 16 years, girls are more at risk than boys for severe progression with a ratio of 3.6 to 1. The aim of the present study was to test the hypothesis that idiopathic scoliosis interferes with the mechanisms responsible for sensory-reweighting during balance control. METHODS: Eight scoliosis patients (seven female and one male; mean age: 16.4 years) and nine healthy adolescents (average age 16.5 years) participated in the experiment. Visual and ankle proprioceptive information was perturbed (eyes closed and/or tendon vibration) suddenly and then returned to normal (eyes open and/or no tendon vibration). An AMTI force platform was used to compute centre of pressure root mean squared velocity and sway density curve. RESULTS: For the control condition (eyes open and no tendon vibration), adolescent idiopathic scoliosis patients had a greater centre of pressure root mean squared velocity (variability) than control participants. Reintegration of ankle proprioception, when vision was either available or removed, led to an increased centre of pressure velocity variability for the adolescent idiopathic scoliosis patients whereas the control participants reduced their centre of pressure velocity variability. Moreover, in the absence of vision, adolescent idiopathic scoliosis exhibited an increased centre of pressure velocity variability when ankle proprioception was returned to normal (i.e. tendon vibration stopped). The analysis of the sway density plot suggests that adolescent idiopathic scoliosis patients, during sensory reintegration, do not scale appropriately their balance control commands. CONCLUSION: Altogether, the present results demonstrate that idiopathic scoliosis adolescents have difficulty in reweighting sensory inputs following a brief period of sensory deprivation

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Rubidium deficiency in dialysis patients

BACKGROUND: Since dialysis has brought long-term survival to uremic patients, we can now speculate on more subtle problems derived from imbalance or sub-optimal regulation of some elements such as trace metals. We focused on the rubidium (Rb) status in dialysis patients (HD), as concerns about its possible deficiency have been raised. METHODS: Rb in uremic patients was evaluated by: A) serum concentration (graphite furnace atomic absorption spectroscopy) from blood samples of 70 patients on chronic hemodialysis (HD) in comparison with 75 controls; B) tissue concentration (neutron activation analysis) from autopsy or biopsy samples (20) of HD patients in comparison with 21 controls; C) in vivo intradialytic mass balance during standard bicarbonate dialysis in 8 HD patients. RESULTS: A) Serum Rb concentrations in HD patients significantly were lower than in normal controls (304 +/- 81 micrograms/L versus 350 +/- 74 micrograms/L p < 0.001, log-transformed 5.68 +/- 0.28 versus 5.84 +/- 0.20, p < 0.001). Univariate logistic regression analysis found a significantly higher risk of serum Rb < 250-300 and 350 micrograms/L in uremic patients than in controls (Odd ratios or 12.6, 95% CI 2.77-57.04; 4.0, 95% CI 1.92-8.4; 2.08, 95% CI 1.02-4.25, respectively). B) Rb was significantly lower in tissues of HD patients, including brain (2250 +/- 1520 ng/g versus 5490 +/- 1250 ng/g, p = 0.0002) than normal controls. C) Rb was transferred from the patients' blood to the dialysis bath during a standard bicarbonate dialysis session, giving mean intradialytic Rb removal of 4.0 +/- 1.1 mg/session. CONCLUSIONS: These results confirm that Rb deficiency may arise in uremic patients, and indicate that diffusive dialysis treatments allow Rb removal which, however, with a standard bicarbonate schedule does not seem to be any greater than that expected with normal urine output (20 mg/week). Further studies are needed to clarify the roles of many factors in this Rb deficiency, including the effects of uremia by itself, pre-dialysis factors (diet, impaired renal function and drugs), dialysis procedures (frequency, hours, diffusive/convective components) or other biochemical/clinical parameters (hemoglobin, body mass index, age). The finding of a Rb deficiency in uremia is important as it has a role in neurobehavioural functions, mainly as an antidepressant. As Rb deficiency may be implicated in central nervous system alterations which strongly influence the quality of life, we believe that monitoring serum Rb in uremic patients and clarifying the causal mechanisms of deficiency will facilitate future therapeutic approaches

Age at menopause, extent of coronary artery disease and outcome among postmenopausal women with acute coronary syndromes

Background: Early menopause has been associated with increased cardiovascular mortality, but prospective studies investigating outcomes of postmenopausal women with acute coronary syndromes (ACS) in relation to menopausal age are lacking.Methods: We analyzed the 1-year outcome of 373 women with acute myocardial infarction enrolled in the Ladies ACS study. All patients underwent coronary angiography, with corelab analysis. Menopause questionnaires were administered during admission. Menopausal age below the median of the study population (50 years) was defined as "early menopause". The composite 1-year outcome included all-cause mortality, recurrent myocardial infarction and stroke.Results: The mean age at index ACS was 73 years (IQR 65-83) for women with early menopause, and 74 (IQR 6580) for those with late menopause. Patients with early menopause had more prevalent chronic kidney disease (12.8% vs 5.9%, p=0.03), whereas there were no differences in all other clinical characteristics, extent of coronary disease at angiography (as assessed by Gensini and SYNTAX scores), as well as interventional treatments. Within 1 year, women with late menopause had significantly better outcome as compared with those with early menopause (6.5% vs 15.3%, p=0.007). At logistic regression analysis, late menopause was independently associated with better outcome(OR 0.28; 95% CI 0.12-0.67; p=0.004). With each year's delay in the menopause the adjusted risk decreased by 12% (OR 0.88, 0.77-0.99, p=0.040).Conclusion: Despite comparable clinical and angiographic characteristics, women with late menopausal age experience better outcomes after an ACS as compared with those with early menopause. (c) 2018 Elsevier B.V. All rights reserved

Age at Menopause and Extent of Coronary Artery Disease Among Postmenopausal Women with Acute Coronary Syndromes

BACKGROUND: Epidemiological studies have shown a higher risk of cardiovascular mortality associated with early menopause, but the relation between menopausal age and extent of coronary artery disease after menopause is unknown. We assessed the relation between menopausal age and extent of coronary disease in postmenopausal women with an acute coronary syndrome. METHODS: A prospective study was conducted in patients 55 years old undergoing coronary angiography for an acute coronary syndrome. Enrollment was stratified by sex (women/men ratio 2:1) and age (55-64, 65-74, 75-85, and &gt;85 years). Women were administered menopause questionnaires during admission. An independent core lab quantified coronary artery disease extent using the Gensini Score, which classifies both significant (&gt;50%) and nonsignificant lesions. Linear correlation was used to appraise the association between the Gensini score and menopausal age. RESULTS: We enrolled 675 patients, 249 men and 426 women (mean age 74 years). The mean Gensini score was 60 36 in men vs 50 32 in women (P &lt;.001), being higher among men at any age. The median menopausal age of women was 50 years. Risk factors and age at first acute coronary syndrome were identical among women below and above the median menopausal age. The Gensini score in women showed a weak association with age (R \ubc 0.127; P \ubc .0129), but not with menopausal age (R \ubc 0.063; P \ubc .228). At multivariable analysis, ejection fraction, female sex, and ST elevation myocardial infarction were independent predictors of the Gensini score in the overall population. CONCLUSIONS: Menopausal age was not associated with the extent of coronary artery disease. Age at first acute coronary syndrome presentation, risk factors, and prior cardiovascular events were not affected by menopausal age