We have previously shown that local heating or leg fidgeting can prevent prolonged sitting-induced leg endothelial dysfunction. However, whether physical activity prevents subsequent sitting-induced ...leg endothelial dysfunction remains unknown. Herein, we tested the hypothesis that sitting-induced leg endothelial dysfunction would be prevented by prior exercise. We also examined if, in the absence of exercise, standing is an effective alternative strategy to sitting for conserving leg endothelial function. Fifteen young healthy subjects completed three randomized experimental trials: (1) sitting without prior exercise; (2) sitting with prior exercise; and (3) standing without prior exercise. Following baseline popliteal artery flow-mediated dilation (FMD) measurements, subjects maintained a supine position for 45 min in the sitting and standing trials, without prior exercise, or performed 45 min of leg cycling before sitting (i.e. sitting with prior exercise trial). Thereafter, subjects were positioned into a seated or standing position, according to the trial, for 3 h. Popliteal artery FMD measures were then repeated. Three hours of sitting without prior exercise caused a significant impairment in popliteal artery FMD (baseline: 3.8±0.5%, post-sitting: 1.5±0.5%,
<0.05), which was prevented when sitting was preceded by a bout of cycling exercise (baseline: 3.8±0.5%, post-sitting: 3.6±0.7%,
>0.05). Three hours of standing did not significantly alter popliteal artery FMD (baseline: 4.1±0.4%, post-standing: 4.3±0.4%,
>0.05). In conclusion, prolonged sitting-induced leg endothelial dysfunction can be prevented by prior aerobic exercise. In addition, in the absence of exercise, standing represents an effective substitute to sitting for preserving leg conduit artery endothelial function.
Prolonged sitting impairs endothelial function in the leg vasculature, and this impairment is thought to be largely mediated by a sustained reduction in blood flow-induced shear stress. Indeed, ...preventing the marked reduction of shear stress during sitting with local heating abolishes the impairment in popliteal artery endothelial function. Herein, we tested the hypothesis that sitting-induced reductions in shear stress and ensuing endothelial dysfunction would be prevented by periodic leg movement, or "fidgeting." In 11 young, healthy subjects, bilateral measurements of popliteal artery flow-mediated dilation (FMD) were performed before and after a 3-h sitting period during which one leg was subjected to intermittent fidgeting (1 min on/4 min off) while the contralateral leg remained still throughout and served as an internal control. Fidgeting produced a pronounced increase in popliteal artery blood flow and shear rate (prefidgeting, 33.7 ± 2.6 s(-1) to immediately postfidgeting, 222.7 ± 28.3 s(-1); mean ± SE; P < 0.001) that tapered off during the following 60 s. Fidgeting did not alter popliteal artery blood flow and shear rate of the contralateral leg, which was subjected to a reduction in blood flow and shear rate throughout the sitting period (presit, 71.7 ± 8.0 s(-1) to 3-h sit, 20.2 ± 2.9 s(-1); P < 0.001). Popliteal artery FMD was impaired after 3 h of sitting in the control leg (presit, 4.5 ± 0.3% to postsit: 1.6 ± 1.1%; P = 0.039) but improved in the fidgeting leg (presit, 3.7 ± 0.6% to postsit, 6.6 ± 1.2%; P = 0.014). Collectively, the present study provides evidence that prolonged sitting-induced leg endothelial dysfunction is preventable with small amounts of leg movement while sitting, likely through the intermittent increases in vascular shear stress.
We and others have recently reported that prolonged sitting impairs endothelial function in the leg vasculature; however, the mechanism(s) remain unknown. Herein, we tested the hypothesis that a ...sustained reduction in flow-induced shear stress is the underlying mechanism by which sitting induces leg endothelial dysfunction. Specifically, we examined whether preventing the reduction in shear stress during sitting would abolish the detrimental effects of sitting on popliteal artery endothelial function. In 10 young healthy men, bilateral measurements of popliteal artery flow-mediated dilation were performed before and after a 3-h sitting period during which one foot was submerged in 42°C water (i.e., heated) to increase blood flow and thus shear stress, whereas the contralateral leg remained dry and served as internal control (i.e., nonheated). During sitting, popliteal artery mean shear rate was reduced in the nonheated leg (pre-sit, 42.9 ± 4.5 s(-1); and 3-h sit, 23.6 ± 3.3 s(-1); P < 0.05) but not in the heated leg (pre-sit, 38.9 ± 3.4 s(-1); and 3-h sit, 63.9 ± 16.9 s(-1); P > 0.05). Popliteal artery flow-mediated dilation was impaired after 3 h of sitting in the nonheated leg (pre-sit, 7.1 ± 1.4% vs. post-sit, 2.8 ± 0.9%; P < 0.05) but not in the heated leg (pre-sit: 7.3 ± 1.5% vs. post-sit, 10.9 ± 1.8%; P > 0.05). Collectively, these data suggest that preventing the reduction of flow-induced shear stress during prolonged sitting with local heating abolishes the impairment in popliteal artery endothelial function. Thus these findings are consistent with the hypothesis that sitting-induced leg endothelial dysfunction is mediated by a reduction in shear stress.
Postprandial hyperglycaemia leads to a transient impairment in endothelial function; however, the mechanisms remain largely unknown. Previous work in cell culture models demonstrate that high glucose ...results in endoplasmic reticulum (ER) stress and, in animal studies, ER stress has been implicated as a cause of endothelial dysfunction. In the present study, we tested the hypothesis that acute oral administration of tauroursodeoxycholic acid (TUDCA, 1500 mg), a chemical chaperone known to alleviate ER stress, would prevent hyperglycaemia-induced endothelial dysfunction. In 12 young healthy subjects (seven men, five women), brachial artery flow-mediated dilation (FMD) was assessed at baseline, and at 60 and 120 min after an oral glucose challenge. Subjects were tested on two separate visits in a single-blind randomized cross-over design: after oral ingestion of TUDCA or placebo capsules. FMD was reduced from baseline during hyperglycaemia under the placebo condition (-32% at 60 min and -28% at 120 min post oral glucose load; P<0.05 from baseline) but not under the TUDCA condition (-4% at 60 min and +0.3% at 120 min post oral glucose load; P>0.05 from baseline). Postprandial plasma glucose and insulin were not altered by TUDCA ingestion. Plasma oxidative stress markers 3-nitrotyrosine and thiobarbituric acid reactive substance (TBARS) remained unaltered throughout the oral glucose challenge in both conditions. These results suggest that hyperglycaemia-induced endothelial dysfunction can be mitigated by oral administration of TUDCA, thus supporting the hypothesis that ER stress may contribute to endothelial dysfunction during postprandial hyperglycaemia.
Purpose: The purpose of this study was to determine the prevalence of self-reported hearing loss and associated risk factors in a representative population-based study of Wisconsin residents. Method: ...Survey of the Health of Wisconsin participants with data on self-reported hearing loss were included. We reported prevalence of self-reported hearing loss with corresponding 95% confidence intervals (CIs), overall, and stratified by age and sex. Age- and sex-adjusted and multivariable logistic regression models were used to evaluate determinants of self-reported hearing loss, and results are presented as odds ratios with corresponding 95% CIs. Results: There were 2,767 participants (50.7% men) with a mean age of 46 years (range: 21--74) in this study. Prevalence of self-reported hearing loss was 26.8% (24.4, 28.4) and was higher in men (30.3% 27.1, 33.4) than in women (22.5% 19.9, 25.0). Prevalence increased with age. After multivariable adjustment, age (per +1 year increase; 1.05 1.04, 1.06), male sex (1.57 1.18, 2.08), having two chronic diseases (vs. 0; 1.93 1.16, 3.23), occupational (2.47 1.91, 3.19) and recreational (1.58 1.22, 2.04) noise exposure, and poor diet (1.88 1.28, 2.78) were associated with higher odds of self-reported hearing loss. Conclusions: Hearing loss is a highly prevalent public health concern and may be at least partially modifiable via interventions to reduce noise exposure and promote health. Statewide prevalence and risk factor data can be used to inform public health practice and promote hearing loss prevention.
Recurrent 16p11.2 duplications produce a wide range of clinical outcomes with varying effects on cognition and social functioning. Family-based studies of copy number variants (CNVs) have revealed ...significant contributions of genomic background on variable expressivity. In this study, we measured the phenotypic effect of 16p11.2 duplications and quantified the modulating effect of familial background on cognitive and social outcomes.
Genomic and clinical data were ascertained from 41 probands with a 16p11.2 duplication and their first-degree relatives. Paired comparisons were completed to determine the duplication's effect on expected vs actual performance on standardized tests of intelligence (IQ) and social functioning (Social Responsiveness Scale-2). Intraclass correlations between relatives and probands were also calculated.
Cognitive and social functioning were significantly lower among individuals with 16p11.2 duplications than their CNV-negative relatives, whereas intraclass correlations between the groups remained high for full-scale IQ and Social Responsiveness Scale-2 scores.
The 16p11.2 duplication confers deleterious effects on cognition and social functioning, whereas familial background significantly influences phenotypic expression of these traits. Understanding variable expressivity in CNV disorders has implications for anticipatory clinical care, particularly for individuals who receive a genetic diagnosis at an early age, long before the full scope of manifestations becomes evident.
Physical inactivity is associated with disruptions in glucose metabolism and energy balance, whereas energy restriction may blunt these adverse manifestations. During hypocaloric feeding, ...higher-protein intake maintains lean mass which is an important component of metabolic health. This study determined whether mild energy restriction preserves glycemic control during physical inactivity and whether this preservation is more effectively achieved with a higher-protein diet.
Ten adults (24 ± 1 yr) consumed a control (64% carbohydrate, 20% fat, 16% protein) and higher-protein diet (50% carbohydrate, 20% fat, 30% protein) during two 10-d inactivity periods (>10,000 → ~5000 steps per day) in a randomized crossover design. Energy intake was decreased by ~400 kcal·d to account for reduced energy expenditure associated with inactivity. A subset of subjects (n = 5) completed 10 d of inactivity while consuming 35% excess of their basal energy requirements, which served as a positive control condition (overfeeding+inactivity).
Daily steps were decreased from 12,154 ± 308 to 4275 ± 269 steps per day (P < 0.05) which was accompanied by reduced V˙O2max (-1.8 ± 0.7 mL·kg·min, P < 0.05), independent of diet conditions. No disruptions in fasting or postprandial glucose, insulin, and nonesterified fatty acids in response to 75 g of oral glucose were observed after inactivity for both diet conditions (P > 0.05). Overfeeding+inactivity increased body weight, body fat, homeostasis model assessment of insulin resistance, and 2-h postprandial glucose and insulin concentrations (P < 0.05), despite no changes in lipid concentrations.
We show that independent of diet (normal vs higher-protein), mild energy restriction preserves metabolic function during short-term inactivity in healthy subjects. That is, metabolic deterioration with inactivity only manifests in the setting of energy surplus.
Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated ...factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016-23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.
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