Eccentric exercise slows in vivo microvascular reactivity during brief contractions in human skeletal muscle

Unaccustomed exercise involving eccentric contractions results in muscle soreness and an overall decline in muscle function, however, little is known about the effects of eccentric exercise on microvascular reactivity in human skeletal muscle. Fourteen healthy men and women performed eccentric contractions of the dorsiflexor muscles in one leg, while the contralateral leg served as a control. At baseline, and 24 and 48 h after eccentric exercise, the following were acquired bilaterally in the tibialis anterior muscle: 1) transverse relaxation time (T2)-weighted magnetic resonance images to determine muscle cross-sectional area (mCSA) and T2; 2) blood oxygen level-dependent (BOLD) images during and following brief, maximal voluntary contractions (MVC) to monitor the hyperemic responses with participants positioned supine in a 3T magnet; 3) muscle strength; and 4) pain pressure threshold. Compared with the control leg, eccentric exercise resulted in soreness, decline in strength (∼20%), increased mCSA (∼7%), and prolonged T2 (∼7%) at 24 and 48 h ( P &lt; 0.05). The BOLD response to a brief MVC was altered 24 and 48 h after eccentric exercise, such that time-to-peak (∼35%, P &lt; 0.05) and time-to-half-recovery (∼23%, P &lt; 0.05) were prolonged. The altered contraction-induced hyperemic response suggests slowed microvascular reactivity and altered matching of O2 delivery to O2 utilization within muscle tissue showing signs of muscle damage. These changes in microvascular regulation after eccentric exercise may impede rapid adjustments in muscle blood flow at exercise onset and during activities involving brief bursts of muscle activation, which may impair O2 delivery and contribute to reduced muscle function after eccentric exercise. </jats:p

Ultra-low-dose non-contrast CT and CT angiography can be used interchangeably for assessing maximal abdominal aortic diameter

BACKGROUND: Routine CT scans may increasingly be used to document normal aortic size and to detect incidental abdominal aortic aneurysms. PURPOSE: To determine whether ultra-low-dose non-contrast CT (ULDNC-CT) can be used instead of the gold standard CT angiography (CTA) for assessment of maximal abdominal aortic diameter. MATERIALS AND METHODS: This retrospective study included 50 patients who underwent CTA and a normal-dose non–contrast CT for suspected renal artery stenosis. ULDNC-CT datasets were generated from the normal-dose non–contrast CT datasets using a simulation technique. Using the centerline technique, radiology consultants (n = 4) and residents (n = 3) determined maximal abdominal aortic diameter. The limits of agreement with the mean (LOAM) was used to access observer agreement. LOAM represents how much a measurement by a single observer may plausibly deviate from the mean of all observers on the specific subject. RESULTS: Observers completed 1400 measurements encompassing repeated CTA and ULDNC-CT measurements. The mean diameter was 24.0 and 25.0 mm for CTA and ULDNC-CT, respectively, yielding a significant but minor mean difference of 1.0 mm. The 95% LOAM reproducibility was similar for CTA and ULDNC-CT (2.3 vs 2.3 mm). In addition, the 95% LOAM and mean diameters were similar for CTA and ULDNC-CT when observers were grouped as consultants and residents. CONCLUSIONS: Ultra-low-dose non–contrast CT exhibited similar accuracy and reproducibility of measurements compared with CTA for assessing maximal abdominal aortic diameter supporting that ULDNC-CT can be used interchangeably with CTA in the lower range of aortic sizes

Postpartum and non-postpartum depression: a population-based matched case-control study comparing polygenic risk scores for severe mental disorders

It remains inconclusive whether postpartum depression (PPD) and depression with onset outside the postpartum period (MDD) are genetically distinct disorders. We aimed to investigate whether polygenic risk scores (PGSs) for major mental disorders differ between PPD cases and MDD cases in a nested case-control study of 50,057 women born from 1981 to 1997 in the iPSYCH2015 sample in Demark. We identified 333 women with first-onset postpartum depression (PPD group), who were matched with 993 women with first-onset depression diagnosed outside of postpartum (MDD group), and 999 female population controls. Data on genetics and depressive disorders were retrieved from neonatal biobanks and the Psychiatric Central Research Register. PGSs were calculated from both individual-level genetic data and meta-analysis summary statistics from the Psychiatric Genomics Consortium. Conditional logistic regression was used to calculate the odds ratio (OR), accounting for the selection-related reproductive behavior. After adjustment for covariates, higher PGSs for severe mental disorders were associated with increased ORs of both PPD and MDD. Compared with MDD cases, MDD PGS and attention-deficit/hyperactivity disorder PGS were marginally but not statistically higher for PPD cases, with the OR of PPD versus MDD being 1.12 (95% CI: 0 .97–1.29) and 1.11 (0.97–1.27) per-standard deviation increase, respectively. The ORs of PPD versus MDD did not statistically differ by PGSs of bipolar disorder, schizophrenia, or autism spectrum disorder. Our findings suggest that relying on PGS data, there was no clear evidence of distinct genetic make-up of women with depression occurring during or outside postpartum, after taking the selection-related reproductive behavior into account

6-OHDA-induced dopaminergic neurodegeneration in <i>Caenorhabditis elegans</i> is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33

<div><p>Oxidative stress is linked to many pathological conditions including the loss of dopaminergic neurons in Parkinson’s disease. The vast majority of disease cases appear to be caused by a combination of genetic mutations and environmental factors. We screened for genes protecting <i>Caenorhabditis elegans</i> dopaminergic neurons from oxidative stress induced by the neurotoxin 6-hydroxydopamine (6-OHDA) and identified the <u>t</u>rans<u>t</u>hyretin-<u>r</u>elated gene <i>ttr-33</i>. The only described <i>C</i>. <i>elegans</i> transthyretin-related protein to date, TTR-52, has been shown to mediate corpse engulfment as well as axon repair. We demonstrate that TTR-52 and TTR-33 have distinct roles. TTR-33 is likely produced in the posterior arcade cells in the head of <i>C</i>. <i>elegans</i> larvae and is predicted to be a secreted protein. TTR-33 protects <i>C</i>. <i>elegans</i> from oxidative stress induced by paraquat or H₂O₂ at an organismal level. The increased oxidative stress sensitivity of <i>ttr-33</i> mutants is alleviated by mutations affecting the KGB-1 MAPK kinase pathway, whereas it is enhanced by mutation of the JNK-1 MAPK kinase. Finally, we provide genetic evidence that the <i>C</i>. <i>elegans</i> cell corpse engulfment pathway is required for the degeneration of dopaminergic neurons after exposure to 6-OHDA. In summary, we describe a new neuroprotective mechanism and demonstrate that TTR-33 normally functions to protect dopaminergic neurons from oxidative stress-induced degeneration, potentially by acting as a secreted sensor or scavenger of oxidative stress.</p></div

Drug discovery: Insights from the invertebrate Caenorhabditis elegans

Therapeutic drug development is a long, expensive, and complex process that usually takes 12–15 years. In the early phases of drug discovery, in particular, there is a growing need for animal models that ensure the reduction in both cost and time. Caenorhabditis elegans has been traditionally used to address fundamental aspects of key biological processes, such as apoptosis, aging, and gene expression regulation. During the last decade, with the advent of large-scale platforms for screenings, this invertebrate has also emerged as an essential tool in the pharmaceutical research industry to identify novel drugs and drug targets. In this review, we discuss the reasons why C. elegans has been positioned as an outstanding cost-effective option for drug discovery, highlighting both the advantages and drawbacks of this model. Particular attention is paid to the suitability of this nematode in large-scale genetic and pharmacological screenings. High-throughput screenings in C. elegans have indeed contributed to the breakthrough of a wide variety of candidate compounds involved in extensive fields including neurodegeneration, pathogen infections and metabolic disorders. The versatility of this nematode, which enables its instrumentation as a model of human diseases, is another attribute also herein underscored. As illustrative examples, we discuss the utility of C. elegans models of both human neurodegenerative diseases and parasitic nematodes in the drug discovery industry. Summing up, this review aims to demonstrate the impact of C. elegans models on the drug discovery pipeline.Fil: Giunti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Andersen, Natalia Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentin