Voluntary exercise-induced changes in β2-adrenoceptor signalling in rat ventricular myocytes

Regular exercise is beneficial to cardiovascular health. We tested whether mild voluntary exercise training modifies key myocardial parameters [ventricular mass, intracellular calcium ([Ca2+]i) handling and the response to β-adrenoceptor (β-AR) stimulation] in a manner distinct from that reported for beneficial, intensive training and pathological hypertrophic stimuli. Female rats performed voluntary wheel-running exercise for 6–7 weeks. The mRNA expression of target proteins was measured in left ventricular tissue using real-time reverse transcriptase-polymerase chain reaction. Simultaneous measurement of cell shortening and [Ca2+]i transients were made in single left ventricular myocytes and the inotropic response to β1- and β2-AR stimulation was measured. Voluntary exercise training resulted in cardiac hypertrophy, the heart weight to body weight ratio being significantly greater in trained compared with sedentary animals. However, voluntary exercise caused no significant alteration in the size or time course of myocyte shortening and [Ca2+]i transients or in the mRNA levels of key proteins that regulate Ca2+ handling. The positive inotropic response to β1-AR stimulation and the level of β1-AR mRNA were unaltered by voluntary exercise but both mRNA levels and inotropic response to β2-AR stimulation were significantly reduced in trained animals. The β2-AR inotropic response was restored by exposure to pertussis toxin. We propose that in contrast to pathological stimuli and to beneficial, intense exercise training, modulation of Ca2+ handling is not a major adaptive mechanism in the response to mild voluntary exercise. In addition, and in a reversal of the situation seen in heart failure, voluntary exercise training maintains the β1-AR response but reduces the β2-AR response. Therefore, although voluntary exercise induces cardiac hypertrophy, there are distinct differences between its effects on key myocardial regulatory mechanisms and those of hypertrophic stimuli that eventually cause cardiac decompensation

Review of the Management of Pediatric Post-Concussion Syndrome—a Multi-Disciplinary, Individualized Approach

Purpose of reviewPost-concussion syndrome (PCS), when the patient's concussion symptoms last longer than 4-6 weeks, affects 10-30% of concussion patients. PCS presents a significant source of morbidity to patients and a management challenge to providers. In this review, we present the current evidence and best management approaches for pediatric PCS.Recent findingsThere is limited high-quality evidence in pediatric PCS. There is some evidence supporting pharmaceutical management of post-traumatic headaches, cognitive symptoms, and emotional symptoms. Vestibular-ocular dysfunction should be evaluated and managed appropriately. Neuropsychological recovery is expected, but requires appropriate attention to Return to Learn. Emotional symptoms are common in PCS and the evidence supports treatment with cognitive behavioral therapy. PCS presents a unique therapeutic challenge affecting multiple domains for patients-physical, sleep, cognitive, and emotional. Successful management of PCS requires a multi-disciplinary and individualized approach. There remains a significant need for further research, specifically looking into the outcomes and effective interventions in pediatric PCS

Can MRI biomarkers for hearing loss in enlarged vestibular aqueduct be measured reproducibly?

OBJECTIVE: Morphological features of an enlarged endolymphatic duct (ED) and sac (ES) are imaging biomarkers for genotype and hearing loss phenotype. We determine which biomarkers can be measured in a reproducible manner, facilitating further clinical prediction studies in enlarged vestibular aqueduct hearing loss.METHODS: A rater reproducibility study. Three consultant radiologists independently measured previously reported MRI ED &amp; ES biomarkers (ED midpoint width, maximal ED diameter closest to the vestibule, ES length, ES width and presence of ES signal heterogeneity) and presence of incomplete partition Type 2 from 80 ears (T2 weighted axial MRI). Interclass correlation coefficients (ICC) and Gwet's Agreement Coefficients (AC) were generated to give a measure of reproducibility for both continuous and categorical feature measures respectively.RESULTS: ES length, width and sac signal heterogeneity showed adequate reproducibility (ICC 95% confidence intervals 0.77-0.95, Gwet's AC for sac heterogeneity 0.64). When determining ED midpoint width, measurements from multiple raters are required for "good" reliability (ICC 95% CI 0.75-0.89). Agreement on the presence of incomplete partition Type 2 ranged from "moderate" to "substantial".CONCLUSIONS: Regarding MR imaging, the opinion of multiple expert raters should be sought when determining the presence of an enlarged ED defined by midpoint width. ED midpoint, ES length, width and signal heterogeneity have adequate reproducibility to be further explored as clinical predictors for audiological phenotype.ADVANCES IN KNOWLEDGE: We report which ED &amp; ES biomarkers are reproducibly measured. Researchers can confidently utilise these specific biomarkers when modelling progressive hearing loss associated with enlarged vestibular aqueduct.</p

Appendiceal involvement in pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2):a diagnostic challenge in the coronavirus disease (COVID) era

BACKGROUND: Many studies on pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS) have described abdominal findings as part of multisystem involvement, with limited descriptions of abdominal imaging findings specific to PIMS-TS.OBJECTIVE: To perform a detailed evaluation of abdominal imaging findings in children with PIMS-TS.MATERIALS AND METHODS: We performed a single-center retrospective study of children admitted to our institution between April 2020 and January 2021 who fulfilled Royal College of Paediatrics and Child Health criteria for PIMS-TS and who had cross-sectional abdominal imaging. We studied clinical data, abdominal imaging, laboratory markers, echocardiography findings, treatment and outcomes for these children. We also reviewed the literature on similar studies.RESULTS: During the study period, 60 PIMS-TS cases were admitted, of whom 23 required abdominal imaging. Most (74%) were from a Black, Asian or minority ethnic background and they had an average age of 7 years (range 2-14 years). All children had fever and gastrointestinal symptoms on presentation with elevated C-reactive protein, D-dimer and fibrinogen. Most had lymphopenia, raised ferritin and hypoalbuminemia, with positive severe acute respiratory syndrome coronavirus 2 immunoglobulin G antibodies in 65%. Free fluid (78%), right iliac fossa mesenteric inflammation (52%), and significantly enlarged mesenteric lymph nodes (52%) were the most common imaging findings. Appendiceal inflammation (30%) and abnormal distal ileum and cecum/ascending colon wall thickening (35%) were also common. All children responded well to medical management alone, with no mortality.CONCLUSION: In addition to free fluid, prominent lymphadenopathy, and inflammatory changes in the right iliac fossa, we found abnormal long-segment ileal thickening and appendicitis to be frequent findings. Recognition of appendiceal involvement as a component of the PIMS-TS spectrum should help clinicians avoid unnecessary surgical intervention as part of a multidisciplinary team approach.</p

UIF, a New mRNA Export Adaptor that Works Together with REF/ALY, Requires FACT for Recruitment to mRNA

Messenger RNA (mRNA) export adaptors play an important role in the transport of mRNA from the nucleus to the cytoplasm. They couple early mRNA processing events such as 5′ capping and 3′ end formation with loading of the TAP/NXF1 export receptor onto mRNA. The canonical adaptor REF/ALY/Yra1 is recruited to mRNA via UAP56 and subsequently delivers the mRNA to NXF1 [1]. Knockdown of UAP56 [2, 3] and NXF1 [4–7] in higher eukaryotes efficiently blocks mRNA export, whereas knockdown of REF only causes a modest reduction, suggesting the existence of additional adaptors [8–10]. Here we identify a new UAP56-interacting factor, UIF, which functions as an export adaptor, binding NXF1 and delivering mRNA to the nuclear pore. REF and UIF are simultaneously found on the same mRNA molecules, and both proteins are required for efficient export of mRNA. We show that the histone chaperone FACT specifically binds UIF, but not REF, via the SSRP1 subunit, and this interaction is required for recruitment of UIF to mRNA. Together the results indicate that REF and UIF represent key human adaptors for the export of cellular mRNAs via the UAP56-NXF1 pathway