Accelerated Development With Increased Bone Mass and Skeletal Response to Loading Suggest Receptor Activity Modifying Protein-3 as a Bone Anabolic Target

Knockout technologies provide insights into physiological roles of genes. Studies initiated into endocrinology of heteromeric G protein-coupled receptors included deletion of receptor activity modifying protein-3, an accessory protein that alters ligand selectivity of calcitonin and calcitonin-like receptors. Initially, deletion of Ramp3-/- appeared phenotypically silent, but it has emerged that mice have a high bone mass phenotype, and more subtle alterations to angiogenesis, amylin homeostasis, and a small proportion of the effects of adrenomedullin on cardiovascular and lymphatic systems. Here we explore in detail, effects of Ramp3-/- deletion on skeletal growth/development, bone mass and response of bone to mechanical loading mimicking exercise. Mouse pups lacking RAMP3 are healthy and viable, having accelerated development of the skeleton as assessed by degree of mineralisation of specific bones, and by microCT measurements. Specifically, we observed that neonates and young mice have increased bone volume and mineralisation in hindlimbs and vertebrae and increased thickness of bone trabeculae. These changes are associated with increased osteoblast numbers and bone apposition rate in Ramp3-/- mice, and increased cell proliferation in epiphyseal growth plates. Effects persist for some weeks after birth, but differences in gross bone mass between RAMP3 and WT mice lose significance in older animals although architectural differences persist. Responses of bones of 17-week old mice to mechanical loading that mimics effects of vigorous exercise is increased significantly in Ramp3-/- mice by 30% compared with WT control mice. Studies on cultured osteoblasts from Ramp3-/- mice indicate interactions between mRNA expression of RAMPs1 and 3, but not RAMP2 and 3. Our preliminary data shows that Ramp3-/- osteoblasts had increased expression β-catenin, a component of the canonical Wnt signalling pathway known to regulate skeletal homeostasis and mechanosensitivity. Given interactions of RAMPs with both calcitonin and calcitonin-like receptors to alter ligand selectivity, and with other GPCRs to change trafficking or ligand bias, it is not clear whether the bone phenotype of Ramp3-/- mice is due to alterations in signalling mediated by one or more GPCRS. However, as antagonists of RAMP-interacting receptors are growing in availability, there appears the likelihood that manipulation of the RAMP3 signalling system could provide anabolic effects therapeutically.

Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease

Objective:Owing to the lack of long-term observations and/or comprehensive adjustment for confounding factors, reliable conclusions regarding long-term effects of exercise and regular physical activity in Parkinson’s disease (PD) have yet to be drawn. Here, using data from the Parkinson’s Progression Markers Initiative study that includes longitudinal and comprehensive evaluations of many clinical parameters, we examined the long-term effects of regular physical activity and exercise habits on the course of PD.Methods:In this observational cohort study, we primarily used the multivariate linear mixed-effects models to analyze the interaction effects of their regular physical activity and moderate-to-vigorous exercise levels, measured through the Physical Activity Scale for the Elderly questionnaire, on the progression of clinical parameters, after adjusting for age, sex, levodopa-equivalent dose, and disease duration. We also calculated bootstrapping 95% confidence intervals (CIs), and conducted sensitivity analyses using the multiple imputation method and subgroup analyses using the propensity score matching to match for all baseline background factors.Results:237 early PD patients [median (interquartile range); age, 63.0 (56.0–70.0) years; Male, 69.2%; follow-up duration, 5.0 (4.0–6.0) years] were included. Regular physical activity and moderate-to-vigorous exercise levels at the baseline did not significantly affect the subsequent clinical progression of PD. However, average regular overall physical activity levels over time were significantly associated with slower deterioration of postural and gait stability [standardized fixed-effects coefficients of the interaction term (βinteraction) = -0.10 (95% CI, -0.14 to -0.06)], activities of daily living [βinteraction = 0.08 (95% CI, 0.04 to 0.12)], and processing speed [βinteraction = 0.05 (95% CI, 0.03 to 0.08)] in PD patients. Moderate-to-vigorous exercise levels were preferentially associated with slower decline of postural and gait stability [βinteraction = -0.09 (95% CI, -0.13 to -0.05)] and work-related activity levels were primarily associated with slower deterioration of processing speed [βinteraction = 0.07 (95% CI, 0.04 to 0.09)]. Multiple imputation and propensity score matching confirmed the robustness of our results.Conclusions:In the long-term, the maintenance of high regular physical activity levels and exercise habits was robustly associated with better clinical course of PD, with each type of physical activity having different effects.Trial Registration Information:Clinicaltrials.gov (NCT01176565). A link to trial registry page is https://clinicaltrials.gov/ct2/show/NCT01141023.Classification of Evidence:This study provides Class II evidence that sustained increase in overall regular physical activity levels in patients with early Parkinson disease was associated with slower decline of several clinical parameters.

Effect of 3 Months Exercise on Ovarian Reserve and Ovulatory Status of Premenopausal Students of Nnamdi Azikiwe University, Nnewi Campus

There is a traditional believe that if premenopausal women engage in prolonged physical exercise, they are likely to have infertility. This study assessed the effect of prolonged moderate – vigorous exercise on ovarian reserve and ovulatory status in premenopausal students of Nnamdi Azikiwe University, Nnewi Campus. The objectives were to determine the effect of moderate – vigorous intensity exercise on Anti-Mullerian hormone (AMH), day 3 Follicle stimulating hormone (FSH), Luteinizing Hormone (LH), day 3 Estrogen, day 21 Estrogen, and day 21 Progesterone levels in premenopausal women. This was a prospective comparative study involving 80 participants aged between 19 and 25 years, randomly selected and assigned to exercise group and control group. The exercise group comprised 40 participants who engaged in moderate – vigorous intensity exercise using elliptical bike for 30 minutes, five days a week for 3 months; however, 30 individuals completed the exercise. The control group comprised of 40 individuals that did not do exercise but 30 individuals completed the study. Blood (8ml) was collected from each of the participants at baseline, 1 month, 2 months, and 3 months. AMH, FSH, LH, Estrogen and Progesterone levels were analyzed using enzyme- linked Immunosorbent assay (ELISA) method. Results were regarded as significant at p˂ 0.05. In the exercise group, the serum level of day 3 FSH, LH, Estrogen were significantly lower from 7.27±0.77 mIU/ml, 7.00±0.77 mIU/ml, 36.33±5.13 pg/ml respectively at baseline to 5.62±0.48 mIU/ml, 5.36±0.80 mIU/ml, 21.36±4.34 pg/ml respectively after 3 months of exercise while there was significantly higher levels of AMH and day 21 progesterone after 3 months of exercise compared with the baseline and respective control (p<0.05). Prolonged Moderate-to-vigorous exercise may enhance fertility and well-being of premenopausal women. Key words: Anti-Mullerian hormone (AMH), day 3 Follicle stimulating hormone (FSH), Luteinizing Hormone (LH), day 3 Estrogen, day 21 Estrogen, day 21 Progesterone, moderate – vigorous exercise, ovarian reserve, ovulatory status, premenopausal women.

The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle

Excitation-contraction coupling (ECC) is the process by which electrical excitation of muscle is converted into force generation. Depolarization of skeletal muscle resting potential contributes to failure of ECC in diseases such as periodic paralysis, intensive care unit acquired weakness and possibly fatigue of muscle during vigorous exercise. When extracellular K+ is raised to depolarize the resting potential, failure of ECC occurs suddenly, over a narrow range of resting potentials. Simultaneous imaging of Ca2+ transients and recording of action potentials (APs) demonstrated failure to generate Ca2+ transients when APs peaked at potentials more negative than –30mV. An AP property that closely correlated with failure of the Ca2+ transient was the integral of AP voltage with respect to time. Simultaneous recording of Ca2+ transients and APs with electrodes separated by 1.6mm revealed AP conduction fails when APs peak below –21mV. We hypothesize propagation of APs and generation of Ca2+ transients are governed by distinct AP properties: AP conduction is governed by AP peak, whereas Ca2+ release from the sarcoplasmic reticulum is governed by AP integral. The reason distinct AP properties may govern distinct steps of ECC is the kinetics of the ion channels involved. Na channels, which govern propagation, have rapid kinetics and are insensitive to AP width (and thus AP integral) whereas Ca2+ release is governed by gating charge movement of Cav1.1 channels, which have slower kinetics such that Ca2+ release is sensitive to AP integral. The quantitative relationships established between resting potential, AP properties, AP conduction and Ca2+ transients provide the foundation for future studies of failure of ECC induced by depolarization of the resting potential.

Assessment of Shift Work and Its Health Related Behaviors Among Employees of Petrochemical Company, Saudi Arabia, 2021 (Preprint)

BACKGROUND Shift work has been reported to lead to adverse health effects and is receiving increased attention. OBJECTIVE The study aimed to understand the relationship between shift work schedules and health behaviours among day-shift workers and rotating day-evening-shift workers and to detect the difference between day-shift work or fixed day-shift and rotating day-evening-shift employees. METHODS A cross-sectional study was conducted among employees of Petrochemical Company during 2021. A self-administered questionnaire was used to collect the data. It consisted of two parts demographic data and General Health Questionnaire (GHQ-28). RESULTS Out of 126 employees, 58 (46.0%) were from group age 41-50 years, 55 (43.7%) were overweight and 41 (32.5%) were obese, 38 (30.2%) were smokers, 99 (78.6%) worked in fixed shift. Two thirds 94 (74.6%) reported 6-8 sleeping hours per day, where 41 (32.5%) reported that they were satisfactory about overall quality of sleep and 40 (31.7%) were somewhat unsatisfactory, 62 (49.2%) reported “playing regular moderate to vigorous exercise”. There was no significant relation between shifts type and general health status (p =0.122). There was a significant association between shift types and the following ; age, BMI, education, nationality, household income, Working experience, Chronic diseases, Frequency of shift work, and Overall amount of sleep per day (p<0.0001, p0.017, p=0.027, p<0.0001, p0.042, p=0.002, p=0.024, p<0.0001, and p=0.044). CONCLUSIONS In the current study, rotating shifts were associated with extra sleeping hours, normal weight and having exercise. There was no significant differences in general health between workers in different shift schedules. Further studies need to be conducted to gather more information in order to decrease the additional health burden allied to non-standard work-schedules.

The association between binge eating and health behaviors during times of high and low stress among first-year university students

The current study examined binge eating behaviors among first-year undergraduate students over the academic year (September 2019, November 2019, January 2020, March 2020), and if between and within person effects of physical activity and sleep impact binge eating behaviours during times of higher-and lower-stress (n=394, Mage=18.6). Participants completed online surveys of moderate and vigorous exercise, hours and quality of sleep, and binge eating behaviours four times over the academic year. Results of multilevel models revealed relatively stable binge eating scores across the academic year. We did not find evidence of robust associations between exercise and sleep and binge eating behaviors during times of high and low stress over the academic year. Large increases in vigorous physical activity may be effective in reducing binge eating behaviors among women. These findings suggest that the effect of exercise on binge eating behaviours may be smaller than previous research suggests and that targeted exercise intervention is needed to see meaningful changes in binge eating behaviors.

Trigger Factors for Spontaneous Intracerebral Hemorrhage: A Case-Crossover Study

Background and Purpose: Whether certain activities can trigger spontaneous intracerebral hemorrhage (ICH) remains unknown. Insights into factors that trigger vessel rupture resulting in ICH improves knowledge on the pathophysiology of ICH. We assessed potential trigger factors and their risk for ICH onset. Methods: We included consecutive patients diagnosed with ICH between July 1, 2013, and December 31, 2019. We interviewed patients on their exposure to 12 potential trigger factors (eg, Valsalva maneuvers) in the (hazard) period soon before onset of ICH and their normal exposure to these trigger factors in the year before the ICH. We used the case-crossover design to calculate relative risks (RR) for potential trigger factors. Results: We interviewed 149 patients (mean age 64, 66% male) with ICH. Sixty-seven (45%) had a lobar hemorrhage, 60 (40%) had a deep hemorrhage, 19 (13%) had a cerebellar hemorrhage, and 3 (2%) had an intraventricular hemorrhage. For ICH in general, there was an increased risk within an hour after caffeine consumption (RR=2.5 [95% CI=1.8–3.6]), within an hour after coffee consumption alone (RR=4.8 [95% CI=3.3–6.9]), within an hour after lifting >25 kg (RR=6.6 [95% CI=2.2–19.9]), within an hour after minor head trauma (RR=10.1 [95% CI=1.7–60.2]), within an hour after sexual activity (RR=30.4 [95% CI=16.8–55.0]), within an hour after straining for defecation (RR=37.6 [95% CI=22.4–63.4]), and within an hour after vigorous exercise (RR=21.8 [95% CI=12.6–37.8]). Within 24 hours after flu-like disease or fever, the risk for ICH was also increased (RR=50.7 [95% CI=27.1–95.1]). Within an hour after Valsalva maneuvers, the RR for deep ICH was 3.5 (95% CI=1.7–6.9) and for lobar ICH the RR was 2.0 (95% CI=0.9–4.2). Conclusions: We identified one infection and several blood pressure related trigger factors for ICH onset, providing new insights into the pathophysiology of vessel rupture resulting in ICH.

ECAST Syndrome (Exercise Collapse Associated with Sickle Cell Trait): First Knock of Sickle Cell in a Young Bodybuilder

ECAST Or exercise collapse associated with sickle cell trait is a rare phenomenon associated with sickle cell trait and is an important presentation of sickle cell disease in sports medicine. Collapse is seen following vigorous physical activity, which is due to excessive heat, dehydration and other factors associated with physical exercise. This rare syndrome is often missed by the treating physicians as a result of a lack of knowledge about this rare entity leading to massive underreporting. It is important to identify ECAST as a cause of the collapse in young athletes to prevent mortality and morbidity and in order to provide prompt treatment. We report a case of a 25- year-old young male who was a bodybuilder and reported to the gym after a one-year-long break due to lockdown restrictions of COVID19. After a vigorous exercise session, he collapsed in the gym and was brought to the emergency department. After proper history taking and examination, he was suspected to be a case of ECAST due to a history of a similar episode three years back which was treated as a case of exertional syncope with intravenous fluid therapy and a family history of Sickle cell trait with his mother and father both having sickle cell AS Pattern. Ultimately our patient turned out to be a case of Sickle Cell Trait with evidence of AS pattern on Hb electrophoresis and a small-sized spleen visualized on CT Scan of the abdomen. The patient was managed successfully with intravenous fluids and blood transfusion and was discharged in a stable condition. He was counseled about moderating his exercise and is doing well on follow-up.

Metabolic Syndrome and Functional Fitness Abilities

Background: It has been pointed out that moderate to vigorous exercise improves metabolic syndrome (MetS) criteria; however, studies on functional fitness in subjects with MetS are scarce. Aim: This study aimed to assess functional fitness abilities in MetS and non-MetS subjects. Methods: Cross-sectional study. Participants living in the Balearic Islands (n = 477, 52% men, 55–80 years old) with MetS (n = 333) and without MetS (n = 144). Anthropometric, socioeconomic and lifestyle characteristics were measured, and blood samples were collected. Functional fitness tests included: one leg balance, standing and sitting handgrip, 30-s chair stand, arm curl, chair sit-and-reach, back scratch, 8-foot time up-and-go, 30-m walk, and 6-min walk tests. A Functional Fitness Score was created from tests that measured agility and dynamic balance, static balance, lower-and-upper body strength, lower-and-upper body flexibility, aerobic endurance, and speed. Results: All functional fitness tests were lower in MetS subjects, except for back scratch and standing handgrip test. After adjusting for possible confounders (sex, age, civil status, education level, leisure-time physical activity) MetS subjects were more likely to be below average for a sex and age specific cut-off value of one leg balance (Odds Ratio, OR: 2.37; 95% Confidence Interval, CI: 1.25–4.48), chair stand (OR: 2.30; 95% CI: 1.26–3.20), arm curl (OR: 3.43; 95% CI:1.90–6.26), back scratch (OR: 3.49; 95% CI: 2.31–5.91), 8-foot up-&-go (OR: 13.03; 95% CI: 6.66–25.55), 30-m walk (OR: 8.10; 95% CI: 4.33–15.57) and 6-min walk test (OR: 3.28; 95% CI: 1.76–6.52), whereas they were more likely to be above average for sitting handgrip test (OR:1.69; 95% CI:1.21–2.95). Functional Fitness Score was lower in MetS subjects (5.44 ± 2.40 vs. 7.04 ± 1.72, p < 0.001), independently of sex and age. Conclusion: MetS participants showed lower functional fitness abilities and lower Functional Fitness Score than non-MetS peers, independently of sex, age, body mass index and waist circumference, showing lower ability to perform everyday activities safely and independently.