Duchenne muscular dystrophy is characterized by muscle wasting and decreased aerobic metabolism. Exercise and blocking of myostatin/activin signaling may independently or combined counteract muscle wasting and dystrophies. The effects of myostatin/activin blocking using soluble activin receptor-Fc (sActRIIB-Fc) administration and wheel running were tested alone or in combination for 7 weeks in dystrophic mdx mice. Expression microarray analysis revealed decreased aerobic metabolism in the gastrocnemius muscle of mdx mice compared to healthy mice. This was not due to reduced home-cage physical activity, and was further downregulated upon sActRIIB-Fc treatment in enlarged muscles. However, exercise activated pathways of aerobic metabolism and counteracted the negative effects of sActRIIB-Fc. Exercise and sActRIIB-Fc synergistically increased expression of major urinary protein, but exercise blocked sActRIIB-Fc induced phosphorylation of STAT5 in gastrocnemius muscle. In conclusion, exercise alone or in combination with myostatin/activin blocking corrects aerobic gene expression profiles of dystrophic muscle toward healthy wild type mice profiles.
OBJECT.: There is an unmet clinical need to develop neuroprotective agents for neurosurgical and endovascular procedures that require transient cerebral artery occlusion. The aim in this study was to explore the effects of a single dose of recombinant human erythropoietin (rhEPO) before middle cerebral artery (MCA) occlusion in a focal cerebral ischemia/reperfusion model.
G-protein-coupled receptors (GPCRs) are the most abundant receptors in the heart and therefore are common targets for cardiovascular therapeutics. The activated GPCRs transduce their signals via heterotrimeric G-proteins. The four major families of G-proteins identified so far are specified through their ?-subunit: G?i, G?s, G?q and G12/13. G?i-proteins have been reported to protect hearts from ischemia reperfusion injury. However, determining the individual impact of G?i2 or G?i3 on myocardial ischemia injury has not been clarified yet. Here, we first investigated expression of G?i2 and G?i3 on transcriptional level by quantitative PCR and on protein level by immunoblot analysis as well as by immunofluorescence in cardiac tissues of wild-type, G?i2-, and G?i3-deficient mice. G?i2 was expressed at higher levels than G?i3 in murine hearts, and irrespective of the isoform being knocked out we observed an up regulation of the remaining G?i-protein. Myocardial ischemia promptly regulated cardiac mRNA and with a slight delay protein levels of both G?i2 and G?i3, indicating important roles for both G?i isoforms. Furthermore, ischemia reperfusion injury in G?i2- and G?i3-deficient mice exhibited opposite outcomes. Whereas the absence of G?i2 significantly increased the infarct size in the heart, the absence of G?i3 or the concomitant upregulation of G?i2 dramatically reduced cardiac infarction. In conclusion, we demonstrate for the first time that the genetic ablation of G?i proteins has protective or deleterious effects on cardiac ischemia reperfusion injury depending on the isoform being absent.
The importance of adequate levels of muscle size and function and physical activity is widely recognized. Myostatin/activin blocking increases skeletal muscle mass but may decrease muscle oxidative capacity and can thus be hypothesized to affect voluntary physical activity. Soluble activin receptor IIB (sActRIIB-Fc) was produced to block myostatin/activins. Modestly dystrophic mdx mice were injected with sActRIIB-Fc or PBS with or without voluntary wheel running exercise for 7 wk. Healthy mice served as controls. Running for 7 wk attenuated the sActRIIB-Fc-induced increase in body mass by decreasing fat mass. Running also enhanced/restored the markers of muscle oxidative capacity and autophagy in mdx mice to or above the levels of healthy mice. Voluntary running activity was decreased by sActRIIB-Fc during the first 3-4 wk correlating with increased body mass. Home cage physical activity of mice, quantified from the force plate signal, was decreased by sActRIIB-Fc the whole 7-wk treatment in sedentary mice. To understand what happens during the first weeks after sActRIIB-Fc administration, when mice are less active, healthy mice were injected with sActRIIB-Fc or PBS for 2 wk. During the sActRIIB-Fc-induced rapid 2-wk muscle growth period, oxidative capacity and autophagy were reduced, which may possibly explain the decreased running activity. These results show that increased muscle size and decreased markers of oxidative capacity and autophagy during the first weeks of myostatin/activin blocking are associated with decreased voluntary activity levels. Voluntary exercise in dystrophic mice enhances the markers of oxidative capacity and autophagy to or above the levels of healthy mice.
Burnout is a stress-induced syndrome, which affects medical students. Some environmental and personal factors can favor burnout onset and its serious consequences as dropping out, sleep disorders, depression, and suicide. The motivation for choosing medicine is a personal aspect that can modulate the distress with academic demands.
To test if the use of a peaked cap protects children against sun radiation, allowing increased exercise performance, nineteen healthy children (10.3 ± 0.8 years old, 146.2 ± 6.9 cm, 36.8 ± 5.5 kg, 1.2 ± 0.1 m2 and 44.1 ± 2.8 mL.kg-1.min-1) took part in 4 experimental situations: 2 initial familiarization runs and 2 self-paced 6km runs (4 × 1.5 km exercise bouts with 3min rest intervals) one of them wearing a peaked cap (CAP) and another situation without the cap (NOCAP). The CAP and NOCAP situations were randomized. Exercise was performed outdoors 3-7 days apart. Environmental variables were measured every 10min, and physiological variables were measured before and after each run and during the rest intervals. Running velocity did not differ between CAP and NOCAP situations. The mean head temperature was reduced by 1.1 °C in the CAP situation (p < .05). Average skin temperature, mean heart rate, rate of perceived exertion and wet bulb and globe temperature did not differ between CAP and NOCAP. The decrease in the mean head temperature was not sufficient to alter running velocity.
The UNC5 receptor family are chemorepulsive neuronal guidance receptors with additional functions outside the central nervous system. Previous studies have implicated that the UNC5B receptor influences the migration of leukocytes into sites of tissue inflammation. Given that this process is a critical step during the pathophysiology of myocardial ischemia followed by reperfusion (IR) we investigated the role of UNC5B during myocardial IR. In initial in-vitro experiments, the functional inhibition of UNC5B resulted in a significant reduction of chemotactic migration of neutrophils. In-vivo, using a model of acute myocardial ischemia in UNC5B(+/-) and wild type (WT) animals, we found a significant reduction of infarct sizes in UNC5B(+/-) animals. This was associated with significantly reduced levels of troponin-I and IL-6 in UNC5B(+/-) mice. The repression of UNC5B using siRNA and the functional inhibition of UNC5B significantly dampened the extent of myocardial IR injury. Following depletion of neutrophils, we were not able to observe any further reduction in infarct size through functional inhibition of UNC5B in WT and UNC5B(+/-) mice. In summary our studies demonstrate an important role for UNC5B during myocardial IR injury, and that UNC5B might be a potential therapeutic target to control reperfusion injury in the future.
The conventional dobutamine (Dob) stress protocol for myocardial perfusion scintigraphy (MPS) is long, with frequent adverse effects, and generally requires atropine injection to reach target heart rate. Atropine is usually administered at the end of the protocol, when adverse effects are more frequent. Earlier atropine injection may be useful to shorten the stress protocol and reduce adverse effects. We sought to compare a Dob stress protocol with early atropine injection to a conventional Dob stress protocol in the same patients undergoing MPS. 30 patients underwent Dob-MPS with a conventional protocol (steps of 10, 20, 30 and 40 mcg/kg/min at 3 min intervals, adding atropine to the maximal Dob dose if necessary to achieve 85% of the age-corrected maximal predicted heart rate) and with an accelerated protocol with early atropine injection (at the end of the first stage). We compared stress duration, maximal heart rate (HR), percentage of maximal predicted HR, rate-pressure product, ST changes, MPS scores and the incidence of adverse effects between the 2 protocols. The accelerated protocol was shorter than the conventional protocol (7.1 ± 3.4 min vs. 11.8 ± 1.3 min; P < 0.0001), had the same efficacy to achieve hemodynamic parameters, without increasing adverse effects. The summed stress scores obtained by automatic analysis were similar in both protocols (6.3 ± 6.3 vs. 6.8 ± 6.3; P = NS) as well as the summed difference scores (2.5 ± 3.6 vs. 2.7 ± 3.4; P = NS). Early atropine injection during dobutamine stress protocol shortens stress duration. Our results suggest that patient safety and accuracy of MPS are unaltered, when compared to the conventional protocol, but further, larger studies are still necessary.
In this work we present a new electromechanical cardiac myocyte model tailored to reproduce the electrical and force generating activities of human ventricular myocytes. The model was created by coupling two existing models: the ten Tusscher electrophysiology model and the Rice myofilament mechanics model. The parameters of the new model were adjusted in order to replicate the available experimental data for human myocytes. The main challenges in this work were the strong feedbacks between the models, the high non-linearity of the models and mainly the lack of human data to make the adjustments.
The present study investigated whether the effects of central cholinergic stimulation on thermoregulation during exercise are modulated by arterial baroreceptors. Wistar rats were submitted to sinoaortic denervation (SAD) or sham denervation (SHAM) and then fitted with a chronic guide cannula into the lateral cerebral ventricle. After 2 weeks, a catheter was implanted into the ascending aorta, and a temperature sensor was implanted into the peritoneal cavity. Two days later, the rats were submitted to exercise on a treadmill at 18 m/min until fatigued. Thermoregulatory and cardiovascular responses were measured after injection of 2 ?L of 10mM physostigmine (Phy) or 0.15M NaCl solution (Sal) into the cerebral ventricle. In SHAM rats, Phy injection induced a greater exercise-induced increase in blood pressure and lower increase in heart rate than Sal treatment. In the SAD group, the attenuation of heart rate in response to Phy was blocked despite an exaggerated increase in blood pressure. SHAM rats treated with Phy had a higher increase in tail skin temperature compared to Sal injection (31.9 ± 0.4 °C Phy-SHAM vs. 30.1 ± 0.6 °C Sal-SHAM, 5 min after injection; p<0.05), resulting in a lower exercise-induced increase in core temperature. In contrast, SAD blocked the Phy injection effects in thermoregulatory responses during exercise (tail temperature: 30.1 ± 1.2 °C Phy-SAD vs. 29.5 ± 1.2 °C Sal-SAD, 5 min, p = 0.65). Therefore, we conclude that the enhancement of cutaneous heat loss induced by central cholinergic stimulation during exercise is mediated primarily by arterial baroreceptors.
Human paracoccidioidomycosis (PCM) is an endemic fungal disease of pulmonary origin. Follow-up of pulmonary lesions by image studies in an experimental model of PCM has not been previously attempted. This study focuses on defining patterns, topography and intensity of lung lesions in experimentally infected PCM mice by means of a comparative analysis between High Resolution Computed Tomography (HRCT) and histopathologic parameters.
Cocaine dependence has become a public health problem, developing a significant number of medical, psychological and social problems. Although there is no consensus regarding how to treat cocaine dependence, effective pharmacotherapy has a potentially major role to play as part of a broader treatment milieu. The anti-convulsant carbamazepine, a tricyclic medication that is widely used to treat a variety of neurological and psychiatric disorders, has been used for treatment of cocaine dependence, although its effectiveness has not been established.
The aim of this study was to evaluate the effectiveness of the non-surgical periodontal treatment in reducing the gingival crevicular fluid (GCF) levels of IL-18 from inflamed periodontal sites. Fourteen patients with periodontal disease were included, being 9 patients with chronic periodontitis (mean age: 48.8 SD ± 7.4 years) and 5 patients with gingivitis (mean age: 43.6 SD ± 11.8). The patients were divided in the following groups: gingivitis sites from periodontitis patients (sites GP), periodontitis sites from periodontitis patients (sites PP), and gingivitis sites from gingivitis patients (sites GG). Probing pocket depth (PPD), probing attachment level (AL), plaque index (PI) and gingival index (GI) were recorded, and gingival fluid samples were collected. The subjects received non-surgical treatment and were re-evaluated 30 days after treatment (day 30 AT). There was a significant reduction in PI in GG (1.0 ± 0.4 to 0.5 ± 0.2), GP (1.2 ± 0.3 to 0.5 ± 0.3), and in PP (1.3 ± 0.4 to 0.7 ± 0.3) 30 AT. There was also a significant reduction in the GI in GG (1.3 ± 0.3 to 0.7 ± 0.4). PPD reduced significantly in GG (2.4 ± 0.6 to 1.9 ± 0.1), and PP (6.7 ± 1.1 to 5.2 ± 0.9) 30 AT. When all the samples were analyzed together, there was a significant reduction in IL-18 (12.9 ± 7.2 to 10.0 ± 3.1). This study showed that non-surgical treatment was effective in reducing GCF levels of IL-18 from inflamed periodontal sites.
Loss of muscle mass and function occurs in various diseases. Myostatin blocking can attenuate muscle loss, but downstream signaling is not well known. Therefore, to elucidate associated signaling pathways, we used the soluble activin receptor IIb (sActRIIB-Fc) to block myostatin and activins in mice. Within 2 wk, the treatment rapidly increased muscle size as expected but decreased capillary density per area. sActRIIB-Fc increased muscle protein synthesis 1-2 days after the treatment correlating with enhanced mTORC1 signaling (phosphorylated rpS6 and S6K1, r = 0.8). Concurrently, increased REDD1 and eIF2B? protein contents and phosphorylation of 4E-BP1 and AMPK was observed. In contrast, proangiogenic MAPK signaling and VEGF-A protein decreased. Hippo signaling has been characterized recently as a regulator of organ size and an important regulator of myogenesis in vitro. The phosphorylation of YAP (Yes-associated protein), a readout of activated Hippo signaling, increased after short- and longer-term myostatin and activin blocking and in exercised muscle. Moreover, dystrophic mdx mice had elevated phosphorylated and especially total YAP protein content. These results show that the blocking of myostatin and activins induce rapid skeletal muscle growth. This is associated with increased protein synthesis and mTORC1 signaling but decreased capillary density and proangiogenic signaling. It is also shown for the first time that Hippo signaling is activated in skeletal muscle after myostatin blocking and exercise and also in dystrophic muscle. This suggests that Hippo signaling may have a role in skeletal muscle in various circumstances.
To assess the association of parents nutritional status, and dietary and sociodemographic factors with overweight/obesity in schoolchildren in Florianópolis Island, Santa Catarina State, Brazil, this cross-sectional epidemiological study examined 2,826 schoolchildren 7 to 14 years old, classified according to body mass index curves for age and sex recommended by the International Obesity Task Force. Data were analyzed using Poisson regression. The final model showed overweight/obesity in boys associated directly with fathers educational level, mothers age, and parents nutritional status, and inversely with mothers educational level, and number of daily meals. Among girls, it associated directly with parents nutritional status and the schoolchildrens age, and inversely with consumption of risk foods. The variables that associated with overweight/obesity differed between the sexes, except parents nutritional status. Boys and girls with both parents overweight or obese were, respectively, 80% and 150% more likely to exhibit the same diagnosis, indicating the need for interventions that include the family environment.
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