Jameshorne7610

Melatonin (MLT) levels fluctuate according to the external light/dark cycle in both diurnal and nocturnal mammals. We previously demonstrated that MT2 receptor knockout (MT2 -/- ) mice show a decreased non-rapid eye sleep over 24-hr and increased wakefulness during the inactive (light) phase. Here, we investigated the role of MT2 receptors in physiological light/dark cycle fluctuations in the activity of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons and anxiety- and depression-like behaviour. We found that the 5-HT burst-firing activity was tonically reduced across the whole 24-hr in MT2 -/- mice. Importantly, the physiological changes in the spontaneous firing activity of DRN 5-HT neurons during the light/dark cycle were nullified in MT2 -/- mice, with an higher DRN 5-HT neural firing activity during the light phase in MT2 -/- mice. The role of MT2 receptors over DRN 5-HT neurons was confirmed by acute pharmacological studies in which the selective MT2 receptors agonist UCM1014 dose-dependently inhibited DRN 5-HT activity, mostly during the dark phase. Compared with WT, MT2 -/- mice displayed an anxiety-like phenotype in the novelty suppressed feeding and in the light/dark box tests; while anxiety levels in the light/dark box test were lower during the dark than the light phase in WT mice, the opposite was seen in MT2 -/- mice. No differences were observed for depression-like behavior in the forced swim and in the sucrose preference tests in MT2 -/- mice. These results suggest that MT2 receptor genetic inactivation impacts 5-HT neurotransmission and interferes with anxiety levels by perturbing the light/dark pattern. This article is protected by copyright. All rights reserved.BACKGROUND Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system. OBJECTIVES To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP. METHODS Twenty-seven families were screened for germline variants in eight XP-related genes. RESULTS All patients (N= 32) were diagnosed with bi-allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251-1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7 years. ERCC2/XPD, DDB2/XPE, and ERCC5/XPG variants were found in a few patients. Aside from melanoma and non-melanoma skin tumors, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovary carcinoma. CONCLUSIONS We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP-related genes, unexpected non-skin cancer lesions, and an anticipation of the clinical manifestation in POLH/XPV cases were also described. This article is protected by copyright. All rights reserved.Postoperative exercise has been found able to accelerate bone-tendon (B-T) healing. In this study, we systematically compared tendon-to-bone healing in mice subjected to postoperative treadmill exercise and free cage recovery in a murine rotator cuff repair model. Specifically, C57BL/6 mice underwent unilateral supraspinatus tendon (SST) detachment and repair were randomly allocated into treadmill group and control group. Treadmill group received daily treadmill running initiated from postoperative day 7 while the control group was allowed free cage activity. Mice were euthanized at postoperative 4 and 8 weeks for synchrotron radiation micro-computed tomography (SR-μCT), histology and biomechanical tests to investigate the effect of treadmill running on B-T healing. The results indicated that treadmill running initiated at day 7 postoperatively was able to accelerate B-T healing, as evidenced by better tendon-to-bone maturation and increased mechanical property. Recent studies show that peripheral neuropeptides are closely associated with musculoskeletal tissue repair. We furtherly conducted quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining to investigate the temporal-spatial expression of calcitonin gene-related peptide (CGRP), substance P (SP), and peripheral neuropeptide Y (NPY) to verify whether they are related to rotator cuff healing. Our results show increased expression of CGRP, SP, and NPY at the healing site under the effect of mechanical stimulation. In conclusion, delayed postoperative exercise with moderate strength appears to accelerate the early phase of B-T healing, a process that may prove to be linked to increased expression of periphery neuropeptides known to play a role in tissue healing. © 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.The extension of the human lifespan has not translated into a parallel extension of a healthy lifespan (or healthspan). Cognitive impairment and dementia are the most common diagnoses that impact the healthspan as we age. This article is protected by copyright. All rights reserved.BACKGROUND Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). read more Animal studies reveal networks of microvessels linking brain-meninges-bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker in extra-axial tissues in migraine with visual aura. METHODS We used simultaneously acquired 11 C-PBR28 PET/MRI data of 18 kDa translocator protein (an inflammatory marker) in MWA patients (n = 11) who experienced headaches and visual aura in the preceding month. We measured mean tracer uptake (SUVR) in four regions of interest comprising the meninges plus the adjacent overlying skull bone (parameningeal tissues, PMT). These data were compared to healthy controls and patients with pain (chronic low-back pain, CLBP). RESULTS MWA had significantly higher mean SUVR in PMT overlying occipital cortex than both other groups, though not in the PMT overlying three other cortical areas.