Articles: human.
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Nerve growth factor (NGF)-R100E is a mutated form of human recombinant NGF that reduces the binding of NGF to its p75NTR receptor while retaining its affinity toward the TrkA receptor. Here, we used human wild type NGF and NGF-R100E knock-in mice to investigate the effects of this NGF mutation on inflammation-induced pain-related behaviors and bone loss. The hNGF-R100E mutation did not alter the nerve fiber density in the sciatic nerve, ankle joint synovium, and skin of naïve mice. ⋯ In conclusion, our study reveals that the hNGF-R100E mutation renders mice insensitive to inflammation-induced impact on joint loading and gait while preserving the development of the peripheral nociceptive neurons and sensitivity to punctate stimulation of the skin. Notably, the mutation uncovers a sex-dependent relationship between NGF and inflammation-induced bone loss. These findings offer valuable insights into NGF as a target for pain management and the interplay between NGF and bone architecture.
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Anesthesia and analgesia · Dec 2024
An Evaluation of the Transfer of Skills and Knowledge from Two World Federation of Societies of Anaesthesiologists Fellowship Programs.
Subspecialist training is an important part of developing human resources for health and for some learners, may require taking place in another, higher-resourced country. Despite effective learning of skills and knowledge in a different, more highly resourced context, transfer of these skills and knowledge back to a more poorly resourced context can be a challenge. We aimed to evaluate the transfer of skills and knowledge in 2 World Federation of Societies of Anaesthesiologists (WFSA) fellowship programs. ⋯ Our study found that the 2 fellowship programs had variable success in the transfer of learned skills and knowledge back to the fellows' "home" institutions. Contextual differences between the fellowship institution and the home institution were the main source of barriers to transfer, and fellows from different countries had diverse needs. Supporting the transfer of knowledge and skills should be an explicit goal of these fellowship programs, and as such, should be considered in the recruitment of fellows, curriculum development, and in how the success of a fellowship is evaluated. Curricula should not just focus on medical knowledge and skills, but also skills in leading change and in education.
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This study aimed to investigate the protective effect of pentoxifylline (PTX) on vascular endothelial dysfunction in uremia. The human aortic endothelial cells (HAECs) required for the experiments were all obtained from the National Collection of Authenticated Cell Cultures (Salisbury, UK). The permeability of HAECs was assessed. ⋯ The expression of NLRP3 (0.810 ± 0.032, P = 0.02) and caspase-1 (0.580 ± 0.041, P = 0.03) was increased, whereas the expression of ZO-1 (0.255 ± 0.038, P = 0.03) and VE-cadherin (0.0546 ± 0.053, P = 0.02) was decreased in the uremia group; compared with the healthy volunteer group, treated with PTX (NLRP3, 0.298 ± 0.042, P = 0.03; caspase-1, 0.310 ± 0.021, P = 0.03; ZO-1, 0.412 ± 0.028, P = 0.02; VE-cadherin, 0.150 ± 0.034, P = 0.02) and MCC950 (NLRP3, 0.432 ± 0.022, P = 0.03; caspase-1, 0.067 ± 0.031, P > 0.05; ZO-1, 0.457 ± 0.026, P = 0.03; VE-cadherin, 0.286 ± 0.017, P = 0.03) these lessened this trend. Pentoxifylline promoted the HAEC permeability mediated by uremic toxins (1.507 ± 0.012, P = 0.02). In conclusion, PTX enhances the release of HMGB1, which is dependent on NLRP3 activation, and consequently exerts positive effects on interconnecting proteins, ultimately leading to an improvement in vascular permeability.
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The urocortin 1 (UCN1)-expressing centrally projecting Edinger-Westphal (EWcp) nucleus is influenced by circadian rhythms, hormones, stress, and pain, all known migraine triggers. Our study investigated EWcp's potential involvement in migraine. Using RNAscope in situ hybridization and immunostaining, we examined the expression of calcitonin gene-related peptide (CGRP) receptor components in both mouse and human EWcp and dorsal raphe nucleus (DRN). ⋯ Targeted ablation of EWcp/UCN1 neurons induced hyperalgesia. A positive functional connectivity between EW and STN as well as DRN has been identified by functional magnetic resonance imaging. The presented data strongly suggest the regulatory role of EWcp/UCN1 neurons in migraine through the STN and DRN with high translational value.
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Thalamic pain can be understood as a network reorganization disorder. This study aimed to investigate functional connectivity (FC) in human patients and a macaque model of thalamic pain. In humans, resting-state FC was compared between patients with thalamic pain and healthy individuals. ⋯ Therefore, the present results suggest that the FC changes in the regions associated with emotion, memory, motivation, and reward are part of the underlying mechanisms of thalamic pain onset present in both human patients and model macaques. This cross-species convergence provides new insights into the neurological mechanisms underlying thalamic pain, paving the way for further studies and the development of therapeutic strategies. PERSPECTIVE: This article presents that the FC changes in the regions associated with emotion, motivation, and reward are part of the underlying mechanisms of thalamic pain in humans and macaques.