Background:Stroke remains the leading cause of long-term disability worldwide. Approximately 60% of individuals with chronic ischemic stroke experience persistent upper limb impairment that limits daily activities. The Repair Study aims to evaluate the safety and efficacy of vagus nerve stimulation (VNS) paired with rehabilitation in patients with chronic ischemic stroke in developing countries, including those with severe upper limb dysfunction, thereby generating evidence to support broader global application. Methods:It is a multicenter, triple-blinded, randomized controlled trial conducted across 13 centers in China. Up to 99 participants with upper limb motor impairment, 9 months to 10 years post-stroke, will be enrolled. All participants will undergo VNS implantation (Model G115R/G115, PINS Medical, Beijing, China) and be randomized 2:1 by a central randomization system to active stimulation (0.8 mA) or sham stimulation (0 mA) paired with standardized upper limb rehabilitation. The blinded phase includes 6 weeks of clinical therapy (three sessions/week, 90-120 min/session, ≥300 stimulation-movement repetitions) followed by 6 weeks of home-based therapy (30 min/day). Post-unblinding, the active VNS group continues home-based therapy, while the sham group receives 6 weeks of clinic-based therapy. Discussion:The primary outcome is the between-group difference in Fugl-Meyer Assessment for Upper Extremity scores at the end of 6 weeks of clinical therapy. Secondary outcomes include additional motor, functional, and quality-of-life measures. Safety will be assessed through adverse event monitoring. The Repair Study is a multicenter randomized controlled trial targeting chronic ischemic stroke populations in developing countries. It supplements the existing clinical evidence by enrolling patients with more servere motor dysfunction and being conducted in a developing country. Trial Registration:ClinicalTrials.gov: NCT06722677.

Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties. A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury. A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity, and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar, thus limiting axonal reentry into the host spinal cord. Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury. We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders, Schwann cells migrated for considerable distances in both rostral and caudal directions. Such Schwann cell migration led to enhanced axonal regrowth, including the serotonergic and dopaminergic axons originating from supraspinal regions, and promoted recovery of locomotor and urinary bladder functions. Importantly, the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury, even when treatment was delayed for 3 months to mimic chronic spinal cord injury. These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.

Vascular disruption is an early and critical event in spinal cord injury (SCI), but its contribution remains poorly understood. Using novel in vivo two-photon dual-dye imaging, we found simultaneous blood-spinal cord barrier (BSCB) leakage and venous dilation in both the injury epicenter and adjacent transitional segment after cervical SCI in rats. Notably, vascular permeability in the transitional zone preceded axonal and neuronal loss, revealing a therapeutic window. Systemic delivery of ferulic acid-glycol chitosan (FA-GC) nanoparticles, a membrane-sealant, rapidly stabilized the compromised vasculature, reduced neuronal loss in the transitional region, and improved forelimb muscle strength. These findings identified acute vascular leakage beyond the injury epicenter as a driver of secondary pathology and highlight early vascular stabilization as promising therapeutic strategy.

As an integral component of China's standardization system, rehabilitation medicine association standards play a pivotal role in regulating clinical practice, ensuring care quality, and nurturing rehabilitation professionals. Grounded in the Standardization Law of the People's Republic of China and drawing on the practical experience of standardization work by the Chinese Association of Rehabilitation Medicine, the formulation of the Guidelines for Standardization Work of Rehabilitation Medicine Association Standards aims to establish a systematic framework for the development of these standards and promote the standardized development of the rehabilitation medicine field. The guidelines detail the principles for the formulation of rehabilitation medicine association standards, scope of application, the qualifications of the entities involved, and the technical specifications. They highlight the importance of combining evidence-based practice with clinical experience in the development of these standards, clarify the fundamental principles of openness, transparency, and consensus, and outline the complete workflow from proposal, project approval, drafting, and solicitation of comments to final publication and periodic review, providing specific recommendations for the dissemination of the standards. By enhancing the quality of rehabilitation medicine association standards, the Guidelines will promote the standardization of rehabilitation medical services and advance the development of rehabilitation medicine in China.

We aimed to test whether heat acclimation (HA) would protect against aircraft noise (AN)-induced neurobehavioral and physiological disorders in mice. A total of 90 adult male mice were equally divided into three groups: control (c) plus non-AN group, c plus AN group, and HA plus AN group. Neurobehavioral performances included passive avoidance tasks (to assess learning and memory function), Y-maze tests (to assess spatial memory ability), and novel object recognition tests. Physiological functions included stress responses, inflammation, and oxidative stress, which were determined biochemically. The severity of endotoxemia was determined by measuring the serum levels of lipopolysaccharide. Both gut barrier and blood-brain barrier permeability were determined by fluorescein isothiocyanate and Evans Blue dye measurement, respectively. Compared to c+non-AN mice, the c+AN mice displayed neurobehavioral disorders along with exacerbated stress reactions, gut barrier disruption, endotoxemia, blood-brain barrier disruption, and hippocampal inflammation and oxidative stress. Compared to c+AN mice, the HA+AN mice had significantly less severity of all the abovementioned behavioral and physiological impairments. These results suggest that HA counteracts neurobehavioral and physiological disorders in mice exposed to aircraft noise.

As an integral component of China's standardization system, rehabilitation medicine group standards play a pivotal role in regulating clinical practice, ensuring care quality, and nurturing rehabilitation professionals. Grounded in the Standardization Law of the People's Republic of China and drawing on the practical experience of the Chinese Association of Rehabilitation Medicine, the Guidelines for the Standardization of Rehabilitation Medicine Group Standards aim to establish a systematic framework for the development of these standards and foster the field's regulated development. The Guidelines detail the principles for the formulation of rehabilitation medicine group standards, their scope, the qualifications of the entities involved, and the technical specifications. They highlight the importance of combining evidence-based practices with clinical experience in the development of these standards, articulate the foundational principles of openness, transparency, and consensus, and outline the comprehensive workflow from proposal to final publication and periodic review, providing concrete recommendations for the dissemination of the standards. By enhancing the quality of rehabilitation medicine group standards, the Guidelines will promote the standardization of rehabilitation medical services and advance the development of rehabilitation medicine in China.

Spinal cord injury (SCI) often leads to neuronal loss, axonal degeneration and behavioral dysfunction. We recently show that in vivo reprogramming of NG2 glia produces new neurons, reduces glial scaring, and ultimately leads to improved function after SCI. By examining endogenous neurons, we here unexpectedly uncover that NG2 glia reprogramming also induces robust axonal regeneration of the corticospinal tract and serotonergic neurons. Such reprogramming-induced axonal regeneration may contribute to the reconstruction of neural networks essential for behavioral recovery.

Objective: Dasatinib and quercetin (D & Q) have demonstrated promise in improving aged-related pathophysiological dysfunctions in humans and mice. Herein we aimed to ascertain whether the heat stress (HS)-induced cognitive deficits in aged or even young adult male mice can be reduced by D & Q therapy. Methods: Before the onset of HS, animals were pre-treated with D & Q or placebo for 3 consecutive days every 2 weeks over a 10-week period. Cognitive function, intestinal barrier permeability, and blood-brain barrier permeability were assessed. Results: Compared to the non-HS young adult male mice, the HS young adult male mice or the aged male mice had significantly lesser extents of the exacerbated stress reactions, intestinal barrier disruption, endotoxemia, systemic inflammation and oxidative stress, blood-brain barrier disruption, hippocampal inflammation and oxidative stress, and cognitive deficits evaluated at 7 days post-HS. All the cognitive deficits and other syndromes that occurred in young adult HS mice or in aged HS mice were significantly attenuated by D & Q therapy (P < 0.01). Compared to the young adult HS mice, the aged HS mice had significantly (P < 0.01) higher severity of cognitive deficits and other related syndromes. Conclusions: First, our data show that aged male mice are more vulnerable to HS-induced cognitive deficits than those of the young adult male mice. Second, we demonstrate that a combination of D and Q therapy attenuates cognitive deficits in heat stressed aged or young adult male mice via broad normalization of the brain-gutendotoxin axis function.

Postoperative cognitive dysfunction (POCD) is a common complication with no effective treatment in elderly patients. POCD, Alzheimer disease (AD), and many other cognitive diseases mostly involve neurotoxic microglia response, and recently, β2-microglobulin (B2M) has been suggested to play a pivotal role. A novel pyromeconic acid-styrene hybrid compound D30 was synthesized by our team and shown to be safe and effective in some neurodegenerative mouse models. In this study, we evaluated D30 on POCD and its potential mechanism. Fourteen- to 18-month-old male C57BL/6 mice were used to establish POCD through isoflurane anesthesia and surgery. The plasma of elderly patients was collected pre- and postoperatively. Primary mouse microglia were subjected to various stimulations in multiple experimental designs to imitate in vivo POCD-like conditions. Morris water maze, fear conditioning, western blot, immunofluorescent staining, and blood-brain barrier (BBB) permeability tests were conducted in this study. D30 administration significantly improved learning and memory in aged mice following POCD. Neurotoxic M1 microglia cells were dramatically increased following POCD, manifested as morphologically changing into fewer and shorter branches, enlarged somatic areas, and upregulated expression of iNOS and C1q. Notably, following POCD, B2M was significantly upregulated in the plasma and the brain. D30 treatment significantly suppressed these pathologic changes, by inhibiting the POCD-induced BBB breakdown while suppressing the surge of plasma B2M levels. D30 treatment suppressed POCD-induced surge of B2M and Aβ plaques in the brain and preserved adult hippocampal neurogenesis vulnerable to POCD. Furthermore, postoperative levels of B2M were significantly elevated over the preoperative levels in patients aged 80 years and over. In parallel with mouse plasma after POCD, the postoperative patient plasma was also much more effective at activating M1 microglia. Of note, this POCD plasma-induced activation of M1 microglia was largely prevented by D30 treatment. Taken together, by inhibiting the surge of plasma B2M, protecting BBB integrity, and reducing inflammatory response, D30 protected aged mice from B2M-facilitated POCD.

Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery and morphological changes following thoracic contusive spinal cord injury. After a 7-day recovery period after spinal cord injury, mice were assigned to either a trained group (10 weeks of voluntary running wheel or forced treadmill exercise) or an untrained group. Bi-weekly assessments revealed that the exercise-trained group, particularly the voluntary wheel exercise subgroup, displayed significantly improved locomotor recovery, more plasticity of dopaminergic and serotonin modulation compared with the untrained group. Additionally, exercise interventions led to gait pattern restoration and enhanced transcranial magnetic motor-evoked potentials. Despite consistent injury areas across groups, exercise training promoted terminal innervation of descending axons. In summary, voluntary wheel exercise shows promise for enhancing outcomes after thoracic contusive spinal cord injury, emphasizing the role of exercise modality in promoting recovery and morphological changes in spinal cord injuries. Our findings will influence future strategies for rehabilitation exercises, restoring functional movement after spinal cord injury.

Mounting preclinical evidence indicates that brain-gut-microbiota axis is involved in the pathogenesis of stress-related psychiatric disorders. Herein we aim to ascertain whether heat acclimatization (HA) protects against aircraft noise (AN)-induced cognitive deficits via overexpression of both HIF-1 and BDNF. Male C57 BL/6J mice were exposed to ambient temperature of 34oC for 4 weeks to induce HA. The levels of both HIF-1 and BDNF mRNA in the hippocampus and other vital organs were upgraded at the end of 4 weeks-HA but returned to their pre-HA levels at 2 weeks post-HA. All of the non-HA mice, HA mice and decay-HA mice were exposed to AN exposure (2 h daily for consecutive 7 days). The non-HA mice exposed to AN display cognitive deficits accompanied by exacerbaled stress reactions, increased upload of lipopolysaccharide translocation into the blood stream, gut barrier disruption, peripheral and central inflammation and oxidative stress, blood-brain-barrier disruption, and central inflammation and oxidative stress. Prior HA conferred significant protection against the AN-induced cognitive deficits and all its complications. However, at 2 weeks post-HA when the expression of both HIF-1 and BDNF mRNA in the hippocampus, heart and duodenum returned to their basal levels, the beneficial effects exerted by HA that occurred during the AN exposure were not significantly notable. These data suggeste that HIF-1-and BDNF-mediated HA protect against AN-induced cognitive deficits via normalizing the brain-gut-bacterial translocation axis function.

Tissue damage resulting from a spinal cord injury (SCI) is primarily driven by a robust neuroimmune/neuroinflammatory response. This intricate process is mainly governed by a multitude of cytokines and cell surface proteins in the central nervous system (CNS). However, the critical components of the neuroimmune/neuroinflammatory response during SCI are still not well-defined. In this study, we investigated the impact of CD1d, an MHC class I-like molecule mostly known for presenting lipid antigens to natural killer T (NKT) cells and regulating immune/inflammatory responses, on neuroimmune/neuroinflammatory responses induced by SCI. We observed an increased expression of CD1d on various cell types within the spinal cord, including microglia/macrophages, oligodendrocytes (ODCs), and endothelial cells (DCs), but not on neurons or astrocytes post-SCI. In comparison to wildtype (WT) mice, a T10 contusive SCI in CD1d knockout (CD1dKO or Cd1d -/- ) mice resulted in markedly reduced proinflammatory cytokine release, microglia/macrophage activation and proliferation. Following SCI, the levels of inflammatory cytokines and activation/proliferation of microglia/macrophages were dramatically reduced, while anti-inflammatory cytokines such as IL-4 and growth factors like VEGF were substantially increased in the spinal cord tissues of CD1dKO mice when compared to WT mice. In the post-acute phase of SCI (day 7 post-SCI), CD1dKO mice had a significantly higher frequency of tissue-repairing macrophages, but not other types of immune cells, in the injured spinal cord tissues compared to WT mice. Moreover, CD1d-deficiency protected spinal cord neuronal cells and tissue, promoting functional recovery after a SCI. However, the neuroinflammation in WT mouse spinal cords was independent of the canonical CD1d/NKT cell axis. Finally, treatment of injured mice with a CD1d-specific monoclonal antibody significantly enhanced neuroprotection and improved functional recovery. Therefore, CD1d promotes the proinflammatory response following a SCI and represents a potential therapeutic target for spinal cord repair. Significance Statement The cell surface molecule, CD1d, is known to be recognized by cells of the immune system. To our knowledge, this is the first observation that the CD1d molecule significantly contributes to neuroinflammation following a spinal cord injury (SCI) in a manner independent of the CD1d/NKT cell axis. This is important, because this work reveals CD1d as a potential therapeutic target following an acute SCI for which there are currently no effective treatments.

Recovery from spinal cord injury (SCI) and other central nervous system (CNS) trauma is hampered by limits on axonal regeneration in the CNS. Regeneration is restricted by the lack of neuron-intrinsic regenerative capacity and by the repressive microenvironment confronting damaged axons. To address this challenge, we have developed a therapeutic strategy that co-targets kinases involved in both extrinsic and intrinsic regulatory pathways. Prior work identified a kinase inhibitor (RO48) with advantageous polypharmacology (co-inhibition of targets including ROCK2 and S6K1), which promoted CNS axon growth in vitro and corticospinal tract (CST) sprouting in a mouse pyramidotomy model. We now show that RO48 promotes neurite growth from sensory neurons and a variety of CNS neurons in vitro, and promotes CST sprouting and/or regeneration in multiple mouse models of spinal cord injury. Notably, these in vivo effects of RO48 were seen in several independent experimental series performed in distinct laboratories at different times. Finally, in a cervical dorsal hemisection model, RO48 not only promoted growth of CST axons beyond the lesion, but also improved behavioral recovery in the rotarod, gridwalk, and pellet retrieval tasks. Our results provide strong evidence for RO48 as an effective compound to promote axon growth and regeneration. Further, they point to strategies for increasing robustness of interventions in pre-clinical models.

BACKGROUND:Androgenetic alopecia (AGA) has been one of the most common progressive hair loss in the world, which affects 80% of white males. To date, only minoxidil and finasteride have been approved by FDA for the treatment of AGA. However, limited therapeutic effect and the toxic adverse events of these drugs limit their applications. Therefore, it is still an urgent clinical problem to find effective therapeutic drugs and medication regimen. OBJECTIVE:The goal was to explore the efficacy and side effects of basic fibroblast growth factor (bFGF) combined with minoxidil in the treatment of male patients with early stage of androgenetic alopecia (AGA). METHODS:Using a randomized control method, 80 male patients with androgenetic alopecia in Hamilton grade II-IV were randomly divided into two groups, with 40 patients in each group. The Group A: 1 ml minoxidil for external use twice a day; Group B: 3500 IU basic fibroblast growth factor (bFGF) and 1 ml minoxidil for external use twice a day. The selected patients received global photograph evaluation before treatment, 3 months after treatment, and 6 months after treatment, and the curative effect was judged according to the changes in the area and degree of hair loss on the top of the head and anterior parietal area of the patients shown in the photographs before and after treatment. At the same time, each patient had a satisfaction questionnaire survey before treatment, 3 months after treatment, and 6 months after treatment. During the research period, the adverse reactions of the patients were recorded. RESULTS:After 3 months and 6 months of treatment, the effective rate of the two groups was statistically significant (p < 0.05), and the patients' hair conditions in the Group B improved significantly compared with those in the Group A. After 6 months of treatment, the difference in treatment satisfaction between the two groups was statistically significant (p < 0.05). The patients in the Group B were more satisfied than those in Group A. During the patient's medication, no serious adverse reactions occurred in the two groups, and the incidence of adverse reactions between the two groups was not statistically significant (p > 0.05). CONCLUSION:Compared with 5% minoxidil alone, the combination of basic fibroblast growth factor (bFGF) +5% minoxidil in the treatment of male patients with early stage of androgenetic alopecia improved treatment efficiency and patient satisfaction.

Alterations in phospholipids have long been associated with spinal cord injury (SCI). However, their specific roles and signaling cascades in mediating cell death and tissue repair remain unclear. Here we investigated whether alterations of cardiolipin (CL), a family of mitochondrion-specific phospholipids, play a crucial role in mitochondrial dysfunction and neuronal death following SCI. Lipidomic analysis was used to determine the profile of CL alteration in the adult rat spinal cord following a moderate contusive SCI at the 10th thoracic (T10) level. Cellular, molecular, and genetic assessments were performed to determine whether CL alterations mediate mitochondrial dysfunction and neuronal death after SCI, and, if so, whether reversing CL alteration leads to neuroprotection after SCI. Using lipidomic analysis, we uncovered CL alterations at an early stage of SCI. Over 50 distinct CL species were identified, of which 50% showed significantly decreased abundance after SCI. The decreased CL species contained mainly polyunsaturated fatty acids that are highly susceptible to peroxidation. In parallel, 4-HNE, a lipid peroxidation marker, significantly increased after SCI. We found that mitochondrial oxidative stress not only induced CL oxidation, but also resulted in CL loss by activating cPLA 2 to hydrolyze CL. CL alterations induced mitochondrial dysfunction and neuronal death. Remarkably, pharmacologic inhibition of CL alterations with XJB-5-131, a novel mitochondria-targeted electron and reactive oxygen species scavenger, reduced cell death, tissue damage and ameliorated motor deficits after SCI in adult rats. These findings suggest that CL alteration could be a novel mechanism that mediates injury-induced neuronal death, and a potential therapeutic target for ameliorating secondary SCI.

Understanding the reorganization of neural circuits spared after spinal cord injury in the motor cortex and spinal cord would provide insights for developing therapeutics. Using optogenetic mapping, we demonstrated a transhemispheric recruitment of neural circuits in the contralateral cortical M1/M2 area to improve the impaired forelimb function after a cervical 5 right-sided hemisection in mice, a model mimicking the human Brown-Séquard syndrome. This cortical reorganization can be elicited by a selective cortical optogenetic neuromodulation paradigm. Areas of whisker, jaw, and neck, together with the rostral forelimb area, on the motor cortex ipsilateral to the lesion were engaged to control the ipsilesional forelimb in both stimulation and nonstimulation groups 8 weeks following injury. However, significant functional benefits were only seen in the stimulation group. Using anterograde tracing, we further revealed a robust sprouting of the intact corticospinal tract in the spinal cord of those animals receiving optogenetic stimulation. The intraspinal corticospinal axonal sprouting correlated with the forelimb functional recovery. Thus, specific neuromodulation of the cortical neural circuits induced massive neural reorganization both in the motor cortex and spinal cord, constructing an alternative motor pathway in restoring impaired forelimb function.