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Purpose To explore the microcirculation formation mechanism of contrast-enhanced (CE) ultrasonography imaging performance in rabbits with limb muscle crush injury. Methods Seventy-two New Zealand white rabbits were randomly divided into two groups. A limb muscle crush injury model was created by airing a balloon cuff device with a force of 40 kpa. CE ultrasonography parameters were detected in the first group. In vivo microcirculation parameters were detected in the second group. Fine blood vessel diameter and blood flow velocity were calculated before extrusion and 0.5, 2, 6, 24 h, and 3 days after decompression. Results Compared with the uninjured muscle, reperfusion of the injured muscles showed early and high enhancement in CE ultrasonography images. The time-intensity curve showed a trend of rapid elevation and gradual drop. Compared with the control group, fine artery and vein diameters in the experimental group were wider and the blood flow velocity was slower, especially in the fine veins. Conclusion In vivo microcirculation detection can reflect changes in muscle microvascular diameter and blood flow velocity, which have a correlation with quantitative ultrasound imaging parameters.

Analysis of synergistic muscle activations during locomotion and anatomical tracing of muscle synergy representations in the rodent spinal cord guide the development of a new spinal implant for neuromodulation therapy. In multiple rodent models of spinal cord injury, spatiotemporal stimulation that mimics naturalistic muscle activation patterns promotes improved functional recovery over previously described continuous stimulation protocols. Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

Current models of somatosensory perception emphasize transmission from primary sensory neurons to the spinal cord and on to the brain 1 – 4 . Mental influence on perception is largely assumed to occur locally within the brain. Here we investigate whether sensory inflow through the spinal cord undergoes direct top-down control by the cortex. Although the corticospinal tract (CST) is traditionally viewed as a primary motor pathway 5 , a subset of corticospinal neurons (CSNs) originating in the primary and secondary somatosensory cortex directly innervate the spinal dorsal horn via CST axons. Either reduction in somatosensory CSN activity or transection of the CST in mice selectively impairs behavioural responses to light touch without altering responses to noxious stimuli. Moreover, such CSN manipulation greatly attenuates tactile allodynia in a model of peripheral neuropathic pain. Tactile stimulation activates somatosensory CSNs, and their corticospinal projections facilitate light-touch-evoked activity of cholecystokinin interneurons in the deep dorsal horn. This touch-driven feed-forward spinal–cortical–spinal sensitization loop is important for the recruitment of spinal nociceptive neurons under tactile allodynia. These results reveal direct cortical modulation of normal and pathological tactile sensory processing in the spinal cord and open up opportunities for new treatments for neuropathic pain. Somatosensory corticospinal neurons facilitate touch sensitivity and touch-evoked neuropathic pain in mice.

After complete spinal cord injuries (SCI), spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. However, it is unknown whether selective manipulation of these circuits can restore locomotor function in the absence of brain-derived inputs. By taking advantage of the compromised blood-spinal cord barrier following SCI, we optimized a set of procedures in which AAV9 vectors administered via the tail vein efficiently transduce neurons in lesion-adjacent spinal segments after a thoracic crush injury in adult mice. With this method, we used chemogenetic actuators to alter the excitability of propriospinal neurons in the thoracic cord of the adult mice with a complete thoracic crush injury. We showed that activating these thoracic neurons enables consistent and significant hindlimb stepping improvement, whereas direct manipulations of the neurons in the lumbar spinal cord led to muscle spasms without meaningful locomotion. Strikingly, manipulating either excitatory or inhibitory propriospinal neurons in the thoracic levels leads to distinct behavioural outcomes, with preferential effects on standing or stepping, two key elements of the locomotor function. These results demonstrate a strategy of engaging thoracic propriospinal neurons to improve hindlimb function and provide insights into optimizing neuromodulation-based strategies for treating SCI. After complete spinal cord injury, spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. Here, the authors show that neurons in these circuits can be chemogenetically modulated to improve locomotor function in mice after spinal cord injury.

BPC 157, a pentadecapeptide with extensive healing effects, has recently been suggested to contribute to angiogenesis. However, the underlying mechanism is not yet clear. The present study aimed to explore the potential therapeutic effect and pro-angiogenic mechanism of BPC 157. As demonstrated by the chick chorioallantoic membrane (CAM) assay and endothelial tube formation assay, BPC 157 could increase the vessel density both in vivo and in vitro, respectively. BPC 157 could also accelerate the recovery of blood flow in the ischemic muscle of the rat hind limb as detected by laser Doppler scanning, indicating the promotion of angiogenesis. Histological analysis of the hind limb muscle confirmed the increased number of vessels and the enhanced vascular expression of vascular endothelial growth factor receptor 2 (VEGFR2) in rat with BPC 157 treatment. In vitro study using human vascular endothelial cells further confirmed the increased mRNA and protein expressions of VEGFR2 but not VEGF-A by BPC 157. In addition, BPC 157 could promote VEGFR2 internalization in vascular endothelial cells which was blocked in the presence of dynasore, an inhibitor of endocytosis. BPC 157 time dependently activated the VEGFR2-Akt-eNOS signaling pathway which could also be suppressed by dynasore. The increase of endothelial tube formation induced by BPC 157 was also inhibited by dynasore. This study demonstrates the pro-angiogenic effects of BPC 157 that is associated with the increased expression, internalization of VEGFR2, and the activation of VEGFR2-Akt-eNOS signaling pathway. BPC 157 promotes angiogenesis in CAM assay and tube formation assay. BPC 157 accelerates the blood flow recovery and vessel number in rats with hind limb ischemia. BPC 157 up-regulates VEGFR2 expression in rats with hind limb ischemia and endothelial cell culture. BPC 157 promotes VEGFR2 internalization in association with VEGFR2-Akt-eNOS activation. Key message BPC 157 promotes angiogenesis in CAM assay and tube formation assay. BPC 157 accelerates the blood flow recovery and vessel number in rats with hind limb ischemia. BPC 157 up-regulates VEGFR2 expression in rats with hind limb ischemia and endothelial cell culture. BPC 157 promotes VEGFR2 internalization in association with VEGFR2-Akt-eNOS activation.

A large set of FoxOs-dependent genes play a primary role in controlling muscle mass during hindlimb unloading. Mitochondrial dysfunction can modulate such a process. We hypothesized that endurance exercise before disuse can protect against disuse-induced muscle atrophy by enhancing peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) expression and preventing mitochondrial dysfunction and energy-sensing AMP-activated protein kinase (AMPK) activation. We studied cross sectional area (CSA) of muscle fibers of gastrocnemius muscle by histochemistry following 1, 3, 7, and 14 days of hindlimb unloading (HU). We used Western blotting and qRT-PCR to study mitochondrial dynamics and FoxOs-dependent atrogenes’ expression at 1 and 3 days after HU. Preconditioned animals were submitted to moderate treadmill exercise for 7 days before disuse. Exercise preconditioning protected the gastrocnemius from disuse atrophy until 7 days of HU. It blunted alterations in mitochondrial dynamics up to 3 days after HU and the expression of most atrogenes at 1 day after disuse. In preconditioned mice, the activation of atrogenes resumed 3 days after HU when mitochondrial dynamics, assessed by profusion and pro-fission markers (mitofusin 1, MFN1, mitofusin 2, MFN2, optic atrophy 1, OPA1, dynamin related protein 1, DRP1 and fission 1, FIS1), PGC1α levels, and AMPK activation were at a basal level. Therefore, the normalization of mitochondrial dynamics and function was not sufficient to prevent atrogenes activation just a few days after HU. The time course of sirtuin 1 (SIRT1) expression and content paralleled the time course of atrogenes’ expression. In conclusion, seven days of endurance exercise counteracted alterations of mitochondrial dynamics and the activation of atrogenes early into disuse. Despite the normalization of mitochondrial dynamics, the effect on atrogenes’ suppression died away within 3 days of HU. Interestingly, muscle protection lasted until 7 days of HU. A longer or more intense exercise preconditioning may prolong atrogenes suppression and muscle protection.

Musculoskeletal disease (MSD) is common in ageing cats, resulting in chronic pain and mobility impairment, but diagnosis can be challenging. We hypothesised that there would be differences between cats with and without MSD in paw pressure and spatiotemporal and kinetic gait metrics. A cohort of 53 cats, aged between 7 and 10 years from the North West of the United Kingdom, underwent an orthopaedic examination and walked on a pressure sensitive walkway. Thirty-one of the cats (58%) were determined to be apparently-healthy, based on a normal orthopaedic examination and having no history of MSD, whilst the remaining 22 cats (42%) had findings consistent with MSD; 13/22 cats (59%) had multiple limb involvement, 7/22 (32%) had forelimb involvement and 2/22 (9%) had hindlimb involvement. Bodyweight ( P = 0.048) and body condition score (BCS; P = 0.015) were both greater in cats with MSD (mean bodyweight 5.4 ± 1.35 kg; median BCS 6, IQR 6–7.75) compared with apparently-healthy cats (mean bodyweight 4.7 ± 0.94 kg; median BCS 5, IQR 4.5–6.5). There was a relatively large intra-cat variation in spatiotemporal and kinetic gait variables (coefficient of variation >3.0%), whilst a linear mixed-effects model suggested no significant difference in spatiotemporal or kinetic gait variables between apparently-healthy cats and those with MSD. Palmar and plantar pressure asymmetry was assessed by pedobarographic statistical parametric mapping (pSPM) within each individual cat, with no significant difference ( P = 0.353) between the apparently heathy cats and those with MSD as to the presence or absence of asymmetry. Given the marked intra-cat variation and the ‘multi-limb’ nature of MSD in this cohort, it was not possible to differentiate healthy cats from those with MSD based on spatiotemporal and kinetic gait metrics or paw pressure asymmetry. Future work should examine gait in cats with defined musculoskeletal disorders (e.g. hip dysplasia) and also to track longitudinal changes within individual cats to better establish age-related trends.

Spinal cord injury (SCI) results in significant neurological deficits, and curative therapies are lacking. Neural progenitor cell (NPC) transplantation shows promise, as graft-derived neurons (GDNs) can integrate into host spinal cord and support axon regeneration. Here, we examined the synaptic integration of GDNs into hindlimb motor circuits in a mouse thoracic contusion SCI model. Transsynaptic tracing revealed that GDNs form synaptic connections with host motor circuits. Axon mapping showed distinct termination patterns of cholinergic and V2a interneurons within host spinal cord. Chemogenetic activation of GDNs induced muscle activity in a subset of transplanted animals, but NPC transplantation alone did not improve locomotor recovery. These findings indicate that GDNs can integrate into and modulate activity of host circuits, yet limited synaptic connectivity constrains functional recovery. Future studies should enhance graft-host connectivity and refine transplantation strategies to maximize therapeutic benefit for SCI. Neural progenitor cell transplantation shows promise for treating spinal cord injury. However, here, the authors show that graft-derived neurons form limited synaptic connections with host spinal motor circuits after injury, constraining functional motor recovery.

Background Cannabinoid-2 receptor (CB2R) plays an important role in the cascading inflammation following ischemic injury. The toll-like receptors 4 (TLR4)/matrix metalloproteinase 9 (MMP9) signal pathway is involved in blood-brain barrier dysfunction induced by ischemia stroke. The aim of this study is to investigate the roles of exogenous activation of CB2R on attenuating neurological deficit and blood-spinal cord barrier (BSCB) disruption during rat spinal cord ischemia reperfusion (I/R) injury, through modulation of the TLR4/MMP9 axis. Methods Animals were intraperitoneally pretreated with TLR4 inhibitor TAK-242, CB2R agonist JWH-133 with or without CB2R antagonist AM630, or equivalent volume of vehicle 1 h before undergoing 14-min occlusion of descending aorta or sham operation. One, two, three, and 7 days after reperfusion, hindlimb locomotor function was evaluated with Basso, Beattie, and Bresnahan (BBB) Locomotor Scale, BSCB integrity was detected by measurement of Evans blue (EB) extravasation and spinal cord edema. The protein expression levels of CB2R, tight junction protein Zonula occluden-1 (ZO-1), TLR4, MMP9, MyD88, NF-κB p65, and NF-κB p-p65 were determined by western blot. The MMP9 activity was analyzed by gelatin zymography. Double immunofluorescence staining was used to identify the perivascular localization of CB2R, TLR4, MMP9, and reactive astrocytes, as well as the colocalization of CB2R, TLR4, and MMP9 with reactive astrocytes. Results JWH-133 pretreatment attenuated hindlimb motor functional deficit and BSCB leakage, along with preventing downregulation of ZO-1 and upregulation of TLR4/MMP9, similar to the effects of TAK-242 preconditioning. JWH-133 or TAK-242 pretreatment reduced the perivascular expression of TLR4/MMP9 and reactive astrocytes following injury. JWH-133 pretreatment also downregulated MyD88/NF-κB level, MMP9 activity, and the astrocytic TLR4/MMP9 after I/R injury. Conclusions Exogenous activation of CB2R by JWH-133 attenuated neurological deficit and BSCB disruption after spinal cord I/R injury via inhibition of TLR4/MMP9 expression.

Lameness detection in horses is a critical challenge in equine veterinary practice, particularly when symptoms are mild. This study aimed to develop a predictive system using a support vector machine (SVM) to identify the affected limb in horses trotting in a straight line. The system analyzed data from inertial measurement units (IMUs) placed on the horse’s head, withers, and pelvis, using variables such as vertical displacement and retraction angles. A total of 287 horses were included, with 256 showing single-limb lameness and 31 classified as sound. The model achieved an overall accuracy of 86%, with the highest success rates in identifying right and left forelimb lameness. However, there were challenges in identifying sound horses, with a 54.8% accuracy rate, and misclassification between forelimb and hindlimb lameness occurred in some cases. The study highlighted the importance of specific variables, such as vertical head and withers displacement, for accurate classification. Future research should focus on refining the model, exploring deep learning methods, and reducing the number of sensors required, with the goal of integrating these systems into equestrian equipment for early detection of locomotor issues.