Multiple and early hyperbaric oxygen treatments enhance muscle healing after muscle contusion injury: a pilot study.

BACKGROUND: The optimal timing of hyperbaric oxygen (HBO2) treatments for the best recovery following muscle injury has yet to be determined. Thus, the optimal number and timing of HBO2 treatments for maximal muscle regeneration were explored. METHODS: The HBO2 treatment protocol consisted of 2.5 ATA 100% oxygen for 120 minutes. Muscle-injured rats were randomized to one of 10 groups: single HBO2 treatment immediately after injury (HBO 1T day 0), one day (HBO 1T day 1), three days (HBO 1T day 3) and five days (HBO 1T day 5) after injury; three HBO2 treatments from immediately after injury to two days after injury (HBO 3T day 0-2), from one to three days after injury (HBO 3T day 1-3), from three to five days after injury (HBO 3T day 3-5), from five to seven days after injury (HBO 3T day 5-7); five daily HBO2 treatments (HBO 5T); and no treatment (NT). RESULTS: HBO 5T and HBO 3T day 0-2, days 1-3 and days 3-5 significantly promoted CD206-positive cell infiltration, satellite cell differentiation and muscle regeneration compared to the NT group. CONCLUSION: Five HBO2 treatments and three HBO2 treatments within three days of injury promote muscle regeneration.

Sema3A regulates bone-mass accrual through sensory innervations.

Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a(-/-) mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a(-/-) mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1(-/-) and Sema3aosx(-/-) mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin(-/-) and Sema3anestin(-/-) mice) had low bone mass, similar to Sema3a(-/-) mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin(-/-) mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin(-/-) mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a(-/-) mice, such as olfactory development, were identified in Sema3asynasin(-/-) mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a(-/-) mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.

Effects of hyperbaric oxygen therapy on recovery acceleration in Japanese professional or semi-professional rugby players with grade 2 medial collateral ligament injury of the knee: A comparative non-randomized study.

INTRODUCTION: The effects of hyperbaric oxygen (HBO2) therapy on sprains, ligament injuries, and muscle strains have been reported in several animal studies. In a dog model of compartment syndrome and in a rat contused skeletal muscle injury model, the significant effects of HBO2 therapy on the reduction of edema and muscle necrosis have been reported. In basic research HBO2 therapy stimulated fibroblast activity to improve the healing process. Because of this it expected that HBO2 therapy might improve focal edema and pain in the acute phase and accelerate the healing of injured tissues in athletes with a medial collateral ligament (MCL) injury of the knee. This study aimed to examine the short-term effects of HBO2 application subjectively, and the long-term effects of HBO2 therapy in Japanese professional or semi-professional rugby players with grade 2 MCL injury of the knee. METHODS: Thirty-two professional or semi-professional rugby players with grade 2 MCL injury of the knee were investigated. First, in the HBO2 group (n=16), HBO2 therapy was performed during the acute phase. Visual analog scales (VASs) immediately before and after HBO2 therapy on the same day were compared. Next, we retrospectively evaluated the time to return to play in the HBO2 (n=16) and non-HBO2 (n=16) groups. RESULTS: VAS scores for pain while walking immediately before and after HBO2 therapy on the same day were 37.4 ± 20.1 (mean ± standard deviation) and 32.4 ± 21.8, respectively (p⟨0.001). The VAS scores for pain while jogging were 50.7 ± 25.6 and 43.9 ± 25.0, respectively (p⟨0.001). The time to return to play was 31.4 ± 12.2 days in the HBO2 group and 42.1 ± 15.8 days in the non-HBO2 group, indicating a significant difference between the groups (p⟨0.05). CONCLUSION: HBO2 therapy may reduce pain and accelerate the return to play in athletes with grade 2 MCL injury of the knee in this non-randomized study.

A multi-train electrical stimulation protocol facilitates transcranial electrical motor evoked potentials and increases induction rate and reproducibility even in patients with preoperative neurological deficits.

This study sought to evaluate the facilitation effect of repetitive multi-train transcranial electrical stimulation (mt-TES) at 2 repetition rates on transcranial electrical motor evoked potential (Tc-MEP) monitoring during spinal surgery, and to assess the induction rate in patients with impaired motor function from a compromised spinal cord or spinal nerve. We studied 32 consecutive patients with impaired motor function undergoing cervical or thoracic spinal surgery (470 muscles). A series of 10 TESs with 5 pulse trains were preoperatively delivered at 2 repetition rates (1 and 5 Hz). All peak-topeak amplitudes of the MEPs of the upper and lower extremity muscles elicited by the 10 TESs were measured. The induction rates of the lower extremity muscles were also assessed with muscle and preoperative lower extremity motor function scores. In each of the muscles, MEP amplitudes were augmented by about 2-3 times at 1 Hz and 5-6 times at 5 Hz. Under the 5-Hz condition, all limb muscles showed significant amplification. Also, in all preoperative motor function score groups, the amplitudes and induction rates of the lower extremity muscles were significantly increased. Moreover, the facilitation effects tended to peak in the last half of the series of 10 TESs. In all score groups of patients with preoperative neurological deficits, repetitive mt-TES delivered at a frequency of 5 Hz markedly facilitated the MEPs of all limb muscles and increased the induction rate. We recommend this method to improve the reliability of intraoperative monitoring during spinal surgery.

A case-control questionnaire survey of decompression sickness risk in Okinawa divers.

BACKGROUND: Decompression sickness (DCS) is a rare condition that is often difficult to diagnose in deep-sea divers. Because of this, prevention and early diagnosis are important. In this case-control study, we examined the risk and preventive factors associated with DCS. METHODS: Our original questionnaire survey was conducted among 269 recreational divers in Okinawa. Divers who were diagnosed with DCS by a physician (n = 94) were compared with healthy recreational divers (n = 175). The questionnaire consisted of 30 items and included a dive profile. Odds ratios and multiple logistic regression analysis were used to estimate the relative risk of DCS. RESULTS: Logistic regression analysis revealed the following risk factors for DCS: a past history of DCS, drinking alcohol the evening before diving, indicating decompression stops, cold exposure after the dive, and maximum depth. Preventive factors included hydration before the dive, deep stops, safety stops and using nitrox gas. The results were reliable according to the Hosmer-Lemeshow and omnibus tests. CONCLUSION: We identified certain risk factors, together with their relative risks, for DCS. These risk factors may facilitate prevention of DCS among Okinawa divers.

Elimination of CT-detected gas bubbles derived from decompression illness with abdominal symptoms after a short hyperbaric oxygen treatment in a monoplace chamber: a case report.

We report the case of a 54-year-old male compressed-air worker with gas bubbles detected by computed tomography (CT). He had complained of strong abdominal pain 30 minutes after decompression after working at a pressure equivalent to 17 meters of sea water for three hours. The initial CT images revealed gas bubbles in the intrahepatic portal vein, pulmonary artery and bilateral femoral vein. After the first hyperbaric oxygen treatment (HBO2 at 2.5 atmospheres absolute/ATA for 150 minutes), no bubbles were detected on repeat CT examination. The patient still exhibited abdominal distension, mild hypesthesia and slight muscle weakness in the upper extremities. Two sessions of U.S. Navy Treatment Table 6 (TT6) were performed on Days 6 and 7 after onset. The patient recovered completely on Day 7. This report describes the important role of CT imaging in evaluating intravascular gas bubbles as well as eliminating the diagnosis of other conditions when divers or compressed-air workers experience uncommon symptoms of decompression illness. In addition, a short treatment table of HBO2 using non-TT6 HBO2 treatment may be useful to reduce gas bubbles and the severity of decompression illness in emergent cases.

The Effect of Teeth Clenching on Dynamic Balance at Jump-Landing: A Pilot Study.

The aim of this study was to analyze the effect of teeth clenching on dynamic balance at jump landing. Twenty-five healthy subjects performed jump-landing tasks with or without teeth clenching. The first 3 trials were performed with no instruction; subsequently, subjects were ordered to clench at the time of landing in the following 3 trials. We collected the data of masseter muscle activity by electromyogram, the maximum vertical ground reaction force (vGRFmax) and center of pressure (CoP) parameters by force plate during jump-landing. According to the clenching status of control jump-landing, all participants were categorized into a spontaneous clenching group and no clenching group, and the CoP data were compared. The masseter muscle activity was correlated with vGRFmax during anterior jump-landing, while it was not correlated with CoP. In comparisons between the spontaneous clenching and the no clenching group during anterior jump-landing, the spontaneous clenching group showed harder landing and the CoP area became larger than the no clenching group. There were no significant differences between pre- and postintervention in both spontaneous clenching and no clenching groups. The effect of teeth clenching on dynamic balance during jump-landing was limited.

Otological complications associated with hyperbaric oxygen therapy.

The objective of the present study was to clarify the features of otological complications for hyperbaric oxygen therapy (HBOT) and the risk factors for these complications. We enrolled 1115 patients (776 males and 339 females; age 5-89 years) who underwent HBOT. All otological symptoms experienced during HBOT sessions were evaluated, and risk factors were analysed using multivariate logistic regression analysis. Otoscopic findings and interventions for otological complications were assessed in 58 symptomatic patients who visited the Otolaryngology Department. Otological symptoms were experienced by 165 (14.8 %) of the 1115 patients. The multivariate logistic regression analysis identified ages of >60 years and female sex as independent risk factors, whereas patients with sports injuries were at lower risk than those with other primary diseases, except for severe infectious disease. Eighty-two patients (49.7 %) suffered from symptoms at the first HBOT session. The most prevalent symptoms were otalgia (157/165), followed by ear fullness (13/165), hearing loss (12/165) and tinnitus (3/165). One patient experienced vertigo and deterioration of the bone-conduction pure-tone thresholds, suggesting inner ear barotrauma. In 116 ears of the 58 symptomatic patients, abnormal otoscopic findings were recognized in 58 ears (50.0 %). Twenty-seven of the 58 ears required myringotomy or tube insertion, and HBOT was stopped in eight ears in four patients. Of the remaining 58 ears with normal otoscopic findings, 51 received no treatment. Physicians should be aware of both middle and inner ear barotrauma as potential complications of HBOT.

The facilitatory effects of hyperbaric oxygen treatment on membrane bone wound healing in a rat calvarial defect model.

We examined the effect of hyperbaric oxygen (HBO2) treatment on bone wound healing in a rat calvarial defect. Critical-sized defects were created in the calvaria of adult Wistar rats. The animals were divided into four groups--HBO2, normobaric oxygen, hyperbaric air, and no treatment. Treatments were performed five days a week, for two weeks. Micro-computerized tomography and histological analysis were used to evaluate the bone defects. Regenerated bone areas were calculated as the percentage of new bone in the cross-sectional area of defect. The new bone cross-sectional area was significantly greater in the HBO2 group than in the other groups. There were no significant differences in the numbers of nucleated cells in the new bone areas. Although new bone volume per defect volume was significantly greater in the HBO2 group than in the other groups, no significant differences in bone mineral density in the new bone area were observed. These findings indicate the facilitatory role of HBO2 treatment on bone wound healing in the rat calvarial bone defect, and it does not appear to have any negative effects on bone maturity. We propose that HBO2 treatment would be useful in promoting bone regeneration following injury in the orofacial region.

Transient osteoporosis of the hip treated with hyperbaric oxygen therapy: a case series.

INTRODUCTION: Transient osteoporosis of the hip (TOH) is a self-limiting disorder characterized by bone marrow edema at the femoral head and neck. Patients report pain as moderate or severe at onset; pain gradually subsides at about six months (range four to 12 months). Differential diagnosis of the early stages of osteonecrosis of the femoral head (ONFH) is sometimes difficult. Because hyperbaric oxygen (HBO2) therapy is effective for reduction of edema in soft tissue injury and early stages of ONFH, we hypothesized that HBO2 could be effective in TOH for accelerated recovery. METHODS: Five cases of TOH treated with HBO2 were clinically evaluated. HBO2 was started from three to eight weeks after onset and performed four or five times a week, averaging a total of 27.8 ± 4.7 treatments (range 20-32). Clinical features were evaluated repeatedly with clinical examination, subjective evaluation of pain, and imaging methods that included magnetic resonance imaging (MRI) and bone scans. RESULTS: The average time to return-to-normal hip range of motion was 15.4 ± 7.8 weeks after onset, and relief of subjective pain was 16.6 ± 4.0 weeks. The average time to return-to-normal signal level in MRI was 22.0 ± 2.5 weeks, which was one to two months after relief of subjective pain. COMCLUSIONS: Multiple HBO2 treatments have the possibility of contributing to recovery acceleration in patients with TOH. However, in this study, we found that HBO2 treatment did not significantly accelerate the recovery of these five patients with TOH. The use of HBO2 should therefore be limited to patients in whom the differential diagnosis between TOH and early stage ONFH cannot be established.

Effect of short-term fatigue, induced by high-intensity exercise, on the profile of the ground reaction force during single-leg anterior drop-jumps.

[Purpose] Fatigue may be an important contributing factor to non-contact anterior cruciate ligament injuries in sports. The purpose of this study was to evaluate the effects of controlled lower limb fatigue, induced by a short-term, high-intensity exercise protocol, on the profile of the ground reaction force during landings from single-leg anterior drop-jumps. [Subjects and Methods] Twelve healthy males, 18 to 24 years old, performed single-leg anterior drop-jumps, from a 20 cm height, under two conditions, 'fatigue' and 'non-fatigue'. Short-term fatigue was induced by high-intensity interval cycling on an ergometer. Effects of fatigue on peak vertical ground reaction force, time-to-peak of the vertical ground reaction force, and loading rate were evaluated by paired t-test. [Results] Fatigue shortened the time-to-peak duration of the vertical ground reaction force by 10% (non-fatigue, 44.0 ± 16.8 ms; fatigue, 39.6 ± 15.8 ms). Fatigue also yielded a 3.6% lowering in peak vertical ground reaction force and 9.4% increase in loading rate, although these effects were not significant. [Conclusion] The effects of fatigue in reducing time-to-peak of the vertical ground reaction force during single-leg anterior drop-jumps may increase the risk for non-contact anterior cruciate ligament injury in males.

Intrathecal AAV serotype 9-mediated delivery of shRNA against TRPV1 attenuates thermal hyperalgesia in a mouse model of peripheral nerve injury.

Gene therapy for neuropathic pain requires efficient gene delivery to both central and peripheral nervous systems. We previously showed that an adenoassociated virus serotype 9 (AAV9) vector expressing short-hairpin RNA (shRNA) could suppress target molecule expression in the dorsal root ganglia (DRG) and spinal cord upon intrathecal injection. To evaluate the therapeutic potential of this approach, we constructed an AAV9 vector encoding shRNA against vanilloid receptor 1 (TRPV1), which is an important target gene for acute pain, but its role in chronic neuropathic pain remains unclear. We intrathecally injected it into the subarachnoid space at the upper lumbar spine of mice 3 weeks after spared nerve injury (SNI). Delivered shTRPV1 effectively suppressed mRNA and protein expression of TRPV1 in the DRG and spinal cord, and it attenuated nerve injury-induced thermal allodynia 10-28 days after treatment. Our study provides important evidence for the contribution of TRPV1 to thermal hypersensitivity in neuropathic pain and thus establishes intrathecal AAV9-mediated gene delivery as an investigative and potentially therapeutic platform for the nervous system.

Effects of hyperbaric oxygen on muscle fatigue after maximal intermittent plantar flexion exercise.

The purpose of this study was to investigate the effects of hyperbaric oxygen (HBO) treatment on muscle fatigue after maximal intermittent plantar flexion exercise. Twenty healthy male volunteers (aged from 21 to 24 years) were randomly assigned to either HBO or normoxic group and were blinded to their treatment and group assignment. The HBO group breathed 100% oxygen under 2.5 atmosphere absolute (ATA) for 60 minutes, whereas the normoxic group breathed room air under 1.2 ATA for 70 minutes. The subjects performed a fatigue test, which consisted of 50 maximal unilateral isometric plantar flexions, before and after intervention. Surface electromyography was recorded from triceps surae muscle. Subjects performed maximal voluntary contractions of isometric plantar flexions, and voluntary activation and twitch contractile properties were evaluated with cutaneous tibial nerve stimuli before and after intervention. Compared with initial values during repetitions 4-10, the plantar flexion torque during repetitions 41-50 decreased to 88.5 and 83.2% after HBO and normoxic treatment, respectively. A smaller decrease in muscle force was observed in the HBO group compared with the normoxic group. No differences in function between treatment groups were observed after nerve stimulation. These results suggest that HBO contributes to sustained force production due to suppressing the muscle fatigue progression. In practice, HBO can contribute to the prevention of excess fatigue of agonist muscles for specific exercises involving repeated jumping.

[Periarthritis scapulohumeralis].

Periarthritis scapulohumeralis, also known as frozen shoulder, is a common disease in which the patient has a painful and restricted range of active and passive shoulder motion involving capsular contraction with no identifiable cause. Pathogenesis is thought to be a progression of inflammation and fibrosis of the capsule. Appropriate physical examination and radiologic studies can help in differentiating this condition from rotator cuff tear and other diseases. The natural progression of a frozen shoulder includes three phases (freezing, frozen and thawing) over a duration of 1 to 3.5 years and resolves spontaneously. Conservative treatment includes physical therapy and medication for pain relief but arthroscopic capsular release is sometimes performed in refractory cases.

Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.

Remodeling of Neuromuscular Junctions in Target Muscle Following Nerve Regeneration in Mice After Delayed Peripheral Nerve Repair.

Peripheral nerve injury (PNI) induces severe functional loss in extremities. Progressive denervation and atrophy occur in the muscles if the nerve repair is delayed for long periods of the time. To overcome these difficulties, detailed mechanisms should be determined for neuromuscular junction (NMJ) degeneration in target muscles after PNI and regeneration after nerve repair. We established two models of end-to-end neurorrhaphy and allogeneic nerve grafting in the chronic phase after common peroneal nerve injury in female mice (n = 100 in total). We evaluated motor function, histology, and gene expression in the target muscles during their regeneration processes and compared the models. We found that the functional recovery with allogeneic nerve grafting was superior to that with end-to-end neurorrhaphy, and the number of reinnervated NMJs and Schwann cells was increased at 12 weeks after allograft. In addition, NMJ- and Schwann cell-related molecules showed high expression in the target muscle in the allograft model. These results suggest that Schwann cell migrating from the allograft might play a crucial role in nerve regeneration in the chronic phase after PNI. The relationship between the NMJ and Schwann cells should be further investigated in the target muscle.

Increase in paravertebral muscle activity in lumbar kyphosis patients by surface electromyography compared with lumbar spinal canal stenosis patients and healthy volunteers.

STUDY DESIGN: Paravertebral muscle activity measurement by surface electromyography (EMG) in lumbar degenerative patients and healthy volunteers. OBJECTIVE: Muscle activity was tested in the standing position, and the influence of low back pain and alignment of the lumbar spine was assessed in the patients with lumbar kyphosis (LDK) or canal stenosis. SUMMARY OF BACKGROUND DATA: The number of kyphosis patients has increased as the population has grown older. Advanced kyphosis can cause difficulties in maintaining a standing position and affect daily living activities. The most direct cause is the atrophy of erector spinae muscles. The activity of these muscles has not yet been sufficiently evaluated and needs to be assessed objectively for the purpose of diagnosis and treatment. METHODS: The subjects were kyphosis patients who were 60 years of age or older, age-matched lumbar spinal canal stenosis patients, and healthy volunteers. Muscular activity at the L1-L2 and the L4-L5 intervertebral areas was recorded by surface EMG in the resting standing position and also with a weight load held in the standing position. Muscle activity and muscle fatigue, and the association between the Visual Analogue Scale, the Japanese Orthopaedic Association score for low back pain, and muscle activity, were analyzed. RESULTS: Kyphosis patients had a greater muscle activity in the lower back in the resting standing position and more severe muscle fatigue at the upper lumbar spine in comparison with patients with lumbar spinal canal stenosis. There was no association between muscle activity and clinical findings in patients with LDK although. CONCLUSIONS: Our study revealed the constant activity of paravertebral muscles and the susceptibility to muscle fatigue in patients with LDK. The quantification of muscle activity by surface EMG may show the pathology of LDK, and the decrease in muscle activity in the standing position may be a potentially useful index for guiding treatment.

Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve.

Neuropathic pain, a heterogeneous condition, affects 7%-10% of the general population. To date, efficacious and safe therapeutic approaches remain limited. Antisense oligonucleotide (ASO) therapy has opened the door to treat spinal muscular atrophy, with many ongoing clinical studies determining its therapeutic utility. ASO therapy for neuropathic pain and peripheral nerve disease requires efficient gene delivery and knockdown in both the dorsal root ganglion (DRG) and sciatic nerve, key tissues for pain signaling. We previously developed a new DNA/RNA heteroduplex oligonucleotide (HDO) technology that achieves highly efficient gene knockdown in the liver. Here, we demonstrated that intravenous injection of HDO, comprising an ASO and its complementary RNA conjugated to α-tocopherol, silences endogenous gene expression more than 2-fold in the DRG, and sciatic nerve with higher potency, efficacy, and broader distribution than ASO alone. Of note, we observed drastic target suppression in all sizes of neuronal DRG populations by in situ hybridization. Our findings establish HDO delivery as an investigative and potentially therapeutic platform for neuropathic pain and peripheral nerve disease.

Transplanted neural progenitor cells expressing mutant NT3 promote myelination and partial hindlimb recovery in the chronic phase after spinal cord injury.

Neutrotrophin-3 (NT3) plays a protective role in injured central nervous system tissues through interaction with trk receptors. To enhance the regeneration of damaged tissue, a combination therapy with cell transplantation and neurotrophins has been under development. We examined whether the transplantation of neural progenitor cells (NPCs) secreting NT3/D15A, a multi-neurotrophin with the capacity to bind both trkB and trkC, would enhance the repair of damaged tissues and the functional recovery in a chronic phase of spinal cord injury. The cultured NPCs with lentiviral vector containing either GFP or NT3/D15A were transplanted into the contused spinal cord at 6 weeks after the initial thoracic injury. Eight weeks after the transplantation, the NT3/D15A transplants displayed better survival than the GFP transplants, and they exhibited enhanced myelin formation and partial improvement of hindlimb function. Our study revealed that NT3/D15A produced positive effects in injured spinal cords even in the chronic phase. These effects suggest an enhanced neurotrophin-trk signaling by NT3/D15A.