NOX4 inhibition promotes the remodeling of dystrophic muscle

The muscular dystrophies (MDs) are genetic muscle diseases that result in progressive muscle degeneration followed by the fibrotic replacement of affected muscles as regenerative processes fail. Therapeutics that specifically address the fibrosis and failed regeneration associated with MDs represent a major unmet clinical need for MD patients, particularly those with advanced stage disease progression. The current study investigates targeting NAD(P)H oxidase (NOX) 4 as a potential strategy to reduce fibrosis and promote regeneration in disease-burdened muscle that models Duchenne muscular dystrophy (DMD). NOX4 is elevated in the muscles of dystrophic mice and DMD patients, localizing primarily to interstitial cells located between muscle fibers. Genetic and pharmacological targeting of NOX4 significantly reduces fibrosis in dystrophic respiratory and limb muscles. Mechanistically, NOX4 targeting decreases the number of fibrosis-depositing cells (myofibroblasts) and restores the number of muscle-specific stem cells (satellite cells) to their physiological niche, thereby, rejuvenating muscle regeneration. Furthermore, acute inhibition of NOX4 is sufficient to induce apoptotic clearing of myofibroblasts within dystrophic muscle. These data indicate that targeting NOX4 is an effective strategy to promote the beneficial remodeling of disease-burdened muscle representative of DMD and, potentially, other MDs and muscle pathologies.

Smooth muscle degeneration of the mesenteric and branching veins causing ischemic enteritis: a case report

Background Ischemic bowel injuries are generally caused by arteriosclerosis, thromboembolism, or vasculitis. Ischemic enteritis is less common than ischemic colitis because of the rich collateral arteries of the small intestine. In the present case, smooth muscle degeneration of the mesenteric to the submucosal veins caused ischemic enteritis and small bowel obstruction. Case presentation An 85-year-old woman with recurrent enteritis eventually developed small bowel obstruction. We performed laparoscopic partial resection of the small intestine. The pathological findings revealed smooth muscle degeneration of the mesenteric veins that caused ischemic enteritis. Venous changes were detected not only in the injured region, but also in a part of the normal region of the resected specimen. She continued to experience some minor symptoms postoperatively; however, these symptoms subsided in a short period with medicine discontinuation. Conclusion This report shows the possibility that a disease causes ischemic enteritis with unique venous pathological changes and may recur postoperatively.

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness due to the alterations of a protein called dystrophin that helps keep muscle cells intact. DMD is one of four conditions known as dystrophinopathies. DMD symptom onset is in early childhood, usually between ages 2 and 3. The daughters each have a 50% chance of being carriers. Very rarely, a female can be affected by the disease. Duchenne muscular dystrophy occurs in about 1 out of every 3600 male infants. The disease primarily affects boys, but in rare cases it can affect girls. Duchenne muscular dystrophy is a form of muscular dystrophy. The main sign of muscular dystrophy is progressive muscle weakness. Specific signs and symptoms begin at different ages and in different muscle groups. No cure for DMD is known, and an ongoing medical need has been recognized by regulatory authorities. Gene therapy has shown some success. Complications includes osteoporosis, nutritional problems, cardiac complication such as cardiomyopathy, chest and breathing complication. This condition can be improved when detected as early as possible.

Lysosomal Function Impacts the Skeletal Muscle Extracellular Matrix

Muscle development and homeostasis are critical for normal muscle function. A key aspect of muscle physiology during development, growth, and homeostasis is modulation of protein turnover, the balance between synthesis and degradation of muscle proteins. Protein degradation depends upon lysosomal pH, generated and maintained by proton pumps. Sphingolipid transporter 1 (spns1), a highly conserved gene encoding a putative late endosome/lysosome carbohydrate/H+ symporter, plays a pivotal role in maintaining optimal lysosomal pH and spns1−/− mutants undergo premature senescence. However, the impact of dysregulated lysosomal pH on muscle development and homeostasis is not well understood. We found that muscle development proceeds normally in spns1−/− mutants prior to the onset of muscle degeneration. Dysregulation of the extracellular matrix (ECM) at the myotendinous junction (MTJ) coincided with the onset of muscle degeneration in spns1−/− mutants. Expression of the ECM proteins laminin 111 and MMP-9 was upregulated. Upregulation of laminin 111 mitigated the severity of muscle degeneration, as inhibition of adhesion to laminin 111 exacerbated muscle degeneration in spns1−/− mutants. MMP-9 upregulation was induced by tnfsf12 signaling, but abrogation of MMP-9 did not impact muscle degeneration in spns1−/− mutants. Taken together, these data indicate that dysregulated lysosomal pH impacts expression of ECM proteins at the myotendinous junction.

A Nomogram for Predicting the Residual Back Pain after Percutaneous Vertebroplasty for Osteoporotic Vertebral Compression Fractures

Objective. Current findings suggest that percutaneous vertebroplasty (PVP) is a suitable therapeutic approach for osteoporotic vertebral compression fractures (OVCFs). However, a significant minority of patients still experience residual back pain after PVP. The present retrospective study was designed to determine the risk factors for residual back pain after PVP and provides a nomogram for predicting the residual back pain after PVP. Methods. We retrospectively reviewed the medical records of patients with single-segment OVCFs who underwent bilateral percutaneous vertebroplasty. Patients were divided into group N and group R according to the postoperative VAS score. Group R is described as the VAS score of residual back pain ≥ 4. Pre- and postoperative factors that may affect back pain relief were evaluated between two groups. Univariate and multivariate logistic regression analysis were performed to identify risk factors affecting residual back pain after PVP. We provided a nomogram for predicting the residual back pain and used the receiver operating characteristic curve (ROC), concordance index (C-index), calibration curve, and decision curve analyses (DCA) to evaluate the prognostic performance. Results. Among 268 patients treated with PVP, 37 (13.81%) patients were classified postoperative residual back pain. The results of the multivariate logistical regression analysis showed that the presence of an intravertebral vacuum cleft (IVC) (OR 3.790, P = 0.026 ), posterior fascia oedema (OR 3.965, P = 0.022 ), severe paraspinal muscle degeneration (OR 5.804, P = 0.01 ; OR 13.767, P < 0.001 ), and blocky cement distribution (OR 2.225, P = 0.041 ) were independent risk factors for residual back pain after PVP. The AUC value was 0.780, suggesting that the predictive ability was excellent. The prediction nomogram presented good discrimination, with a C-index of 0.774 (0.696∼0.852) and was validated to be 0.752 through bootstrapping validation. The calibration curve of the nomogram demonstrated a good consistency between the probabilities predicted by the nomogram and the actual probabilities. The nomogram showed net benefits in the range from 0.06 to 0.66 in DCA. Conclusions. The presence of IVC, posterior fascia oedema, blocky cement distribution, and severe paraspinal muscle degeneration were significant risk factors for residual back pain after PVP for OVCFs. Patients with OVCFs after PVP who have these risk factors should be carefully monitored for the possible development of residual back pain. We provide a nomogram for predicting the residual back pain after PVP.

Paraspinal Muscle Degeneration as an Independent Risk for Loss of Local Alignment in Degenerative Lumbar Scoliosis Patients After Corrective Surgery

Study Design: Retrospective study. Objectives: To investigate the effect of paraspinal muscle degeneration on the maintenance of local and global alignment among degenerative lumbar scoliosis (DLS) patients after corrective surgery. Methods: 98 DLS patients with a mean follow-up period of 38.3 months after corrective surgery were included. The T1 pelvic angle (TPA), lumbar lordosis (LL), pelvic incidence were measured preoperatively, immediate postoperatively and at last follow-up. All patients were divided into LL maintenance group (n = 21) and LL loss group (n = 77). For patients with well-aligned correction (immediate postoperative TPA ≤ 20°, n = 73), they were divided into TPA maintenance group (last follow-up TPA ≤ 20°) and TPA loss group (last follow-up TPA > 20°). The relative gross cross-sectional area (rGCSA) and fat infiltration (FI) of multifidus (MF) and erector spinae (ES), and the relative functional CSA (rFCSA) of psoas major (PS) were measured at L3, L4 and L5 on preoperative magnetic resonance imaging. Results: MF rGCSA were significantly smaller in LL loss group than in LL maintenance group. Both MF rGCSA and PS rFCSA were significantly smaller and MF FI was significantly higher in TPA loss group than in TPA maintenance group. Binary logistic regression revealed that the MF rGCSA was an independent factor of LL loss; Large immediate postoperative TPA was an independent risk factor of TPA loss, but not the parameters of paraspinal muscles. Conclusion: The effect of paraspinal muscles in lower lumbar segments might be mainly focused on the maintenance of local alignment rather than the global alignment.