Transcriptomics reveals transient and dynamic muscle fibrosis and atrophy differences following spinal cord injury in rats.

BACKGROUND: The rate and magnitude of skeletal muscle wasting after severe spinal cord injury (SCI) exceeds most other disuse conditions. Assessing the time course of molecular changes can provide insight into the progression of muscle wasting post-SCI. The goals of this study were (1) to identify potential targets that may prevent the pathologic features of SCI in soleus muscles and (2) to establish therapeutic windows for treating these pathologic changes. METHODS: Four-month-old Sprague-Dawley male rats received T9 laminectomy (SHAM surgery) or severe contusion SCI. Hindlimb locomotor function was assessed weekly, with soleus muscles obtained 1 week, 2 weeks, 1 month and 3 months post-surgery (n = 6-7 per group per timepoint). RNA was extracted from muscles for bulk RNA-sequencing analysis (n = 3-5 per group per timepoint). Differentially expressed genes (DEGs) were evaluated between age-matched SHAM and SCI animals. Myofiber size, muscle fibre type and fibrosis were assessed on contralateral muscles. RESULTS: SCI produced immediate and persistent hindlimb paralysis, with Basso-Beattie-Bresnahan locomotor scores remaining below 7 throughout the study, contributing to a progressive 25-50% lower soleus mass and myofiber atrophy versus SHAM (P < 0.05 at all timepoints). Transcriptional comparisons of SCI versus SHAM resulted in 184 DEGs (1 week), 436 DEGs (2 weeks), 133 DEGs (1 month) and 1200 DEGs (3 months). Upregulated atrophy-related genes included those associated with cell senescence, nuclear factor kappa B, ubiquitin proteasome and unfolded protein response pathways, along with upregulated genes that negatively influence muscle growth through the transforming growth factor beta pathway and inhibition of insulin-like growth factor-I/Akt/mechanistic target of rapamycin and p38/mitogen-activated protein kinase signalling. Genes associated with extracellular matrix (ECM), including collagens, collagen crosslinkers, proteoglycans and those regulating ECM integrity, were enriched within upregulated DEGs at 1 week but subsequently downregulated at 2 weeks and 3 months and were accompanied by >50% higher ECM areas and hydroxyproline levels in SCI muscles (P < 0.05). Myofiber remodelling genes were enriched in upregulated DEGs at 2 weeks and 1 month and were downregulated at 3 months. Genes that regulate neuromuscular junction remodelling were evident in muscles post-SCI, along with slow-to-fast fibre-type shifts: 1 week and 2 weeks SCI muscles were composed of 90% myosin heavy chain (MHC) type I fibres, which decreased to only 16% at 3 months and were accompanied by 50% fibres containing MHC IIX (P < 0.05). Metabolism genes were enriched in upregulated DEGs at 1 month and were further enriched at 3 months. CONCLUSIONS: Our results substantiate many known pathologic features of SCI-induced wasting in rat skeletal muscle and identify a progressive and dynamic transcriptional landscape within the post-SCI soleus. Future studies are warranted to consider these therapeutic treatment windows when countering SCI muscle pathology.

Scleral burn and perforation following transscleral cyclophotocoagulation.

Purpose: This case report highlights scleral perforation as a complication of diode laser transscleral cyclophotocoagulation in the treatment of refractory primary open-angle glaucoma, as well as the management of this complication. Observations: A 78-year-old woman with primary open-angle glaucoma refractory to medication had transscleral cyclophotocoagulation performed in her left eye. During the procedure, it was noted that conjunctival burns and scleral perforation had occurred, at which point the procedure was aborted. Limited peritomy and patch graft with split-thickness donor cornea was done in the area of the scleral thinning and perforation. The patient had a good outcome with an intraocular pressure of 8 mm Hg, appropriate integration of the patch graft, and no significant conjunctival inflammation at the 2-month post-operative visit. Conclusions and importance: This patient, without any known risk factors for scleral thinning or necrosis, experienced conjunctival burn as well as scleral perforation during transscleral cyclophotocoagulation, underscoring this possible complication of the procedure. Additionally, split-thickness donor cornea was used to patch graft the area of scleral thinning and perforation, which is a method of managing this complication that had not been previously reported.

The current state, challenges, and future directions of deep brain stimulation for obsessive compulsive disorder.

INTRODUCTION: Obsessive-compulsive disorder (OCD) is clinically and pathologically heterogenous, with symptoms often refractory to first-line treatments. Deep brain stimulation (DBS) for the treatment of refractory OCD provides an opportunity to adjust and individualize neuromodulation targeting aberrant circuitry underlying OCD. The tailoring of DBS therapy may allow precision in symptom control based on patient-specific pathology. Progress has been made in understanding the potential targets for DBS intervention; however, a consensus on an optimal target has not been agreed upon. AREAS COVERED: A literature review of DBS for OCD was performed by querying the PubMed database. The following topics were covered: the evolution of DBS targeting in OCD, the concept of an underlying unified connectomic network, current DBS targets, challenges facing the field, and future directions which could advance personalized DBS in this challenging population. EXPERT OPINION: To continue the increasing efficacy of DBS for OCD, we must further explore the optimal DBS response across clinical profiles and neuropsychiatric domains of OCD as well as how interventions targeting multiple points in an aberrant circuit, multiple aberrant circuits, or a connectivity hub impact clinical response. Additionally, biomarkers would be invaluable in programming adjustments and creating a closed-loop paradigm to address symptom fluctuation in daily life.

Successful Treatment of Linear IgA Disease and Ulcerative Colitis With Sulfasalazine.

Linear IgA disease (LAD) is an uncommon autoimmune blistering disease that has been associated with medications, malignancy, and other autoimmune diseases, such as ulcerative colitis (UC). In this case report, a patient with a history of UC developed characteristic LAD lesions. While dapsone is considered first-line therapy for LAD, the treatment team opted for an underutilized, plausibly less toxic, and more simplified treatment regimen with sulfasalazine, successfully utilizing the two distinct actions of sulfasalazine's components - sulfapyridine and 5-aminosalicylate (5-ASA) - to concurrently treat both the LAD and UC symptoms. The authors discuss the pathophysiology of LAD and UC and expound on the mechanistic theory of their association. Additionally, the pharmacodynamics of sulfasalazine and considerations of its side effect profile are examined.