A transcriptomics-based drug repositioning approach to identify drugs with similar activities for the treatment of muscle pathologies in spinal muscular atrophy (SMA) models.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three SMN-augmentation therapies are clinically approved that significantly slow down disease progression, they are unfortunately not cures. Thus, complementary SMN-independent therapies that can target key SMA pathologies and that can support the clinically approved SMN-dependent drugs are the forefront of therapeutic development. We have previously demonstrated that prednisolone, a synthetic glucocorticoid (GC) improved muscle health and survival in severe Smn-/-;SMN2 and intermediate Smn2B/- SMA mice. However, long-term administration of prednisolone can promote myopathy. We thus wanted to identify genes and pathways targeted by prednisolone in skeletal muscle to discover clinically approved drugs that are predicted to emulate prednisolone's activities. Using an RNA-sequencing, bioinformatics, and drug repositioning pipeline on skeletal muscle from symptomatic prednisolone-treated and untreated Smn-/-; SMN2 SMA and Smn+/-; SMN2 healthy mice, we identified molecular targets linked to prednisolone's ameliorative effects and a list of 580 drug candidates with similar predicted activities. Two of these candidates, metformin and oxandrolone, were further investigated in SMA cellular and animal models, which highlighted that these compounds do not have the same ameliorative effects on SMA phenotypes as prednisolone; however, a number of other important drug targets remain. Overall, our work further supports the usefulness of prednisolone's potential as a second-generation therapy for SMA, identifies a list of potential SMA drug treatments and highlights improvements for future transcriptomic-based drug repositioning studies in SMA.

Incidence of Vestibular Schwannoma in Patients with Unilateral Tinnitus: A Systematic Review and Meta-Analysis.

OBJECTIVES: Vestibular schwannoma (VS) is a tumor of the vestibulocochlear nerve. Current literature indicates that 1.6% of patients undergoing magnetic resonance imaging of the internal auditory meatus (MRI IAM) for audiovestibular symptoms are diagnosed with a VS. However, there is limited research reporting on patients who present with unilateral tinnitus without asymmetrical hearing loss. This study is a systematic review and meta-analysis evaluating how many of those patients had a VS diagnosed on MRI IAM. DATABASES USED: Online searches of PubMed, Medline, and Embase databases were performed up to October 2022. METHODS: This meta-analysis was undertaken aligning with PRISMA guidelines. Articles reporting on patients having MRI IAM for unilateral tinnitus without asymmetrical hearing loss were included. Outcomes measures were patient demographics, VS cases, incidental findings, size, and management of tumor. A meta-analysis of proportions was performed using a random-effects model with the restricted maximum likelihood method. Quality assessment was performed using the Joanna Briggs Institute critical appraisal checklist. RESULTS: Seven case series were included in the review: a total of 1,394 patients. Seven patients had a VS, with a median size of 4 mm. The pooled detection rate for VS was 0.08% (95% confidence interval = 0.00-0.45). Subsequent management was reported in six cases of which four were actively monitored and two surgically excised. The most common incidental finding was sinus disease (49 patients). CONCLUSION: Our findings indicate that MRI IAM has a low diagnostic yield for VS detection in patients presenting with unilateral tinnitus without asymmetrical hearing loss, with mostly small tumors that are conservatively managed.

Multidisciplinary team approach to diagnosing lymphangioleiomyomatosis.

A 42-year-old woman with chronic obstructive pulmonary disease was referred to the respiratory team due to shortness of breath on exertion and significant deterioration in pulmonary function tests. Her symptoms were progressively getting worse. This prompted a referral to the specialist team where further investigations were undertaken including a high-resolution CT scan followed by lung biopsy, which eventually revealed a diagnosis of lymphangioleiomyomatosis (LAM). Successful referral to the National LAM Centre in Nottingham provided the key therapeutic approach required to manage this rare condition. Diagnosing this rare condition was due to the multidisciplinary team approach, which involved input from the general practitioner, radiologist and respiratory consultant. The patient has been making good progress with pharmacological management.