Bethlem myopathy: An autosomal dominant myopathy with flexion contractures,keloids, and follicular hyperkeratosis

Bethlem myopathy and Ullrich congenital muscular dystrophy form a spectrum of collagenopathies caused by genetic mutations encoding for any of the three subunits of collagen VI. Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis. Three patients from a single family were diagnosed to have Bethlem myopathy based on European Neuromuscular Centre Bethlem Consortium criteria. Affected father and his both sons had slowly progressive proximal dominant weakness and recurrent falls from the first decade. Both children aged 18 and 20 years were ambulant at presentation. All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy. Creatinine kinase was mildly elevated and electromyography revealed myopathic features. Muscle imaging revealed severe involvement of glutei and vasti with “central shadow” in rectus femoris. Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans, and dysferlin.Key Words: Bethlem myopathy, collagen VI, contractures, immunohistochemistry, keloids     

Kearns Sayre syndrome: an atypical presentation

Kearns Sayre syndrome is a rare presentation which usually involves a triad of factors: external ophthalmoplegia, retinal pigmentary degeneration, and heart block. We present a clinically and histopathologically confirmed case of Kearns Sayre syndrome that involved no retinal pathology.     

Disulfiram (DSF) acts as a copper ionophore to induce copper‐dependent oxidative stress and mediate anti‐tumor efficacy in inflammatory breast cancer

Cancer cells often have increased levels of reactive oxygen species (ROS); however, acquisition of redox adaptive mechanisms allows for evasion of ROS‐mediated death. Inflammatory breast cancer (IBC) is a distinct, advanced BC subtype characterized by high rates of residual disease and recurrence despite advances in multimodality treatment. Using a cellular model of IBC, we identified an oxidative stress response (OSR) signature in surviving IBC cells after administration of an acute dose of an ROS inducer. Metagene analysis of patient samples revealed significantly higher OSR scores in IBC tumor samples compared to normal or non‐IBC tissues, which may contribute to the poor response of IBC tumors to common treatment strategies, which often rely heavily on ROS induction. To combat this adaptation, we utilized a potent redox modulator, the FDA‐approved small molecule Disulfiram (DSF), alone and in combination with copper. DSF forms a complex with copper (DSF‐Cu) increasing intracellular copper concentration both in vitro and in vivo, bypassing the need for membrane transporters. DSF‐Cu antagonized NFκB signaling, aldehyde dehydrogenase activity and antioxidant levels, inducing oxidative stress‐mediated apoptosis in multiple IBC cellular models. In vivo, DSF‐Cu significantly inhibited tumor growth without significant toxicity, causing apoptosis only in tumor cells. These results indicate that IBC tumors are highly redox adapted, which may render them resistant to ROS‐inducing therapies. DSF, through redox modulation, may be a useful approach to enhance chemo‐ and/or radio‐sensitivity for advanced BC subtypes where therapeutic resistance is an impediment to durable responses to current standard of care.     

Deep sclerectomy-trabeculectomy with mitomycin C in treating glaucoma: postoperative long-term results

AIM: To determine the long-term postoperative outcomes of deep sclerectomy-trabeculectomy (DST) with mitomycin C (MMC) in the treatment of glaucoma. METHODS: Patients who underwent DST with MMC between 2010 and 2017 were included in this retrospective observational study. Complete success was defined as postoperative intraocular pressure (IOP) ≤21 mm Hg or 30% reduction of IOP from baseline without any topical IOP-lowering agent, and qualified success defined as IOP≤21 mm Hg or 30% reduction of IOP from baseline with/without single topical agent. We evaluated the surgical success rates and complication rates of this procedure, as well as described the IOP profiles, best corrected visual acuity (BCVA) profiles and mean deviations (MD) of Humphrey visual field (HVF) 24-2 performance at each follow-up time point. Mixed linear regression models were constructed to determine estimated predictive values of demographic data, use of topical IOP-lowering agents, baseline and postoperative IOP and optical profiles (e.g., BCVA and MD). RESULTS: Totally 98 eyes (mean postoperative follow-up 67.5mo) showed mean IOP reduction at every follow-up interval. Both median BCVA and MD of visual fields were maintained throughout the follow-up intervals when comparing to baseline. The number of IOP-lowering medications decreased from 2.8±0.8 to 0.3±0.7 (P=0.068). Totally 84 (85.7%) eyes achieved complete success at final follow-up. Transient hyphaema and transient choroidal effusion developed in 15 eyes (15.3%) and 11 eyes (11.2%) respectively. Other complications included shallow anterior chamber in 5 eyes (5.1%), bleb leak in 4 eyes (4.1%), bleb revision in 7 eyes (7.1%), bleb needling in 9 eyes (9.2%) and repeat trabeculectomy in 1 eye (1.0%). There was no endophthalmitis, blebitis or macular oedema. There was no significant correlation between postoperative IOP control and postoperative BCVA. CONCLUSION: DST with MMC demonstrates effective and sustained long-term outcomes in the treatment of glaucoma with no major complication.     

Low dose injectable contraceptive norethisterone enanthate 20mg monthly — I. Clinical trials

Clinical trials were undertaken with an injectable low dose progestational contraceptive, norethisterone enanthate 20 mg monthly (Net-en — 20). Data from the study indicate that Net-en — 20 is an effective contraceptivs with lower incidence of menstrual cycle disturbances than the currently used injectable progestogens. There was a prompt return of fertility after the withdrawal of the drug. Net-en — 20 did not have any adverse effect on maternal nutritional status as assessed by anthropometric indices of nutritional scatus, and clinical sign of nutritional deficiencies or on lactational performance as assessed by mothers' impression on milk output and mean duration of lactation.     

Sorbitol Crystallization Can Lead to Protein Aggregation in Frozen Protein Formulations

Purpose This work examines the cause of aggregation of an Fc-fusion protein formulated in sorbitol upon frozen storage for extended periods of time at −30°C.Materials and Methods We designed sub-ambient differential scanning calorimetry (DSC) experiments to capture the effects of long-term frozen storage. The physical stability of formulation samples was monitored by size exclusion high performance liquid chromatography (SE-HPLC).Results DSC analysis of non-frozen samples shows the expected glass transitions (T_g′) at −45°C for samples in sorbitol and at −32°C in sucrose. In time course studies where sorbitol formulations were stored at −30°C and analyzed by DSC without thawing, two endothermic transitions were observed: a melting endotherm at −20°C dissipated over time, and a second endotherm at −8°C was seen after approximately 2 weeks and persisted in all later time points. Protein aggregation was only seen in the samples formulated in sorbitol and stored at −30°C, correlating aggregation with the aforementioned melts.Conclusions The observed melts are characteristic of crystalline substances and suggest that the sorbitol crystallizes over time. During freezing, the excipient must remain in the same phase as the protein to ensure protein stability. By crystallizing, the sorbitol is phase-separated from the protein, which leads to protein aggregation.     

Clinical and magnetic resonance imaging findings in patients with Leigh syndrome and SURF1 mutations

Background: Mutation in the SURF1 is one of the most common nuclear mutations associated with Leigh syndrome and cytochrome c oxidase deficiency. This study aims to describe the phenotypic and imaging features in four patients with Leigh syndrome and novel SURF1 mutation. Methods: The study included four patients with Leigh syndrome and SURF1 mutations identified from a cohort of 25 children with Leigh syndrome seen over a period of six years (2006–2012). All the patients underwent a detailed neurological assessment, muscle biopsy, and sequencing of the complete mitochondrial genome and SURF1. Results: Three patients had classical presentation of Leigh syndrome. The fourth patient had a later age of onset with ataxia as the presenting manifestation and a stable course. Hypertrichosis, facial dysmorphism and hypopigmentation were the additional phenotypic features noted. On magnetic resonance imaging all patients had brainstem and cerebellar involvement and two had basal ganglia involvement in addition. The bilateral symmetrical hypertrophic olivary degeneration in these patients was striking. The SURF1 analysis identified previously unreported mutations in all the patients. On follow-up three patients expired and one had a stable course. Conclusions: Patients with Leigh syndrome and SURF1 mutation often have skin and hair abnormalities. Bilateral symmetrical hypertrophic olivary degeneration was a consistent finding on magnetic resonance imaging in these patients.     

Pre-surgery immune profiles of adult glioma patients

Journal of Neuro-Oncology - Although immunosuppression is a known characteristic of glioma, no previous large studies have reported peripheral blood immune cell profiles prior to patient surgery...