Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice.

Pompe disease is a rare glycogen storage disorder caused by a deficiency in the lysosomal enzyme acid α-glucosidase, which leads to muscle weakness, cardiac and respiratory failure, and early mortality. Alglucosidase alfa, a recombinant human acid α-glucosidase, was the first approved treatment of Pompe disease, but its uptake into skeletal muscle via the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) is limited. Avalglucosidase alfa has received marketing authorization in several countries for infantile-onset and/or late-onset Pompe disease. This recently approved enzyme replacement therapy (ERT) was glycoengineered to maximize CIMPR binding through high-affinity interactions with ∼7 bis-M6P moieties. Recently, small molecules like the glucosylceramide synthase inhibitor miglustat were reported to increase the stability of recombinant human acid α-glucosidase, and it was suggested that an increased serum half-life would result in better glycogen clearance. Here, the effects of miglustat on alglucosidase alfa and avalglucosidase alfa stability, activity, and efficacy in Pompe mice were evaluated. Although miglustat increased the stability of both enzymes in fluorescent protein thermal shift assays and when incubated in neutral pH buffer over time, it reduced their enzymatic activity by ∼50%. Improvement in tissue glycogen clearance and transcriptional dysregulation in Pompe mice correlated with M6P levels but not with miglustat coadministration. These results further substantiate the crucial role of CIMPR binding in lysosomal targeting of ERTs. SIGNIFICANCE STATEMENT: This work describes important new insights into the treatment of Pompe disease using currently approved enzyme replacement therapies (ERTs) coadministered with miglustat. Although miglustat increased the stability of ERTs in vitro, there was no positive impact to glycogen clearance and transcriptional correction in Pompe mice. However, increasing mannose-6-phosphate levels resulted in increased cell uptake in vitro and increased glycogen clearance and transcriptional correction in Pompe mice, further underscoring the crucial role of cation-independent mannose-6-phosphate receptor-mediated lysosomal targeting for ERTs.

Correlation of Spinal Cord Injury With Development Of Spinal Arachnoid Cysts: Two Case Reports.

BACKGROUND: Spinal arachnoid cysts are rare entities, which are composed of a duplication in the arachnoid membrane and resultant cerebrospinal fluid collection, which may present with a progressive myelopathy. The most common symptoms caused by spinal cord compression are paraesthesia, neuropathic pain, paresis and gait ataxia. CLINICAL CASES: We report here 2 cases from different perspectives of a spinal arachnoid cysts in spinal cord injury. The first case was the occurrence of a spinal cord injury due to compression of a spinal arachnoid cysts causing myelopathy. The second case is a patient who had a traumatic paraplegia for which stabilizing surgery was required and who subsequently developed a spinal arachnoid cysts with neuropathic pain. Both cases required surgery with immediate improvement. However, after a few months both patients needed a revision due to recurrence. CONCLUSION: Spinal arachnoid cysts may present with a heterogeneous clinical picture. If cysts are not clinically apparent, a conservative treatment with careful observation can be a justifiable option. In patients with progressive symptoms, surgery is the gold standard of care. However, the literature describes the need for revision surgery in only 12.5% of cases. Regular follow-up is necessary because both of the patients reported here needed revision surgery.

Evidence of rehabilitation therapy in task-specific focal dystonia: a systematic review.

INTRODUCTION: Task-specific dystonias are primary focal dystonias characterized by excessive muscle contractions producing abnormal postures during selective motor activities that often involve highly skilled, repetitive movements. Based on the idea of excessive motor excitability and aberrant sensorimotor integration in the pathophysiology of task-specific dystonia, sensorimotor retraining may hold promise. The purpose of this systematic review was to investigate the available evidence about the role of rehabilitation therapy as a treatment for task-specific dystonia. EVIDENCE ACQUISITION: A systematic review was performed of studies identified through Pubmed and Embase in a structured search strategy by independent author screening. The JBI (Joanna Briggs Institute) Critical Appraisal Checklist and RoB 2 were used to evaluate their methodological quality. EVIDENCE SYNTHESIS: Twenty-one studies were included for qualitative synthesis. Most of the reports are small single group pre-/post-test study designs with a variability in the type of task-specific dystonia and the type of evaluated outcome measures. Rehabilitation interventions were grouped into six categories based upon the underlying theoretical basis of different approaches: 1) movement practice; 2) training with constraint; 3) sensory reorganization; 4) biofeedback training; 5) neuromodulation with training; and 6) compensatory strategies. CONCLUSIONS: Although it appears that a number of task-specific dystonia patients may improve with rehabilitation therapy, no definitive conclusions can be drawn. More research in this field is needed, using standardized approaches and clearly defined outcome measures in larger cohorts of task-specific dystonia patients that are clinically and diagnostically well characterized.

Novel role for vascular endothelial growth factor (VEGF) receptor-1 and its ligand VEGF-B in motor neuron degeneration.

Although vascular endothelial growth factor-B (VEGF-B) is a homolog of the angiogenic factor VEGF, it has only minimal angiogenic activity, raising the question of whether this factor has other (more relevant) biological properties. Intrigued by the possibility that VEGF family members affect neuronal cells, we explored whether VEGF-B might have a role in the nervous system. Here, we document that the 60 kDa VEGF-B isoform, VEGF-B(186), is a neuroprotective factor. VEGF-B(186) protected cultured primary motor neurons against degeneration. Mice lacking VEGF-B also developed a more severe form of motor neuron degeneration when intercrossed with mutant SOD1 mice. The in vitro and in vivo effects of VEGF-B(186) were dependent on the tyrosine kinase activities of its receptor, Flt1, in motor neurons. When delivered intracerebroventricularly, VEGF-B(186) prolonged the survival of mutant SOD1 rats. Compared with a similar dose of VEGF, VEGF-B(186) was safer and did not cause vessel growth or blood-brain barrier leakiness. The neuroprotective activity of VEGF-B, in combination with its negligible angiogenic/permeability activity, offers attractive opportunities for the treatment of neurodegenerative diseases.

Protective isolation precautions for the prevention of nosocomial colonisation and infection in burn patients: A systematic review and meta-analysis.

OBJECTIVES: To assess the impact of protective isolation precautions on nosocomial colonisation and infection rates in burn patients. RESEARCH METHODOLOGY: A systematic review and meta-analysis were performed of studies identified through Pubmed and Web of Science. Only articles in English were considered. The Downs and Black tool was used to evaluate their methodological quality. Random-effects meta-analysis obtained pooled risk ratios (RRs) and 95% confidence intervals (CIs) of nosocomial colonisation and infection rates. RESULTS: Five eligible before-after studies were identified, encompassing a total of 3033 patients (1192 in the experimental group; 1841 in the control group). Varying protective isolation precautions were investigated, resulting in high clinical heterogeneity. Quality assessment revealed overall poor methodological quality. Protective isolation significantly reduces combined colonisation and infection rates compared to baseline care (RR 0.52, 95% CI 0.40-0.69; P<0.0001). Subgroup analyses indicated significant reductions in both nosocomial colonisation (RR 0.65, 95% CI 0.51-0.83; P=0.02) and infection rates (RR 0.53, 95% CI 0.49-0.58; P<0.0001). CONCLUSIONS: Protective isolation precautions appear to decrease the risk of colonization and infection in burn patients. Because of the absence of higher quality study designs, clinical heterogeneity and the small number of studies involved, these results must be interpreted cautiously.