CNS regeneration is a desirable goal for diseases of brain and spinal cord. Current therapeutic strategies for the treatment of multiple sclerosis (MS) aim to eliminate detrimental effects of the immune system, so far without reversing disability or affecting long-term prognosis in patients. Approachable molecular targets that stimulate CNS repair are not part of the clinical praxis or have not been identified yet. The purpose of this study was to identify the molecular target of the human monoclonal antibody HIgM12. HIgM12 reverses motor deficits in chronically demyelinated mice, a model of MS. Here we identified polysialic acid (PSA) attached to the Neural Cell Adhesion Molecule (NCAM) as the antigen for HIgM12 by using different NCAM knockout strains and through PSA removal from the NCAM protein core. Antibody binding to CNS tissue and primary cells, antibody-mediated cell adhesion and neurite outgrowth on HIgM12-coated nitrocellulose was detected only in the presence of PSA as assessed by Western blotting, immunoprecipitation, immunocytochemistry and histochemistry. We conclude that HIgM12 mediates it's in vivo and in vitro effects through binding to PSA and has the potential to be an effective therapy for MS and neurodegenerative diseases.
Methods A prospective analysis of all Micra VA implants performed at Royal Papworth Hospital was carried out. This included pacing checks for up to 24 months post device insertion, evaluating complications and specifically noting thresholds and R-wave amplitude changes. Results A total of 24 Micra leadless pacemakers were implanted at our centre between 2017 and 2020. The age range for the patients was 37 to 92 years, mean age 71 ± 13 yrs. 8 out of 24 (33%) patients had poor venous access, with bilateral subclavian obstruction, requiring the use of a leadless pacemaker. 2 out of 24 had bilateral previous pacemaker infections and extraction. For the remaining patients, 12/24 (50%) had atrial fibrillation with slow ventricular response as the primary indication for the device. 6 out of 24 (25%) patients had a history of LV impairment (4 patients severe LVSD, 2 moderate LVSD). One patient had a previous cardiac transplant.The implant was successful for all patients. One patient required the procedure to be repeated under general anaesthetic as she did not tolerate the insertion of the femoral sheath under sedation. 2 patients (8%) required repositioning of the device during the case, as initial placement was unsatisfactory. 23/24 patients had the device placed in the septum and 1 patient in the RV apex. This patient had undergone multiple previous tricuspid valve surgeries, which made septal positioning challenging, and so an apical placement was accepted. Mean procedure time was 62 ± 16 mins. Mean fluoroscopy time was 5.8 ± 4.2 mins. Implant threshold was 0.6 V ± 0.4 V. Threshold at 1 year follow up was 0.5 V ± 0.2 V and 0.6 V ± 0.2 V at 2 years. Paired T testing showed no statistically significant difference in threshold values at implant, and year 1 (p = 0.7, n =13), or implant and year 2 (p = 0.78, n =6). The R wave at implant was 9.5 ± 4.1mV, and 9.8 mV ± 2.5mV at year 1, again with no statistically significant difference (p = 0.87, n = 13). Mean battery life at 2 year follow up was 7 ± 0.5 years. Pacing percentages varied from 0.1% to 99.99%. Conclusion Although are numbers are small, particularly for follow up over 2 years (n = 6), the initial results are encouraging, and support a low complication rate, and no evidence of premature battery failure or issues with device threshold requiring re intervention. It is imperative that further studies are carried out to give a picture of longer term follow up for the leadless Micra VA pacemaker focussing on these two key issues.
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