Polysialic acid as an antigen for monoclonal antibody HIgM12 to treat multiple sclerosis and other neurodegenerative disorders.

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 its in vivo and in vitro effects through binding to PSA and has the potential to be an effective therapy for MS and neurodegenerative diseases. The human antibody HIgM12 stimulates neurite outgrowth in vitro and promotes function in chronically demyelinated mice, a model of multiple sclerosis. The cellular antigen for HIgM12 was undetermined. Here, we identified polysialic acid attached to NCAM (neural cell adhesion molecule) as the cellular target for HIgM12. This includes glial fibrillary acidic protein (GFAP)-positive mouse astrocytes (GFAP, red; HIgM12, green; DAPI, blue) among other cell types of the central nervous system. These findings indicate a new strategy for the treatment of neuro-motor disorders including multiple sclerosis.

Outcome of noncardiac surgery in children with congenital heart disease performed outside a cardiac center.

OBJECTIVE: The objective of this study was to review the outcome of children with congenital heart disease (CHD) undergoing noncardiac surgery requiring general anesthesia (GA) in a tertiary pediatric center between January 2010 and December 2012. STUDY DESIGN: A retrospective case note review of children <16years of age with confirmed CHD undergoing a surgical or interventional procedure requiring GA was performed. Patients were categorized into three risk groups according to White and Peyton's anesthetic risk classification of children with CHD undergoing noncardiac surgery [Critical Care and Pain 2012;12:17-22]. RESULTS: 117 children with CHD were identified with a total of 240 procedures conducted. 36 procedures were conducted in the high-risk group, 135 in the intermediate-risk group, and 69 in the low-risk group. 40% of these were major operations such as small bowel and colonic procedures. Overall mortality rate at 7days and 30days was 0% and 0.4%, respectively, with a 1% mortality rate in minor procedures and 0% mortality rate in major procedures. There were no unexpected deaths. 17% of procedures resulted in complications. A higher rate of complications was recorded in emergency procedures. 17% of these procedures required admission to the intensive care unit, with the highest admissions rate in the high-risk group. The median duration of hospital stay for the whole cohort was 1day (range of 0-71days). CONCLUSION: Our study shows that procedures requiring GA can be safely conducted on children from any of the three risk groups in a nonspecialist cardiac center provided that there is close liaison and careful planning between the different specialties.