Objective Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with pathogenic autoantibodies against the astrocyte water channel protein aquaporin-4 (AQP4). The presence of neutrophils is a characteristic feature in NMO lesions in humans. Neutrophils are not generally found in multiple sclerosis lesions. We evaluated the role of neutrophils in a mouse NMO model. Methods NMO lesions were produced in mice by intracerebral injection of immunoglobulin G (IgG) isolated from NMO patient serum and human complement. We previously reported that this mouse model produces the characteristic histological features of NMO, including perivascular complement activation, inflammatory cell infiltration, and loss of myelin, AQP4, and glial fibrillary acidic protein. Lesions are absent when AQP4 null mice are used or when IgG from non-NMO patients is injected. Results We found remarkably reduced neuroinflammation, myelin loss, and AQP4 loss in brains of neutropenic mice at 24 hours and 7 days, and increased severity of NMO lesions in mice made neutrophilic by granulocyte colony stimulating factor. NMO lesions were greatly reduced by intracerebral administration of the neutrophil protease inhibitors Sivelestat and cathepsin G inhibitor I or by intraperitoneal injection of Sivelestat alone. Immunostaining of human NMO lesions for neutrophil elastase revealed many degranulating perivascular neutrophils, with no equivalent perivascular neutrophils in human multiple sclerosis lesions. Interpretation Our data implicate a central role of neutrophils in the pathogenesis of early NMO lesions and suggest the potential utility of neutrophil protease inhibitors such as Sivelestat in NMO therapy.

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GeneX may cause soft tissue inflammation and destruction and should not be placed next to thin walled structures, such as skin or pharynx, because it may erode through these tissues. Bone graft substitutes should undergo mandatory detailed safety testing prior to approval. This could be achieved by reclassifying them as drugs.

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Background. The choroid plexus (CP) is suggested to be involved in neuroimmune regulation avia the interaction between central and peripheral inflammation. Quantitative imaging has demonstrated volumetric CP change in psychosis, schizophrenia and depression. This study histologically examines CP epithelial cell morphology in these illnesses to identify the biological source of such volumetric changes. Methods. Formalin-fixed paraffin-embedded FFPE blocks were obtained bilaterally from the lateral ventricles of 13 cases of sex- and age-matched brains from each of schizophrenia (SZ) with psychosis, major depressive disorder (MDD) and matched controls. FFPE blocks were sectioned at 7μm and routinely stained for H&E. Morphological analysis of 180 CP epithelia/case was conducted blindly on digital images collected x600 magnification. Calcification was assessed in all CP regions manually. Results. Linear General Model analysis shows a significant effect of diagnosis on somal width (p=0.006, r2=0.33, adj=0.25), with a significant difference between SZ non-medicated v nonmedicated NPD controls (p=0.032), demonstrating increased somal width in SZ with psychotic medication but not in unmedicated SZ cases. No effects were observed in calcification. Discussion. Epithelial cells examined were adhered to CP fibrous surface so width expansion describes the primary methods for these cells to expand with adherence to this surface. The interaction of antipsychotic medication and diagnosis demonstrates that this is an illness specific change and mediated through the DA-system, although the mechanism is unclear at present.