The induction of polyarthritis in rats by intradermal immunisation with homologous or heterologous type II collagen incomplete or incomplete Freund's adjuvant was reported recently by Trentham et al. We have now produced a similar disease in certain strains of mice.
SUMMARY In a prospective study of 70 unselected patients with chronic liver disease, clinical signs of a peripheral neuropathy were observed in 13 patients. Abnormal nerve conduction was demonstrated in nine of these and in one further patient who had no abnormal neurological signs. The occurrence of a neuropathy (in patients with cryptogenic cirrhosis, haemochromatosis, active chronic hepatitis as well as in alcoholic cirrhosis) could not be related to liver function, although it was associated with higher IgA and IgM values. Clinical diabetes was present in six of the 14 patients with neuropathy but there was no relation in the non-diabetic patients between neuropathy and minor impairment of carbohydrate tolerance. Those with neuropathy had a significantly higher incidence of oesophageal varices and there was also a relationship to a history of previous encephalopathy. Sural nerve biopsy was carried out on 14 patients, eight of whom had clinical or electrodiagnostic evidence of neuropathy. Single nerve fibres were examined by teasing and in all nerves histological evidence was found of an indolent process which had damaged whole Schwann cells and which resulted in demyelination and remyelination. Diabetic angiopathy was not seen and axonal degeneration, which was never severe, was found in all disease groups equally.
Mouse hepatitis virus (MHV3) can persist for months in strains of mice with genetically controlled "semisusceptibility" to this virus. The pathology of the chronic neurological disease induced in these animals has been investigated by conventional histology and immunofluorescence. A2G mice develop a chronic choroidoependymitis and meningitis leading to severe hydrocephalus and hydromyelia. In C3H mice a widespread vasculitis was observed, with both viral antigens and bound immunoglobulins in vessel walls. No significant glomerulonephritis was found. Systemic amyloidosis was present in the spleen, liver, and kidneys. The virus was not detected in neural tissues, but brain and spinal cord lesions were found near inflammatory areas surrounding damaged vessels. It is suggested that viral persistence in ependymal cells is directly responsible for the lesions in A2G mice, whereas an immunopathological lesion of blood vessels of the central nervous system underlines the damage to mice of the C3H strain.
For gene therapy to improve lung function in cystic fibrosis (CF) subjects, repeated administration of the gene transfer agent over the lifetime of patients is likely to be necessary. This requirement limits the utility of adenoviral and adeno-associated viral vectors (both previously evaluated in CF gene therapy trials) because of induced adaptive immune responses that render repeated dosing ineffective. For CF gene therapy trials, non-viral vectors are currently the only viable option. We previously showed that the cationic lipid formulation GL67A is the most efficient of several non-viral vectors analysed for airway gene transfer. Here, we assessed the efficacy and safety of administering 12 inhaled doses of GL67A complexed with pGM169, a CpG-free plasmid encoding human CFTR complementary DNA, into mice. We show that repeated administration of pGM169/GL67A to murine lungs is feasible, safe and achieves reproducible, dose-related and persistent gene expression (>140 days after each dose) using an aerosol generated by a clinically relevant nebuliser. This study supports progression into the first non-viral multidose lung trial in CF patients.
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