Post-poliomyelitis syndrome (PPS) is a clinical syndrome of new weakness, fatigue, and pain in individuals who have previously recovered from acute paralytic poliomyelitis. The primary objective of this study was to identify factors which predict subsequent PPS. Among patients with prior polio, cases were those with new weakness and fatigue, and controls were those without these complaints. A chart review of 353 patients evaluated at the Montreal Neurological Institute post-polio clinic identified 127 cases and 39 controls. In univariate analyses, significant risk factors for PPS were a greater current age (odds ratio of 1.8 per decade, 95% confidence interval 1.3 to 2.6), a longer time since acute polio (odds ratio of 1.6 per decade, 95% confidence interval 1.1 to 2.3), more weakness at acute polio (odds ratio 1.5, 95% confidence interval 1.1 to 2.0), a recent weight gain (odds ratio 3.8, 95% confidence interval 1.6 to 9.4), muscle pain with exercise (odds ratio 3.8, 95% confidence interval 1.5 to 9.5), muscle pain (odds ratio 2.6, 95% confidence interval 1.3 to 5.5), and joint pain (odds ratio 2.3, 95% confidence interval 1.1 to 5.3). The multivariate analyses revealed that a model containing current age (odds ratio 1.7 per decade, 95% confidence interval 1.1 to 2.6), weakness at acute polio (odds ratio 1.6, 95% confidence interval 1.1 to 2.5), muscle pain with exercise (odds ratio 4.9, 95% confidence interval 1.6 to 15.6), recent weight gain (odds ratio 6.4, 95% confidence interval 2.02 to 20.3), and joint pain (odds ratio 2.33, 95% confidence interval 0.8 to 7.1) was the most effective in predicting who would develop PPS. Age at acute polio, degree of recovery after polio, weakness at best point after polio, physical activity, and sex were not contributing factors.

Neurofibromatosis type 2 (NF2) is a dominantly inherited genetic disorder predisposing to the development of nervous system tumors such as bilateral vestibular schwannomas, cranial and spinal meningiomas, nerve root schwannomas and ependymomas. The majority of NF2 patients develop juvenile lens opacities often presenting prior to the development of tumors usually in early teens. The NF2 gene had been identified by positional cloning. It encodes a recessive tumor suppressor protein mutated in both sporadic and familial schwannomas and meningiomas. We have isolated the mouse homologue of the NF2 gene (Nf2) from an 18-day old mouse brain cDNA library. Nf2 encodes a 596 amino acid-protein, schwannomin (alternatively merlin), with 98% identity to the human NF2 protein. By characterizing a dinucleotide repeat polymorphism within the 3$ sp prime$ untranslated region of Nf2, we have mapped the mouse gene to the proximal end of chromosome 11 at a small region of conserved synteny to human chromosome 22. These results indicate that Nf2 is highly conserved and suggest that analysis of the mouse Nf2 gene might yield insights into the human gene. / Schwannomin shares homology with members of erythrocyte band 4.1 superfamily which are known to be localized in the membrane-cytoskeleton interface. The predicted secondary structure of schwannomin includes an amino-terminal domain which is highly conserved within the superfamily and is proposed to associate with plasma membrane proteins, and a carboxy-terminal domain of lower homology but hypothesized to associate with the cytoskeleton. By Northern and Western analyses, Nf2 is expressed in all tissues studied. However, analysis by RNA in situ hybridization and immunohistochemistry revealed a widespread but cell-type specific pattern of expression. Furthermore, immunofluorescence technique showed cytoplasmic localization in neuronal and non-neuronal cells. When analysed in lens and Schwann cells, two cell types affected by the NF2 phenotype, schwannomin localized to dynamic structures such as the ruffling membrane and leading edges. Fractionation of cellular proteins revealed the presence of schwannomin in the detergent-insoluble cytoskeletal fraction as an $ sim$80 kDa protein, consistent with the hypothesis that it functions in association with cytoskeleton proteins. Moreover, schwannomin's expression pattern in the lens indicated that it plays a role in differentiation-specific events. With these observations together with information on related proteins, we propose a working model that defines the role of schwannomin as a membrane organizing protein in the leading edge.

Measles virus (MV) infects an estimated 30 million individuals each year, leading to ∼880,000 deaths. The mechanisms that underlie both MV-associated immunosuppression and the dramatic benefit of vitamin A remain poorly understood. Vitamin A supplements are also important for the eradication of vitamin A deficiency, which is implicated in the death of ∼1 million children each year, due to blindness and severe infections. In recent years, there has been increasing pressure to include vitamin A supplements in "universal" childhood vaccination programs in the developing world (e.g.: EPI). In this thesis, three studies dealing with the relationship between measles virus, vitamin A and the immune system are presented. First, the induction of PBMC apoptosis by MV is described and correlated with viral output and proliferation of these cells. In the second study, the results from a large trial of vitamin A supplementation at the time of MV vaccination are presented. Finally, as part of ongoing studies into the mechanism underlying the beneficial effect of vitamin A supplementation in MV infections, changes in the retinoid (vitamin A) signaling cascade during MV infection of a monocytic cell line (U937) were measured. (Abstract shortened by UMI.)

Interleukin-2 (IL-2), an immunomodulatory cytokine first isolated from the immune system, plays an essential role in the maturation of T lymphocytes. This thesis focusses on the neuroanatomical features of IL-2 and IL-2 receptors in the central nervous system, the neuromodulatory role of IL-2 on hippocampal acetylcholine release, and possible intracellular signalling mechanisms following IL-2 receptor activation in the brain. / Using immunoautoradiography, IL-2-like immunoreactivities were observed in a selected pattern in the central nervous system, with particularly high densities seen in the hippocampal formation and the hypothalamus of the rodent brain. The cellular localisation of the immunostaining using immunohistochemical approaches reveals that this staining was seen most evidently on cell perikarya especially in areas of high labelling density. The distribution of IL-2 receptor binding sites using both in vitro receptor autoradiography and immunoautoradiography (anti-TAC antibody against the IL-2 receptor a chain) shows that IL-2 receptors are selectively distributed in the rodent brain, with the highest densities observed in the hippocampal formation and the hypothalamus, in accordance with the localisation of IL-2 peptide immunostaining. The postulated neuromodulatory role of IL-2 and IL-2 receptors in the hippocampus was investigated next focusing on cholinergic parameters (acetylcholine release) on the basis of previous results from our laboratory (Araujo et al., 1989). / The neuromodulatory effects of IL-2 on acetylcholine (ACh) release was investigated using in vitro rat brain slices superfusion. IL-2 exerted potent effects on hippocampal ACh release, acting as a potentiating agent at low (pM) concentrations, while inhibiting release at higher (low nM) concentrations. An inhibitory effect (10 nM IL-2) on ACh release was also observed in the frontal cortex, but not in the parietal cortex or the striatum. This action was not shared by other interleukins such as IL-6. Both the stimulatory and inhibitory effects of IL-2 in hippocampal ACh release were blocked by an anti-IL-2 receptor antibody (TAC), suggesting the requirement of a genuine IL-2 receptor for both effects. The potentiating, in contrast to the inhibitory effect, was insensitive to tetrodotoxin, suggesting a direct action (or in close proximity) of IL-2 on cholinergic terminals to stimulate hippocampal ACh release. The inhibitory effect of IL-2 on ACh release was abolished by both bicuculline and phaclofen, suggesting the involvement of GABA acting on both GABA$ sb{ rm A}$ and GABA$ sb{ rm B}$ receptors present in the rat hippocampal formation. / The signalling mechanisms of the IL-2 receptor in the rat brain was studied next in vitro by measuring the effects of IL-2 on cytidine-diphosphate diacylglycerol (CDP-DAG) turnover in rat brain slices. IL-2 potently inhibited basal CDP-DAG turnover in the frontal cortex and hypothalamus, but not in the hippocampus or striatum. However, IL-2 inhibited carbachol-stimulated CDP-DAG turnover in the hippocampus. This decrease was in parallel to an increase in choline production, suggesting a role for phospholipase D in brain IL-2 receptor signalling. (Abstract shortened by UMI.)

We studied the effect of Trichuris trichiura on growth in a randomized, double-blind trial in which 508 Mexican children (2 to 10 years) with asymptomatic infections were randomized to one of 3 medication regimes that were selected to differ in efficacy against Trichuris: a single II mg/kg dose of pyrantel pamoate (low efficacy), a single 400 mg dose of albendazole (moderate efficacy) and 3 daily 400 mg doses of albendazole (high efficacy). All three treatment regimes are effective against a range of parasites, and conventional wisdom at the start of the trial was that asymptomatic Trichuris infection is harmless and has no effect on growth. The hypothesis was that children treated with 3 doses of albendazole grow better than children treated with a single dose of albendazole who, in turn, grow better than children treated with pyrantel pamoate. The children were measured and treated at baseline and every 4 months over 12 months. In spite of the differential efficacy of the 3 treatments against Trichuris, there were no differences in overall increment in height, weight, and arm circumference between the three treatment groups. However, the children who received the 3 daily 400 mg regime of albendazole had a significantly lower increment in triceps skinfold thickness than those who received pyrantel pamoate. The children who had higher intensities of Trichuris at baseline and who received the single 400 mg albendazole regime grew more in height than children in the same treatment group with lower initial levels of infection. The increment in weight, arm circumference, and triceps skinfold thickness was also a positive function of the initial intensity of Trichuris infection in the children who received 3 daily 400 mg doses of albendazole. This study provides evidence that low, asymptomatic levels of Trichuris can impair growth, and suggests that either albendazole or pyrantel pamoate or both may have an effect on the growth of children, independent of a therapeuti

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