HTLV-I/II seroindeterminate Western blot reactivity in a cohort of patients with neurological disease.
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The human T-cell lymphotropic virus type I (HTLV-I) is associated with a chronic, progressive neurological disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis. Screening for HTLV-I involves the detection of virus-specific serum antibodies by EIA and confirmation by Western blot. HTLV-I/II seroindeterminate Western blot patterns have been described worldwide. However, the significance of this blot pattern is unclear. We identified 8 patients with neurological disease and an HTLV-I/II seroindeterminate Western blot pattern, none of whom demonstrated increased spontaneous proliferation and HTLV-I-specific cytotoxic T lymphocyte activity. However, HTLV-I tax sequence was amplified from the peripheral blood lymphocytes of 4 of them. These data suggest that patients with chronic progressive neurological disease and HTLV-I/II Western blot seroindeterminate reactivity may harbor either defective HTLV-I, novel retrovirus with partial homology to HTLV-I, or HTLV-I in low copy number. (+info)
Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a novel developmental disorder in Gypsies maps to 18qter.
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We have identified a novel developmental disorder with complex phenotypic characteristics involving primarily the nervous system, which appears to be common in a specific Gypsy group in Bulgaria. We propose to refer to the syndrome as congenital cataracts facial dysmorphism neuropathy (CCFDN). We have assigned the disease locus to the telomeric region of chromosome 18q. Linkage disequilibrium and highly conserved haplotypes suggest genetic homogeneity and founder effect. CCFDN co-localises with an EST which shows high homology to a conserved Drosophila gene involved in the regulation of nervous system development in vertebrates. (+info)
Introduction of heteroplasmic mitochondrial DNA (mtDNA) from a patient with NARP into two human rho degrees cell lines is associated either with selection and maintenance of NARP mutant mtDNA or failure to maintain mtDNA.
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Mitochondria from a patient heteroplasmic at nucleo-tide position 8993 of mitochondrial DNA (mtDNA) were introduced into two human tumour cell lines lacking mtDNA. The donor mitochondria contained between 85 and 95% 8993G:C mtDNA. All detectable mtDNA in the mitochondrially transformed cells contained the pathological 8993G:C mutation 3 months after transformation. These results suggest that 8993G:C mtDNA had a selective advantage over 8993T:A mtDNA in both lung carcinoma and osteo-sarcoma cell backgrounds. In contrast, two other presumed pathological mtDNA variants were lost in favour of 'wild-type' mtDNA molecules in the same lung carcinoma cell background. Taken together, these findings suggest that the transmission bias of mtDNA variants is dependent upon a combination of nuclear background and mtDNA genotype. A second phenomenon observed was a marked decrease in the growth rate of many putative transformed cell lines after 6 weeks of culturing in selective medium, and in these cell lines mtDNA was not readily detectable by Southern blotting. Restriction endonuclease analysis and sequencing of amplified mtDNA demonstrated that the slow growing cells contained little or no mtDNA. It is concluded that these cells represented transient mitochondrial transformants. (+info)
Lessons from genetically engineered animal models. II. Disorders of enteric neuronal development: insights from transgenic mice.
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Understanding the development of congenital defects of the enteric nervous system, such as Hirschsprung's disease, was, until recently, an intractable problem. The analysis of transgenic mice, however, has now led to the discovery of a number of genetic abnormalities that give rise to aganglionic congenital megacolon or neuronal intestinal dysplasia. The identification of the responsible genes has enabled the developmental actions of their protein products to be investigated, which, in turn, has made it possible to determine the causes of aganglionoses. Two models of pathogenesis have emerged. One, associated with mutations in genes encoding endothelin-3 or its receptor, endothelin B, posits the premature differentiation of migrating neural crest-derived progenitors, causing the precursor pool to become depleted before the bowel has been fully colonized. The second, associated with mutations in genes encoding glial cell line-derived neurotrophic factor (GDNF), its preferred receptor GFRalpha1, or their signaling component, Ret, appears to deprive a GDNF-dependent common progenitor of adequate support and/or mitogenic drive. In both cases, the terminal bowel becomes aganglionic when the number of colonizing neuronal precursors is inadequate. (+info)
Adult-onset neurologic dysfunction associated with cortical malformations.
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BACKGROUND AND PURPOSE: Malformations of cerebral cortical development are common anomalies of the brain, typically causing developmental delay or seizures that are classically thought to begin in childhood. We present clinical and MR imaging data of 16 patients with cortical malformations in whom evidence of neurologic dysfunction was first noted in adulthood, and attempt to determine whether these malformations had any differentiating features from those presenting in childhood. METHODS: Imaging studies and clinical records of 16 patients with adult-onset neurologic dysfunction were reviewed retrospectively. The patients ranged in age from 17 to 64 years (mean age, 35 years) at the time of imaging. Imaging findings were correlated with seizure history. RESULTS: Fourteen patients had subependymal heterotopia (seven women, seven men), and two patients had closed-lip schizencephalies. Eleven patients had epilepsy, with age of onset ranging from 14 to 45 years (mean age, 22 years); four of them were successfully controlled by medication. The remaining five patients had no seizure disorder. All patients, except one, had normal intelligence. The bilaterality or multiplicity of location of heterotopias was not associated with the presence or absence of seizures, seizure frequency, or electroencephalographic results. CONCLUSION: Subependymal heterotopia and small closed-lip schizencephaly may have minor clinical manifestations that are not evident until adulthood, or may, occasionally, never cause neurologic signs or symptoms whatsoever. (+info)
Neuropsychological function in retired workers with previous long-term occupational exposure to solvents.
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OBJECTIVES: It is plausible that neurodegenerative processes of aging might have a contributing role in the development of chronic effects of exposure to organic solvents. This study evaluated the risk for neuropsychological deficits among retired workers, relative to their histories of exposure to occupational solvents. METHODS: This cross sectional study evaluated retired male workers, 62-74 years of age, including 89 people with previous long-term occupational exposure to solvents (67 retired painters and 22 retired aerospace manufacturing workers), and 126 retired carpenters with relatively minimal previous exposure to solvents. Subjects completed a standardised neuropsychological evaluation and psychiatric interview, structured interviews for histories of occupational exposure and alcohol consumption, and questionnaires assessing neurological and depressive symptoms. RESULTS: By comparison with the carpenters, the painters on average reported greater cumulative alcohol consumption and had lower scores on the WAIS-R vocabulary subtest, usually presumed to reflect premorbid intellectual functioning. These findings, however, were not sufficient to account for the other study findings. Controlling for age, education, vocabulary score, and alcohol use, the painters had lower mean scores on test measures of motor, memory, and reasoning ability; and a subgroup of aerospace workers with moderate to high cumulative exposure to solvents (n = 8) had lower mean scores on measures of visuomotor speed, and motor, attention, memory, and reasoning ability. Subjects were more likely to have an increased number of relatively abnormal test scores (three or more outlier scores on 17 test measures) among both the painter group (odds ratio (OR), 3.1; 95% confidence interval (95% CI) 1.5 to 6.2) and the subgroup of aerospace workers with higher cumulative exposure (OR 5.6; 95% CI 1.0 to 38). The painters, but not the aerospace workers, reported significantly more neurological and depressive symptoms. CONCLUSIONS: The findings are consistent with residual central nervous system dysfunction from long-term exposure to organic solvents, persisting years after the end of exposure. (+info)
Multiple presentation of mitochondrial disorders.
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The aim of this study was to assess the heterogeneous clinical presentations of children with mitochondrial disorders evaluated at a metabolic neurogenetic clinic. The charts of 36 children with highly suspected mitochondrial disorders were reviewed. Thirty one children were diagnosed as having a mitochondrial disorder, based on a suggestive clinical presentation and at least one of the accepted laboratory criteria; however, in five children with no laboratory criteria the diagnosis remained probable. All of the patients had nervous system involvement. Twenty seven patients also had dysfunction of other systems: sensory organs in 15 patients, cardiovascular system in five, gastrointestinal system in 20, urinary system in four, haematopoietic system in four, and endocrine system in nine. The clinical presentation was compatible with an established syndrome in only 15 children. Severe lactic acidosis or ragged red muscle fibres were encountered in very few patients. These results suggest that mitochondrial disorders should be evaluated in children presenting with a complex neurological picture or multisystem involvement. (+info)
Sexual dimorphism in phencyclidine in vitro metabolism and pharmacokinetics in rats.
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Studies were conducted to determine the differences in phencyclidine (PCP) in vitro metabolism and pharmacokinetics in female and male Sprague-Dawley (SD) rats. Formation rates of five major PCP metabolites in liver microsomes were significantly higher (p <.05) in males compared with females in three different rat strains (SD, Fischer 344, and Dark Agouti). In addition, the formation rate for an irreversibly bound PCP metabolite in males was the second highest of the six metabolites measured in these studies. However, the liver microsomes from the females produced essentially no metabolite binding in any strain. To determine the in vivo consequences of these in vitro metabolism results, we determined PCP's pharmacokinetic profile in female SD rats after a pharmacologically active i.v. dose of PCP (1 mg/kg) and then compared these data with the pharmacokinetic profile in male SD rats. The value for PCP systemic (and nonrenal) clearance was more than 45% lower (p <.05) in female rats. In addition, the terminal elimination T(1/2) was significantly longer (p <.05) in the female rats (5.5 versus 3.4 h, respectively). Because the initial serum concentration, volume of distribution at steady state, and renal clearance were not significantly different between the sexes, the longer half-life was attributed directly to a decreased ability of females to metabolize the drug. Consequently, these pharmacokinetic data suggest pharmacological differences in PCP effects between female and male rats are due primarily to a decreased ability of female rats to metabolize the drug. (+info)