Statistically significant differences in the number of CD24 positive muscle fibers and satellite cells between sarcoglycanopathy and age-matched Becker muscular dystrophy patients.
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OBJECT: The aim of this study was to reveal variations in the patterns of expression of the cell surface proteins in regenerating fibers and those in the number of satellite cells to gain an understanding of the pathological processes involved in sarcoglycanopathy. METHODS: We have reported that there is a reduction of the beta-1 subunit of laminin, heparan sulfate proteoglycan (HSPG), and HCAM (CD44) in Japanese patients with sarcoglycanopathy. Here, we investigated immunohistochemically the expression of the neural cell adhesion molecule (NCAM), which is a marker for human regenerating muscle and satellite cell, and CD24, which appears to be expressed in the early stages of the regeneration process. PATIENTS: We investigated six Japanese patients with sarcoglycanopathy, and compared to age-matched Becker muscular dystrophy. RESULTS: We found that the incidences of muscle fibers with increased NCAM were not statistically different between the two groups. However, the incidences of muscle fibers with increased CD24 and those of NCAM positive satellite cells were very low in sarcoglycanopathy and were statistically different between sarcoglycanopathy and age-matched Becker muscular dystrophies. CONCLUSION: The poor expression of CD24 and the fewer satellite cells in sarcoglycanopathy without significant difference in the number of total regenerating fibers suggest that a different regeneration process is involved in sarcoglycanopathy compared to that in other types of muscular dystrophy. (+info)
Prevalence of people reporting sensitivities to chemicals in a population-based survey.
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To describe the prevalence and correlates of reports about sensitivities to chemicals, questions about chemical sensitivities were added to the 1995 California Behavior Risk Factor Survey (BRFS). The survey was administered by telephone to 4,046 subjects. Of all respondents, 253 (6.3%) reported doctor-diagnosed "environmental illness" or "multiple chemical sensitivity" (MCS) and 643 (15.9%) reported being "allergic or unusually sensitive to everyday chemicals." Sensitivity to more than one type of chemical was described by 11.9% of the total sample population. Logistic regression models were constructed. Hispanic ethnicity was associated with physician-diagnosed MCS (adjusted odds ratio (OR) = 1.82, 95% confidence interval (CI) 1.21-2.73). Female gender was associated with individual self-reports of sensitivity (adjusted OR = 1.63, 95% CI 1.23-2.17). Marital status, employment, education, geographic location, and income were not predictive of reported chemical sensitivities or reported doctor diagnosis. Surprising numbers of people believed they were sensitive to chemicals and made sick by common chemical exposures. The homogeneity of responses across race-ethnicity, geography, education, and marital status is compatible with a physiologic response or with widespread societal apprehensions in regard to chemical exposure. (+info)
Transmission disequilibrium test (TDT) when only one parent is available: the 1-TDT.
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The transmission disequilibrium test (TDT) is a useful method to locate mutations linked to disease genes associated with complex diseases. TDT requires genotypes of affected individuals and their parents. Recently, Ewens and Spielman (Am J Hum Genet 1998;62:450-8) extended the TDT for use in sibships with at least one affected and one unaffected individual and devised a new test called the sib transmission/disequilibrium test (S-TDT). The S-TDT can be applied to diseases with late age at onset such as non-insulin-dependent diabetes mellitus, psychiatric disorders, and diseases related to aging. For some disorders, it might be relatively easy to obtain the genotype of one parent either because the other parent is not available for study or he/she is not cooperative. Curtis and Sham (Ann Hum Genet 1995;59:323-36) showed that bias in transmitting certain alleles is introduced if only heterozygous parents and homozygous offspring are used in the TDT. In this paper, the authors propose a new test, the 1-TDT, to detect linkage between a candidate locus and a disease locus using genotypes of affected individuals and only one available parent for each affected individual. The test is not biased under the null hypothesis of no linkage or association. The authors validate their test using both simulated and real data sets. Finally, they show how to combine data from different types of families. (+info)
Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Abeta42 secretion.
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We previously described a splice donor site mutation in intron 4 of presenilin-1 (PSEN1) in two patients with autopsy-confirmed early-onset Alzheimer's disease (AD). Here we provide evidence that the intron 4 mutation is present in four additional unrelated early-onset AD cases, that the mutation segregates in an autosomal dominant manner and that all cases have one common ancestor. We demonstrate that the intron 4 mutation produces three different transcripts, two deletion transcripts (Delta4 and Delta4cryptic) and one insertion transcript (insTAC), by aberrant splicing. The deletion transcripts result in the formation of C-truncated (approximately 7 kDa) PSEN1 proteins while the insertion transcript produces a full-length PSEN1 with one extra amino acid (Thr) inserted between codons 113 and 114 (PSEN1 T113-114ins). The truncated proteins were not detectable in vivo in brain homogenates or lymphoblast lysates of mutation carriers. In vitro HEK-293 cells overexpressing Delta4, Delta4cryptic or insTACPSEN1 cDNAs showed increased Abeta42 secretion (approximately 3.4 times) only for the insertion cDNA construct. Increased Abeta42 production was also observed in brain homogenates. Our data indicate that in the case of intron 4 mutation, the AD pathophysiology results from the presence of the PSEN1 T113-114ins protein comparable with cases carrying dominant PSEN1 missense mutations. (+info)
Antiphospholipid antibodies syndrome in 'Stroke in young'.
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Antiphospholipid antibodies syndrome has emerged as an important entity responsible for stroke in young. Seven cases of young stroke (< 40 years of age) with mean age of 30.1 years (age range 25-39 years, 2 males and 5 females), who tested positive for antiphospholipid antibodies are being reported. All subjects had completed strokes. Six had arterial ischaemic and one patient had venous stroke. One patient suffered from four episodes, three ischaemic and one intracerebral haemorrhage. Two patients suffered from foetal loss. Generalised tonic clonic seizures occurred in three patients. Deep vein thrombosis was observed in one case. Thrombocytopenia was not observed in any case. All the patients had elevated anticardiolipin antibodies (aCL) IgM or IgG, while Lupus anticoagulant (LA) was elevated in 4 cases. Six cases belonged to primary antiphospholipid antibodies syndrome and one to lupus like illness. Oral anticoagulants were administered to maintain a high intensity international normalized ratio (INR). No recurrences were observed during a follow up period of 6-18 months. (+info)
Plasma antithrombin III deficiency in ischaemic stroke in the young.
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A deficiency of plasma antithrombin III has been identified as a potential risk factor for thrombosis. In a pilot study of 56 patients aged less than 40 years who presented with ischaemic stroke of unknown etiology, we detected only one case of plasma antithrombin III deficiency. Antithrombin III activity was estimated by a chromogenic assay. Hence, antithrombin III deficiency, though rare, should be considered while evaluating young patients with stroke of unknown etiology. (+info)
Augmented production of chemokines (monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta) in patients with systemic sclerosis: MCP-1 and MIP-1alpha may be involved in the development of pulmonary fibrosis.
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To determine the role of chemokines in the pathogenesis of systemic sclerosis (SSc), we examined serum levels, spontaneous production by peripheral blood mononuclear cells (PBMC), and histological distribution in the affected skin, of MCP-1, MIP-1alpha and MIP-1beta in SSc patients. Serum levels of these chemokines were examined by ELISA in 58 patients with SSc and 20 normal controls. The levels of these chemokines in culture supernatants from PBMC were also measured by ELISA. Serum levels and spontaneous production levels by PBMC of MCP-1, MIP-1alpha, and MIP-1beta were significantly elevated in patients with SSc compared with normal controls. Elevated serum levels of MCP-1 and MIP-1alpha significantly correlated with the presence of pulmonary fibrosis. MCP-1 expression in the skin of SSc was immunohistochemically examined using anti-MCP-1 MoAb. MCP-1 was strongly expressed in the epidermis, inflammatory mononuclear cells, and vascular endothelial cells in the sclerotic skin of SSc patients, but not expressed in any control skin. Furthermore, the MCP-1 expression in inflammatory mononuclear cells and endothelial cells significantly correlated with earlier onset of SSc. Thus, MCP-1, MIP-1alpha and MIP-1beta may be involved in the disease process, possibly by augmenting leucocyte migration into the affected tissues in SSc. Furthermore, MCP-1 and MIP-1alpha may play an important role in the development of pulmonary fibrosis in SSc. (+info)
Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors.
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OBJECTIVE: To establish the characteristics of patients following a benign course of multiple sclerosis and evaluate the importance of potential prognostic factors. Also, an assessment of the value of the Kurtzke EDSS as a prognostic indicator has been undertaken in patients previously determined to have benign multiple sclerosis, after 10 years of follow up. METHODS: A prevalence study in the Coleraine, Ballymena, Ballymoney, and Moyle districts of Northern Ireland used the Kurtzke expanded disability scale score (EDSS) in 259 patients with multiple sclerosis. Of these, 181 had had multiple sclerosis for>/=10 years, 36 having benign disease (EDSS/=10 years after onset. Clinical and demographic details of the various patient groups, including the minimal record of disability, were compared. The 1987 study in Northern Ireland identified 33 patients with benign multiple sclerosis. Twenty eight were available for follow up in 1996 along with 42 contemporary non-benign patients. RESULTS: Patients with benign multiple sclerosis were predominantly women (ratio 4.1:1 v 2.1:1) and younger at onset (25.8 v 31.2 years). Commonest symptoms at onset were sensory and optic neuritis (33.3% each). Patients with late onset (older than 40 years) were less likely to have a benign course, more likely to have a progressive course from onset, significantly more likely to have motor disturbance at presentation, and had a lesser female predominance. Optic neuritis was significantly more common in those with a younger age at onset. In the follow up study, patients with benign multiple sclerosis continued to have a more favourable course than non-benign counterparts but progression of disability and to the secondary progressive phase remained significant. CONCLUSIONS: The association of female sex, early onset, and presentation with optic neuritis and sensory symptoms with a favourable course is confirmed. However, although the EDSS does provide a useful indicator of prognosis, the label "benign multiple sclerosis" is often temporary as apparently benign disease often becomes disabling. (+info)