Genetic susceptibility to MS: a second stage analysis in Canadian MS families.

Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.

A full genome search in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

Disabling encephalopathy during 5-fluorouracil and levamisole adjuvant therapy for resected colorectal cancer: a report of two cases.

We observed leukoencephalopathy in 1 patient, and progressive dementia in another, during the administration of 5-fluorouracil (5-FU) and levamisole. A retrospective search, among 80 other patients with resected colorectal cancer receiving 5-FU and levamisole as adjuvant therapy, 166 resected malignant melanoma patients receiving adjuvant levamisole, and 254 advanced colorectal cancer patients receiving 5-FU often combined with leucovorin, for other cases of encephalopathy was negative. The frequency of this neurotoxicity is low (about 2% of patients receiving 5-FU and levamisole), but it appears specific for this combination of drugs. The lack of complete reversibility on stopping the drugs is worrisome, as this therapy is used to improve the curability of resected colon cancer.

Stroke prevention in nonvalvular atrial fibrillation: a review of prospective randomized trials.

Patients with atrial fibrillation are at risk for cerebral embolism; however, the roles of chronic anticoagulation or antiplatelet therapy for stroke prevention in patients with nonvalvular atrial fibrillation have been controversial. Recently, the results of three large prospective randomized trials that examined the risks and benefits of warfarin or aspirin for stroke prophylaxis in patients with nonvalvular atrial fibrillation were reported. All three studies revealed a reduction in the stroke rate for patients treated with warfarin and a small incidence of major bleeding. One of the studies also reported a reduced stroke rate in aspirin-treated patients. The reduction of thromboembolic events associated with chronic warfarin therapy appears to outweigh the risks of significant bleeding for most patients with nonvalvular atrial fibrillation. Aspirin may offer an alternative for subgroups of patients who are at low risk for stroke or those who are not good candidates for anticoagulation.

Cerebral edema associated with meningiomas.

The cerebral edema, as judged by computed tomographic scan, associated with supratentorial meningiomas was assessed in 55 cases. No relationship to the occurrence or the degree of edema could be established with respect to meningioma location, histological type, tumor vascularity, cellularity, number of mitotic figures, necrosis, calcification, or cortical invasion. The larger the meningioma, the more likely the presence of and the severity of cerebral edema. The edema is a significant factor in the occurrence of clinical signs and symptoms. A biopsy of cerebral cortex and white matter underlying a transitional meningioma in a patient with associated cerebral edema demonstrated perivascular astrocytic end-feet swelling in the cortex and considerable extracellular fluid in the white matter. The ultrastructural appearance is similar to that seen with primary and metastatic brain tumors and with experimental vasogenic cerebral edema.

The value of combining noninvasive techniques in exercise testing.

A 3-stage cycle ergometer exercise test which combines the noninvasive measurement of systolic time intervals (STI's), stroke volume (SV), mean systolic ejection rate (MSER) and blood pressure was administered to 2 groups of middle-aged men. Group 1 included 15 healthy men. Group 2 consisted of 20 men with coronary artery disease (CAD), confirmed by a proven myocardial infarction. The groups were matched for age, weight and height. Over the range of heart rates (HR's) encountered (70--173 beats min-1) the STI's described an inversely linear relationship with HT. At all exercise HR's, group 2 displayed higher values for total electromechanical systole (QS2), left ventricular ejection time (LVET) and the pre-ejection period (PEP), and lower values for SV and MSER. Statistical comparison of all variables at a common HR of 100 beats min-1 indicated that QS2 and MSER best discriminated between the groups. It was concluded that this test is sufficiently sensitive to detect differences in cardiac performance in groups of subjects, but not for the diagnosis of CAD in individual patients.