Chromosome 17q22-q24 and multiple sclerosis genetic susceptibility. American-French Multiple Sclerosis Genetic Group

Recently, genome-wide searches for multiple sclerosis (MS) susceptibility genes have suggested that the chromosome 17q22-q24 region might contain susceptibility genes in two sets of families of different ethnic backgrounds (Finnish and British). Therefore, we decided to test this region in two sets of families of different ethnic backgrounds (American and French), but collected according to the same diagnostic criteria. All lod-score values were non-significant. Moreover, we could exclude that the 17q22-24 region might contain a gene increasing the sibling recurrence risk of MS over 1.4, rendering the existence of such a gene very unlikely, at least in the group of tested families.     

Threatened abortion: prediction of viability based on signs and symptoms

OBJECTIVE: To examine the relationship between signs and symptoms associated with threatened abortion and viability of the pregnancy. DESIGN: A prospective observational study SETTING: A university teaching hospital PARTICIPANTS: One thousand consecutive women presenting with a threatened abortion. INTERVENTION: A structured history and an examination were performed as initial clinical assessment. These were followed by transvaginal sonography to determine the status of the pregnancy. MAIN OUTCOMES: The relationship between individual signs and symptoms and the status of the pregnancy was determined. Logistic regression was performed to determine which signs or symptoms were independent predictors of spontaneous abortion. RESULTS: A history of having passed a tissue mass, the presence of products of conception in the vagina and an open cervix were the only sign or symptom associated with a greater than 90% chance that the pregnancy was non-viable. Logistic regression of signs and symptoms at presentation indicated that maternal age greater than 35 years, a history of passing clots vaginally, vaginal bleeding similar to normal menstruation, increasing vaginal bleeding and discrepancy of 4 or more weeks between the uterine size on examination and that which would have been expected by menstrual dates were significant predictors of nonviable pregnancy. A history of vomiting was predictive of a viable pregnancy. CONCLUSION: The clinical assessment of threatened abortion is unreliable in most cases and should be superseded by ready access to sonographic assessment.     

Distribution of WDR36 DNA sequence variants in patients with primary open-angle glaucoma

PURPOSE: To determine the distribution of WDR36 sequence variants in a cohort of patients with primary open-angle glaucoma (POAG) in the United States. METHODS: All of the 23 coding exons and flanking introns of the WDR36 gene were sequenced in 118 probands from families with at least two members affected by POAG, 6 probands from juvenile-onset POAG families, and 108 control individuals. RESULTS: Thirty-two WDR36 sequence variants were found in this population of patients with POAG. Nonsynonymous single-nucleotide polymorphisms (SNPs), including those previously described as "disease-causing" and "disease susceptibility," were found in 17% of POAG patients and 4% of control subjects. Although the distribution of WDR36 variants in the pedigrees did not show consistent segregation with the disease, the WDR36 sequence variants were found more frequently in patients with more severe disease. CONCLUSIONS: The results of this study suggest that abnormalities in WDR36 alone are not sufficient to cause POAG. The association of WDR36 sequence variants with more severe disease in affected individuals suggests that defects in the WDR36 gene can contribute to POAG and that WDR36 may be a glaucoma modifier gene.     

Skinfold thickness, body mass index, and fatal coronary heart disease: 30 year follow up of the Northwick Park heart study

STUDY OBJECTIVE: To examine the effect of baseline body mass index (BMI) and skinfold thickness (ST) on fatal coronary heart disease (CHD) and all cause mortality after 30 years of follow up. DESIGN: Prospective cohort study. SETTING: Northwick Park heart study (NPHS) designed to investigate the role of haemostatic variables on CHD. PARTICIPANTS: 1511 men and 691 women enrolled in NPHS aged 40 to 64 years at entry. MAIN RESULTS: Baseline BMI (kg/m(2)) and forearm, triceps, subscapular, and suprailiac skinfolds ST (mm) were measured. Cox regression was used to calculate hazard ratios for fatal CHD and total mortality for each standard deviation unit increase in obesity adjusting for age, smoking status, total cholesterol, systolic blood pressure, fibrinogen, and factor VII activity. Subjects experienced 250 fatal CHDs and 819 all cause deaths over 30 years (median: 26 years; IQR: 22-28 years). Among men, only BMI (RR = 1.29, 95%CI = 1.12 to 1.49) significantly increased the risk of fatal CHD. Among women, BMI (RR = 1.48, 95%CI = 1.07 to 2.06), as well as, subscapular (RR = 1.65, 95%CI = 1.19 to 2.30), forearm (RR = 1.46, 95%CI = 1.08 to 1.97), and triceps (RR = 1.63, 95%CI = 1.12 to 2.39) skinfolds were predictive of fatal CHD. None of the estimates for all cause mortality were significant except for subscapular skinfold in women (RR = 1.20, 95%CI = 1.02 to 1.42). There was no evidence of interaction between obesity and sex for fatal CHD or all cause death. The effect of obesity on fatal CHD or all cause deaths does not seem to be mediated substantially by cholesterol, systolic blood pressure, or haemostatic variables. CONCLUSIONS: BMI is an important risk factor for fatal CHD where its prognostic significance remains after up to 30 years of follow up.     

Development of an unbiased method for the estimation of liver steatosis

BACKGROUND: Steatosis significantly contributes to an organ's transplantability. Livers with >30% fat content have a 25% chance of developing primary non-function (PNF). The current practice of evaluating a hematoxylin and eosin (H&E) stained donor biopsy by visual interpretation is subjective. We hypothesized that H&E staining of frozen sections fails to accurately estimate the degree of steatosis present within a given liver biopsy. To address this problem of evaluating steatosis in prospective donor organs, we developed a fast, user friendly computer methodology to objectively assess fat content based on the differential quantification of color pixels in Oil Red O (ORO) stained liver biopsies. METHODS: The accuracy of human visual estimation of fat content by H&E and ORO stains was compared with computer-based measurements of the same slides from 25 frozen sections of donor biopsies. RESULTS: Samples with a fat content >20% showed marked variation between human interpretation and computer analysis. There was also a significant difference in the human interpretation of fat based on the method of staining. This difference ranged from 3 to 37% with H&E. DISCUSSION: Use of ORO resulted in a more consistent estimation of liver steatosis compared with H&E, but human interpretations failed to correlate with computer measurements. Such differences in fat content estimations might result in the rejection of a potentially transplantable organ or the acceptance of a marginal one. Ideally, our protocol can rapidly be applied to clinical practice for accurate and consistent measurement of fat in liver sections for the ultimate purpose of increasing the number of successful transplantable organs.     

Early adult-onset POAG linked to 15q11-13 using ordered subset analysis

PURPOSE: Primary open-angle glaucoma (POAG) is a complex inherited disorder. It has been demonstrated in other complex disorders that phenotypic heterogeneity may be the result of genetic heterogeneity and that stratification analysis can be used to increase the power of detection. Ordered subset analysis (OSA) is a recently described method that utilizes the variability of phenotypic traits to determine underlying genetic heterogeneity. METHODS: Eighty-six multiplex families with POAG were clinically ascertained for genetic analysis. Age at diagnosis (AAD) was used as a surrogate for age of onset in affected family members. Nine genetic markers within the 15q11-13 interval on chromosome 15 were used for OSA analysis. RESULTS: An 11-cM linkage interval with a peak LOD score of 3.24 centered at the GABRB3 locus (P = 0.013 by permutation test) was identified in a subset of 15 families, which represents 17% of the total dataset (15/86 families). The mean AAD for the affected OSA families was 44.1 +/- 9.1 years (SD). The mean AAD for the complementary group was 61.3 +/- 10.4 years. African-American and white families were well represented in the OSA subset. CONCLUSIONS: Linkage was identified for POAG to an 11-cM region on chromosome 15, designated GLC1I. This result provides further evidence that AAD and other phenotypic traits can be used as stratification variables to identify genes in complex disorders such as POAG and suggests that the 15q11-13 locus is one of the largest genetic contributors to POAG identified to date.     

Unraveling the web: an evaluation of the content quality, usability, and readability of nutrition web sites

OBJECTIVE: To determine the content quality, general readability, and usability characteristics of consumer nutrition information on the World Wide Web. DESIGN: Almost 500 Web sites were identified for evaluation through 2 different approaches. Of these, 150 were included for further evaluation. Each site was rated on a 27-item tool covering content quality, readability, and usability. ANALYSIS: Summary statistics, means, ranges, and standard deviation were calculated for each study variable. The statistical significance of differences between item means by search strategy was determined using Student's t tests. RESULTS: Web sites identified using popular search engines scored significantly lower for content quality (P < .0001), were easier to navigate (P < .001), had better overall adherence to usability standards (P < .0001), and had lower reading levels compared with those sites identified using a government Web portal. CONCLUSIONS AND IMPLICATIONS: Nutrition Web sites obtained using popular search engines may be aesthetically appealing and easy to use, but they often provide inaccurate nutrition information. As consumers increasingly turn to the World Wide Web for nutrition advice and education, it is imperative that the needs of diverse user populations be identified and addressed. Future nutrition education research should build on these findings by creating strategies that help users find reliable user-friendly gateways to accurate nutrition information on the Internet.