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41.
Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome 总被引:20,自引:0,他引:20 下载免费PDF全文
Richards A Kemp EJ Liszewski MK Goodship JA Lampe AK Decorte R Müslümanoğlu MH Kavukcu S Filler G Pirson Y Wen LS Atkinson JP Goodship TH 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(22):12966-12971
Membrane cofactor protein (MCP; CD46) is a widely expressed transmembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10-20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237/S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237/S238 deletion had reduced MCP levels and approximately 50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of protein, but demonstrated approximately 50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies. 相似文献
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If a proper gold standard is not available, then the predictive value of a test cannot be estimated. In this paper the concept of etiologic predictive value (EPV) is introduced. It is a quantity that will yield the predictive value of a test to predict presence of a specified disease in situations for which no proper gold standard is available. This is achieved by using information obtained from a healthy control population. This quantity requires that the marker in our test is present in all individuals having the specified disease, as in the case where the marker is the aetiologic factor for the specified disease. Furthermore this quantity requires that asymptomatic carriers are present. This means that not all individuals with the marker has the specified disease. EPV is developed with special reference to the evaluation of bacterial cultures, or rapid tests to detect a bacterium, but the quantity might be used in other circumstances as well. EPV is applied to an example in which conventional throat culture is evaluated. Further information concerning EPV can be found at http://www.infovice.se/fou/epv. 相似文献
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This work tested the hypothesis that animals with a high energy status are more successful in dealing with stress than animals with a low energy status. Daphnids (Daphnia magna) were reared for 2 weeks in four different concentrations of food. Survival was not affected by food supply, and growth and reproduction increased with increasing food ration. This increase correlated well with the energy status, as was measured by scope for growth on day 15. After 2 weeks, the daphnids in the four different food ration groups were exposed for another 2 weeks to a range of increased salinities or cadmium concentrations, while remaining in their respective food concentrations. In the salinity groups, survival, growth, or reproduction were not influenced at low salinities. Exposure to higher salinity significantly decreased survival and reproduction, but this decrease was more pronounced in the highest food concentrations. In the cadmium exposed daphnids, cadmium content increased with increasing exposure concentrations, but accumulation was independent of food rations. Cadmium exposure significantly decreased survival, growth, and reproduction and this decrease again was more pronounced with increasing food concentration. Thus, the high energy status of the daphnids from the high food concentrations at the start of the exposure did not provide an increased capacity to cope with additional stress. Instead, the sensitivity of the daphnids to stress increased with increasing food ration. This increased sensitivity is likely to be the result of a change in life history from emphasizing survival at low food supply to stressing reproduction at high food supply. 相似文献
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Effects of environmental pollution on microsatellite DNA diversity in wood mouse (Apodemus sylvaticus) populations 总被引:1,自引:0,他引:1
Berckmoes V Scheirs J Jordaens K Blust R Backeljau T Verhagen R 《Environmental toxicology and chemistry / SETAC》2005,24(11):2898-2907
Ten microsatellite DNA loci were surveyed to investigate the effects of heavy metal pollution on the genetic diversity and population genetic structure of seven wood mouse (Apodemus sylvaticus) populations along a heavy metal pollution gradient away from a nonferrous smelter in the south of Antwerp (Flanders, Belgium). Analysis of soil heavy metal concentrations showed that soil Ag, As, Cd, Cu, and Pb decreased with increasing distance from the smelter. Genetic analyses revealed high levels of genetic variation in all populations, but populations from the most polluted sites in the gradient did not differ from those of less-polluted sites in terms of mean observed and expected heterozygosity level and mean allelic richness. No correlation was found between measures of genetic diversity and the degree of heavy metal pollution. However, an analysis of molecular variance and a neighbor-joining tree suggested a contamination-related pattern of genetic structuring between the most polluted and less polluted sites. Pairwise F(ST) values indicated that populations were significantly genetically differentiated, and assignment tests and direct estimates of recent migration rates suggested restricted gene flow among populations. Additionally, genetic differentiation increased significantly with geographical distance, which is consistent with an isolation-by-distance model. We conclude that, at least for our microsatellite DNA markers, genetic diversity in the studied wood mouse populations is not affected greatly by the heavy metal pollution. 相似文献
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The purpose of the study is to explore cancer screening predictors and practices among Lumbee Indians in eastern North Carolina. Interviewers from the community conducted phone interviews with 333 men and 456 women aged 40 and older randomly selected from the Lumbee Tribal roll as part of the Lumbee Diabetes and Health Survey. The survey has sections on demographic information and health conditions, family history of chronic conditions, and health behaviors. This paper reports on cancer screening behaviors. Rates of ever being screened for breast, cervical, prostate and colon cancer were relatively high compared with overall national rates. Predictors included younger age, better health, more education, and lifestyle factors such as engaging in regular physical activity and not smoking. Future research should focus on developing culturally appropriate campaigns to increase the frequency of cancer screening to conform to guidelines, and educational programs and interventions to reach Lumbee Indians most at risk for not being screened. 相似文献
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Daniely M Rona R Kaplan T Olsfanger S Elboim L Zilberstien Y Friberger A Kidron D Kaplan E Lew S Leibovitch I 《Urology》2005,66(6):1354-1359
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It has recently been shown that the iron isotopic composition of blood differs between individuals and sexes, which is supposed to reflect individual differences in iron metabolism. We hypothesized that patients suffering from hereditary hemochromatosis would demonstrate alterations in the iron isotopic composition of blood due to persistent up-regulation of intestinal iron absorption. Blood from 30 patients with homozygous C282Y hemochromatosis was analyzed for iron isotopic composition by a newly developed technique using multicollector inductively coupled plasma mass spectrometry (MC-ICP-MS). Blood of patients with hemochromatosis is characterized by a higher 56Fe/54Fe isotope ratio than blood of healthy individuals, which are either members of an age-matched control group (n = 10; P < .001) or young adults (n = 36; P < .001). In patients with hereditary hemochromatosis, the 56Fe/54Fe isotope ratio of blood significantly correlates with total-body iron accumulation, severity of clinical disease, and the need for regular phlebotomies to prevent iron reaccumulation. We conclude that blood of patients with hereditary hemochromatosis contains more of the heavier iron isotopes than blood of healthy individuals. The primary determinant of the iron isotopic composition of blood appears to be isotope-sensitive iron absorption in the intestine and the efficiency of this process. 相似文献