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1.
Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1 cM of major candidate genes, namely APOB (LOD=2.1), LDLR (LOD=1.9) and APOE (LOD=1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate.  相似文献   
2.
Classical evolutionary theory predicts the existence of genes with antagonistic effects on longevity and various components of early-life fitness. Quantitative genetic studies have provided convincing evidence that such genes exist. However, antagonistic pleiotropic effects have rarely been attributed to individual loci. We examine several classes of longevity-assurance genes: those involved in regulation of the gonad; the insulin-like growth factor pathway; free-radical scavenging; heat shock proteins and apoptosis. We find initial evidence that antagonistic pleiotropic effects are pervasive in each of these classes of genes and in various model systems--although most studies lack explicit studies of fitness components. This is particularly true of human studies. Very little is known about the early-life fitness effects of longevity loci. Given the possible medical importance of such effects we urge their future study.  相似文献   
3.
OBJECTIVE: To determine whether population differences can explain the contrasting impacts on HIV observed in the Mwanza trial of sexually transmitted disease (STD) syndromic treatment (ST), the Rakai trial of STD mass treatment (MT), and the Masaka trial of information, education, and communication (IEC) with and without ST as well as to predict the effectiveness of each intervention strategy in each population. METHODS: Stochastic modeling of the transmission of HIV and 6 STDs was used with parameters fitted to demographic, sexual behavior, and epidemiological data from the trials and general review of STD/HIV biology. RESULTS: The baseline trial populations could be simulated by assuming higher risk behavior in Uganda compared with Mwanza in the 1980s, followed by reductions in risk behavior in Uganda preceding the trials. In line with trial observations, the projected HIV impacts were larger for the ST intervention in Mwanza than for the MT intervention in Rakai or the IEC and IEC + ST interventions in Masaka. All 4 simulated intervention strategies were more effective in reducing incidence of HIV infection in Mwanza than in either Rakai or Masaka. CONCLUSIONS: Population differences in sexual behavior, curable STD rates, and HIV epidemic stage can explain most of the contrast in HIV impact observed between the 3 trials. This study supports the hypothesis that STD management is an effective HIV prevention strategy in populations with a high prevalence of curable STDs, particularly in an early HIV epidemic.  相似文献   
4.
When the lateral olfactory tract (LOT) of the golden hamster, Mesocricetus auratus, is transected in the first week of postnatal life, axons can grow back past the lesion and achieve functional reinnervation of caudal projection regions. In contrast, when the tract is sectioned after postnatal day 7 (P7), axons do not reinnervate regions caudal to the cut. The experiments reported here investigated whether regenerative failure after tract section in pups older than P7 is accompanied by developmental changes in the astrocytic response. LOT transections were performed at P3 and P9 and the glial reaction was observed at survival times ranging from 12 hr to 2 weeks. Immunocytochemistry with glial fibrillary acidic protein (GFAP) was employed for histological visualization of astrocytic reactivity. Staining for GFAP immunoreactivity showed an appreciable glial reaction after tract section at both P3 and P9, but the extent of astrocytic hypertrophy and proliferation of glial processes was considerably greater and more extensive after tract section at P9. Radial glial cells were observed 2 weeks after LOT transection at P3 but were absent after lesions made at P9. The results from this study suggest that the developmental loss of regenerative capacity after LOT transection may be related to maturational changes in the glial response. In particular, the presence of radial glial elements after P3 lesions could serve to establish a more favorable microenvironment for axonal elongation.  相似文献   
5.
beta(2)-Glycoprotein I (beta(2)GPI) is a principal target antigen for antiphospholipid antibodies associated with recurrent pregnancy loss and fetal growth restriction in women. The significance of disrupted beta(2)GPI activity in contributing to pregnancy pathology in antiphospholipid syndrome (APS) is not clear. In this study the physiological requirement for functional beta(2)GPI in pregnancy was investigated by evaluating reproductive outcomes in beta(2)GPI null mutant (beta(2)GPI-/-) mice. beta(2)GPI-/- mice were fertile and carried viable fetuses to term. However, there was an 18% reduction in the number of viable implantation sites in beta(2)GPI-/- mice and reduced fetal weight and fetal:placental weight ratio in late gestation, suggesting compromised placental function. Placental architecture was altered in beta(2)GPI-/- implantation sites with a 24% increase in the junctional zone: labyrinthine ratio, but placentae showed no evidence of increased thrombosis in the absence of beta(2)GPI. The effect of beta(2)GPI genotype on pregnancy success after passive transfer of human and mouse antibodies reactive with beta(2)GPI was also explored. Two of five anti-beta(2)GPI antibodies induced pregnancy loss in beta(2)GPI+/+ mice but beta(2)GPI-/- mice were refractory to antibody-induced pregnancy failure. We conclude that functional beta(2)GPI is not essential for successful pregnancy in mice, but optimal placental development and fetal growth require this molecule. Together these data are consistent with pathogenic mechanisms in antiphospholipid syndrome involving both neutralization of beta(2)GPI function and beta(2)GPI-immunoglobulin complex formation.  相似文献   
6.
INTRICATE is a prospective double-blind placebo-controlled feasibility study, assessing the influence of combined vitamin K2 and vitamin D3 supplementation on micro-calcification in carotid artery disease as imaged by hybrid Sodium [18F]Fluoride (Na[18F]F) positron emission tomography (PET)/ magnetic resonance imaging (MRI). Arterial calcification is an actively regulated process and results from the imbalance between calcification promoting and inhibiting factors. Considering the recent advancements in medical imaging, ultrasound (US), PET/MRI, and computed tomography (CT) can be used for the selection and stratification of patients with atherosclerosis. Fifty-two subjects with asymptomatic carotid artery disease on at least one side of the neck will be included in the study. At baseline, an Na[18F]F PET/MRI and CT examination will be performed. Afterwards, subjects will be randomized (1:1) to a vitamin K (400 µg MK-7/day) and vitamin D3 (80 µg/day) or to placebo. At the 3-month follow-up, subjects will undergo a second Na[18F]F PET/MRI and CT scan. The primary endpoint is the change in Na[18F]F PET/MRI (baseline vs. after 3 months) in the treatment group as compared to the placebo arm. Secondary endpoints are changes in plaque composition and in blood-biomarkers. The INTRICATE trial bears the potential to open novel avenues for future large scale randomized controlled trials to intervene in the plaque development and micro-calcification progression.  相似文献   
7.
8.
OBJECTIVE: To establish whether bilateral standing with visual feedback therapy after stroke improves postural control compared with conventional therapy and to evaluate the generalization of the effects of visual feedback therapy on gait and gait-related activities. DESIGN: A systematic review. METHODS: A computer-aided literature search was performed. Randomized controlled trials and controlled clinical trials, comparing visual feedback therapy with conventional balance treatments were included up to April 2005. The methodological quality of each study was assessed with the the Physiotherapy Evidence Database scale. Depending on existing heterogeneity, studies with a common variable of outcome were pooled by calculating the summary effect-sizes using fixed or random effects models. RESULTS: Eight out of 78 studies, presenting 214 subjects, were included for qualitative and quantitative analysis. The methodological quality ranged from 3 to 6 points. The meta-analysis demonstrated non-significant summary effect-sizes in favour of visual feedback therapy for weight distribution and postural sway, as well as balance and gait performance, and gait speed. CONCLUSION: The additional value of visual feedback therapy in bilateral standing compared with conventional therapy shows no statistically significant effects on symmetry of weight distribution between paretic and non-paretic leg, postural sway in bilateral standing, gait and gait-related activities. Visual feedback therapy should not be favoured over conventional therapy. The question remains as to exactly how asymmetry in weight distribution while standing is related to balance control in patients with stroke.  相似文献   
9.
10.
ABSTRACT: BACKGROUND: Partner notification (PN) among individuals newly diagnosed with HIV/STI is seen as a vital tool to identify others at risk of infection. However, hardly any data are available on the effectiveness of PN on HIV/STI transmission in the Netherlands. This study aims to fill this gap by assessing current PN practices, case-finding effectiveness, and determinants of being notified among men having sex with men (MSM) in the Netherlands. METHODS: Nurses from five STI centers participated in a prospective pilot study on PN outcomes (partners being: at risk, notifiable, notified, and tested) for HIV/STI, by completing a newly developed PN registration form (PN database). PN outcomes including case-finding effectiveness (number of newly diagnosed cases in partners/number of partners being tested) for HIV, syphilis, and gonorrhoea were studied among MSM. Furthermore, the national STI database was analyzed to identify determinants of being notified. The number of infections that remained undetected was estimated based on these two databases. RESULTS: In total 105 MSM, newly diagnosed with HIV/STI, reported 612 sexual partners at risk of whom 41% were notifiable and 31% were notified. Patient referral was the predominant PN method (90%). The overall case-finding percentage was 36% (HIV: 15-33%, gonorrhoea: 17- 50% and syphilis: 4-11%). Case-finding percentages were lower in the national STI database: 21% (5%, 28%, 12%). Persons with one or more sexual partners, known HIV positives, and IDU were more likely to be notified to the STI clinic. Notified clients were more likely to have HIV/STI than unnotified clients (OR 1.7-2.5). Based on these two databases, an estimated 75 to 133 infections remained undetected (HIV: 12-90; gonorrhoea: 28-97; syphilis: 5-12 infections). CONCLUSIONS: Partner notification among MSM in the Netherlands is suboptimal; an extensive number of STI/HIV infections remained undetected mainly due to unnotifiable partners. To enhance PN practices, combined and innovative PN interventions such as Internet-based PN will be implemented for hard-to-reach MSM and other risk groups.  相似文献   
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