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Results for “complex diseases”

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At least 541 records · Page 30Linked to original sources
PubMed1997

Clarithromycin and ethambutol with or without clofazimine for the treatment of bacteremic Mycobacterium avium complex disease in patients with HIV infection.

OBJECTIVE: To compare the efficacy of two- and three-drug regimens for treating Mycobacterium avium complex (MAC) bacteremia in patients with AIDS. DESIGN: Randomized open-label clinical trial. SETTING: Outpatient HIV specialty centers' clinics. PATIENTS: A total of 106 adults with AIDS and MAC bacteremia. INTERVENTIONS: Patients were treated with clarithromycin 500 mg twice daily and ethambutol 800-1,000 mg daily and were randomized to receive clofazimine 100 mg daily or no clofazimine. MAIN OUTCOME MEASURES: Quantitative blood MAC cultures, symptoms, adverse reactions and survival. RESULTS: Patients randomly assigned to three drugs had significantly higher baseline colony counts of MAC in blood than patients receiving two drugs. The proportion of patients becoming culture-negative was 65% in the two-drug group and 54% in the three-drug group. The median time to negative culture was 58 days for patients in the two-drug and 63 days for the three-drug group. At the last visit during treatment, the mean reduction in colony forming units/ml of MAC in blood was 1.8 log10 for the two-drug group and 2.3 log10 for the three-drug group. Improvement in fever and night sweats was reported by 87 and 89% of the two-drug patients and 84 and 86% of the three-drug patients. During the study, 38% of two-drug patients and 61% of three-drug patients died (P = 0.032), and time to death was shorter in patients treated with three drugs (P = 0.012). In a multivariate analysis, both assignment to clofazimine and high baseline colony counts of MAC bacteremia were significantly associated with death (P < 0.05). CONCLUSION: The addition of clofazimine to a regimen of clarithromycin and ethambutol for MAC bacteremia in AIDS patients does not contribute to clinical response and is associated with higher mortality.

AIDS-Related Opportunistic Infections↗
PubMed2005

Large recursive partitioning analysis of complex disease pharmacogenetic studies. II. Statistical considerations.

Identifying genetic variations predictive of important phenotypes, such as disease susceptibility, drug efficacy, and adverse events, remains a challenging task. There are individual polymorphisms that can be tested one at a time, but there is the more difficult problem of the identification of combinations of polymorphisms or even more complex interactions of genes with environmental factors. Diseases, drug responses or side effects can result from different mechanisms. Identification of subgroups of people where there is a common mechanism is a problem for diagnosis and prescribing of treatment. Recursive partitioning (RP) is a simple statistical tool for segmenting a population into non-overlapping groups where the response of interest, disease susceptibility, drug efficacy and adverse events are more homogeneous within the segments. We suggest that the use of RP is not only more technically feasible than other search methods but it is less susceptible to multiple-testing problems. The numbers of combinations of gene-gene and gene-environment interactions is potentially astronomical and RP greatly reduces the effective search and inference space. Moreover, the certain reliance of RP on the presence of marginal effects is justifiable as was found by using analytical and numerical arguments. In the context of haplotype analysis, results suggest that the analysis of individual SNPs is likely to be successful even when susceptibilities are determined by haplotypes. Retrospective clinical studies where cases and controls are collected will be a common design. This report provides methods that can be used to adjust the RP analysis to reflect the population incidence of the response of interest. Confidence limits on the incidence of the response in the segmented subgroups are also discussed. RP is a straightforward way to create realistic subgroups, and prediction intervals for the within-subgroup disease incidence are easily obtained.

Biomedical Research↗
PubMed2006

Geminivirus disease complexes: the threat is spreading.

Symptom-modulating DNA satellites associated with geminiviruses have come to our attention only recently but have proven to be widespread, associated with many diseases throughout the Old World, and economically significant, particularly in developing countries. Recent developments are elucidating the role played by these novel molecules in pathogenicity and in overcoming host plant defense. Further investigation into the promiscuous nature of these satellites and their ability to recruit further begomoviruses indicates that regions not yet affected by such begomovirus-satellite complexes are at great risk.

Crops, Agricultural↗
PubMed2006

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.

Gene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three two-marker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

Autistic Disorder↗
PubMed1997

A retrospective comparison of clarithromycin versus rifampin in combination treatment for disseminated Mycobacterium avium complex disease in AIDS: clarithromycin decreases transfusion requirements.

SETTING: Urban county medical center. OBJECTIVE: To compare clinical outcomes associated with two treatment regimens for AIDS-associated disseminated Mycobacterium avium complex (DMAC). From 1989 to mid-1992, patients were treated with rifampin, ethambutol, and clofazimine; in mid-1992 clarithromycin replaced rifampin. DESIGN: A retrospective review of patients with DMAC; the main outcome measures assessed were toxicity associated with DMAC treatment, transfusions after the diagnosis of DMAC, and survival. RESULTS: 88 patients received the rifampin-based regimen and 86 were treated with the clarithromycin-based regimen. Drug-related adverse events were recorded less frequently with clarithromycin treatment (21% vs. 42%, P = 0.005), and additional antimycobacterial agents were used less often (28% vs. 44%, P = 0.04). In a multivariate logistic regression model, severe anemia at the time of DMAC diagnosis was associated with transfusion-dependence (relative risk [RR] 5.6, 95% confidence interval [CI] 2.2, 13.8, P < 0.001) and clarithromycin treatment was inversely associated with transfusion dependence (RR 0.4, 95% CI 0.1, 0.98, P = 0.04). In a multivariate Cox regression model including other factors affecting survival, clarithromycin treatment did not confer a survival advantage (P = 0.74). CONCLUSIONS: The clarithromycin-containing regimen was better tolerated and was associated with substantially lower transfusion requirements than the rifampin-based regimen; survival was not affected.

AIDS-Related Opportunistic Infections↗
PubMed1992

Cholesteryl ester storage disease: complex molecular effects of chronic lovastatin therapy.

To better characterize the in vivo effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition on human lipid metabolism, an adolescent male with cholesteryl ester storage disease (CESD) was treated chronically with lovastatin. Therapy was associated with decreased liver-spleen size, improved but not normal serum lipids, a 26% decrease in hepatic cholesteryl ester, a 12% decrease in unesterified hepatic cholesterol, and a fourfold increase in hepatic low density lipoprotein (LDL) receptor protein. Hepatic mRNA levels for the LDL receptor and apolipoprotein (apo) B standardized to levels of hepatic gamma actin mRNA were unchanged with therapy. Kinetic studies revealed no change in the LDL fractional catabolic rate and a decrease in the LDL production rate. Size exclusion chromatography showed striking reductions in plasma very low density lipoprotein (VLDL) cholesterol and intermediate density lipoprotein (LDL) cholesterol but not LDL cholesterol with therapy. Mean LDL particle size and the LDL particle size range were increased by treatment. However, there was no difference in the ability of pretreatment or treatment LDL to bind to the LDL receptor on cultured cells consistent with previous studies in animals, indicating that lovastatin may alter LDL particles to impair interaction with the LDL receptor in vivo but not in vitro. Lovastatin therapy in CESD appears to be clinically beneficial and has complex effects on lipid metabolism that may include a dominant inhibitory effect on hepatic lipoprotein production, posttranscriptionally mediated induction of the LDL receptor, and alterations of LDL particles that interfere with their clearance by the LDL receptor in vivo.

Actins↗
PubMed1995

Identification of susceptibility loci contributing to a complex disease using conventional segregation, linkage, and association methods.

We set out to apply conventional analytic methods to a GAW data set of nuclear families with an oligogenic disease that has a population prevalence of 0.023. We chose methods generally applied to disorders with at least one major gene. Our approaches included: 1) complex segregation analysis under two models of ascertainment, 2) linkage analysis assuming either a single-locus trait with possible genetic heterogeneity or a two-locus trait, and 3) allelic association studies using both a case/control approach and the haplotype relative risk (HRR) test. The association study was the only analysis of the three that provided evidence for genes playing a role in the etiology of this disorder.

Alleles↗