Showing papers by "Michael Hughes published in 2005"
TL;DR: Evidence is presented that Drosophila immune-competent cells have the potential to express more than 18,000 isoforms of the immunoglobulin-superfamily receptor Down syndrome cell adhesion molecule (Dscam), and the molecular diversity of Dscam transcripts generated through a mechanism of alternative splicing is highly conserved across major insect orders, suggesting an unsuspected molecular complexity of the innate immune system of insects.
Abstract: The extensive somatic diversification of immune receptors is a hallmark of higher vertebrates. However, whether molecular diversity contributes to immune protection in invertebrates is unknown. We present evidence that Drosophila immune-competent cells have the potential to express more than 18,000 isoforms of the immunoglobulin (Ig)-superfamily receptor Down syndrome cell adhesion molecule (Dscam). Secreted protein isoforms of Dscam were detected in the hemolymph, and hemocyte-specific loss of Dscam impaired the efficiency of phagocytic uptake of bacteria, possibly due to reduced bacterial binding. Importantly, the molecular diversity of Dscam transcripts generated through a mechanism of alternative splicing is highly conserved across major insect orders, suggesting an unsuspected molecular complexity of the innate immune system of insects.
674 citations
TL;DR: CX3CR1 genotypes and haplotypes impact HIV-1 disease progression independently of CD4+ lymphocyte count and plasma HIV- 1 RNA load, suggesting that the fundamental role of CX3 CR1 in the alteration of disease progression might be the recruitment of immunomodulatory cells responsible for the control of HIV-2.
Abstract: Background. The impact of CX 3 CR1 polymorphisms on human immunodeficiency virus type 1 (HIV-1) pathogenesis is controversial, with conflicting reports of their role in disease progression in HIV-1-infected adults. Methods. A cohort of 1055 HIV-1-infected children were genotyped for 2 CX 3 CR1 polymorphisms, V/I249 and T/M280, and their impact on HIV-1-related disease progression, including central nervous system (CNS) impairment, was evaluated. Results. Children with the CX 3 CR1 1/1249 genotype experienced more-rapid disease progression (1/1249 vs. V/ V249: relative hazard [RH], 2.19 [95% confidence interval {CI}, 1.30-3.68], P = .003; 1/1249 vs. V/I249: RH, 1.77 [95% CI, 1.00-3.14], P = .05) and a trend toward more CNS impairment (1/1249 vs. V/V249: RH, 2.19 [95% CI, 1.00-4.78], P = .049; 1/1249 vs. V/I249: RH, 2.02 [95% CI, 0.85-4.83], P = .11). Children with the V249-T280 haplotype experienced significantly less disease progression (RH, 0.42 [95% CI, 0.24-0.73]; P = .002) and CNS impairment (RH, 0.39 [95% CI, 0.39-0.22]; P = .001). Of note, these effects remained significant after CD4 + lymphocyte count and plasma HIV-1 RNA load at baseline were adjusted for and in a longitudinal, multivariate analysis. Conclusions. CX 3 CR1 genotypes and haplotypes impact HIV-1 disease progression independently of CD4 + lymphocyte count and plasma HIV-1 RNA load, suggesting that the fundamental role of CX 3 CR1 in the alteration of disease progression might be the recruitment of immunomodulatory cells responsible for the control of HIV-1.
44 citations
TL;DR: In this population of children with HIV, total lymphocyte count was a strong predictor of short-term disease progression, being only marginally less predictive than CD4-cell percentage, and when the markers were compared at the threshold values at which mortality risks were about equal, this resulted in an earlier start of antiretroviral therapy.
37 citations
TL;DR: A combination regimen of ritonavir, zidovudine and lamivudine was generally safe and produced sustained viral suppression in more than one-third of infants who initiated therapy before 2 years of age.
Abstract: Background:Few data are available regarding clinical outcomes or dosing requirements for the protease inhibitor ritonavir in human immunodeficiency virus (HIV)-infected children younger than under 24 months of age.Methods:This prospective, multicenter phase I/II open label treatment trial used riton
35 citations
TL;DR: Although claims databases are not representative of all care delivery, their predisposition toward serious unintended injury can complement resource-intensive chart reviews and guide patient safety initiatives and suggest diagnosis-related negligent adverse events are a serious problem in the healthcare industry.
Abstract: Objective Although claims databases are not representative of all care delivery, their predisposition toward serious unintended injury can complement resource-intensive chart reviews and guide patient safety initiatives. Materials and methods Non-Veterans Health Administration (VA) practitioners reviewed 1,949 VA malpractice claims paid during fiscal years 1998 through 2003. The portion associated with substandard care, the severity of harm, and types of negligence were identified. Results Negligent adverse events occurred in 37% (n = 723) of paid VA malpractice claims. These had high proportions of serious injury (55%) and morbidity (37%). Diagnostic negligent adverse events were most frequent (45%) and with 41% associated morbidity. The annual incidence of diagnosis-related paid VA malpractice claims was 1.95 per 100,000 patients and predicts that 122 of every 100,000 patients may have diagnostic negligent adverse events. Comparisons against non-VA data suggest this to be a healthcare industry problem. Conclusions Diagnosis-related negligent adverse events are a serious problem in the healthcare industry.
26 citations
Journal Article•
TL;DR: The data suggest that nelfinavir is well tolerated in infants at these doses, but exposure was frequently less than that seen in adults taking standard nELFinavir dosing.
Abstract: The safety and pharmacokinetics of nelfinavir coadministered with zidovudine and lamivudine were studied in 26 infants during the first 6 weeks of life. Cohort 1 infants (n = 7) received 10 mg/kg 3 times a day, and cohort 2 infants (n = 19) received 40 mg/kg twice a day. Two cohort 1 infants at week 1 and none at week 6 exceeded the target 24-hour area under the curve (AUC) of 30 mug.h/mL, equal to the 10th percentile of the AUC for adults receiving standard nelfinavir dosing. In cohort 2, the median 24-hour AUC was 38 mug.h/mL at both time points, with considerable variability among the infants. Three of 11 cohort 2 infants at week 1 and 4 of 11 at week 6 did not meet the AUC target. Median nelfinavir oral clearance was 2.1 L/h/kg at weeks 1 and 6. The median ratio of the plasma concentrations of the nelfinavir metabolite M8 to unchanged nelfinavir increased from 0.16 (range: 0-0.38) during week 1 to 0.56 (range: 0.4-1.47) during week 6 (P < 0.01). There were no significant differences in any of the other pharmacokinetic parameters when week 1 and week 6 results were compared. Few adverse events were attributed to nelfinavir. These data suggest that nelfinavir is well tolerated in infants at these doses, but exposure was frequently less than that seen in adults taking standard nelfinavir dosing. Further investigations of larger doses, such as 75 mg/kg twice a day, should be undertaken.
20 citations
15 Jul 2005
19 citations
TL;DR: Combination therapy containing NFV + RTV + ddI appears more efficacious in NRTI-experienced children than a regimen containingNFV + NVP + d4T, and exposure to the NFV metabolite, M8, was significantly higher in subjects receiving RTV.
Abstract: Introduction:Few combinations of highly active antiretrovirals have been studied in nucleoside reverse transcription inhibitor (NRTI)-experienced, human immunodeficiency virus (HIV)-infected children We tested the efficacy, tolerability and pharmacokinetics of 2 combination therapies containing an
16 citations
01 Jan 2005
7 citations
TL;DR: The goal in this article is to describe some of the more problematic areas in HIV clinical trial design using examples from the literature.
Abstract: The interpretation of HIV clinical trials can be challenging. To reach an appropriate conclusion about the validity of study results, a reader should have a clear understanding of how trial characteristics can influence results in powerful and sometimes contradictory ways. These factors include, but are not limited to, subtleties of data analysis and study design, the means by which risk is assessed, characteristics of the study population, and the impact of antiretroviral treatment history on the results. Recognizing the characteristics and pitfalls inherent in HIV clinical trial design and execution is crucial to understanding the clinical significance and importance of a specific study's findings. Our goal in this article is to describe some of the more problematic areas in HIV clinical trial design using examples from the literature.
2 citations