Biomedical subjects

Tracy Mills

Publications and source records attributed to Tracy Mills.

4 recordsLinked to original sources

PubMed2006

Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster.

OBJECTIVES: The use of carbamazepine (CBZ), the most commonly prescribed antiepileptic drug, is hampered by the occurrence of severe, potentially lethal hypersensitivity reactions. The pathogenesis of hypersensitivity is not yet known, but immune mechanisms are involved. Predisposition to CBZ hypersensitivity is likely to be genetically determined, and genes within the major histocompatibility complex (MHC) have been implicated. The heat shock protein (HSP70) gene cluster is located in the MHC class III region. METHODS: Using a case-control study design, we compared 61 patients with CBZ hypersensitivity (22 with a severe reaction) to 44 patients on CBZ with no signs of hypersensitivity and 172 healthy controls. The genotyping strategy involved identification of common and rare single nucleotide polymorphisms (SNPs) within the HSP70 gene cluster by sequencing, estimation of linkage disequilibrium (LD) and haplotype structure, and thereafter, analysis of SNP/haplotype frequencies in the cases and controls. Population substructure was evaluated by genotyping of 34 microsatellites. RESULTS: Twenty-five SNPs were detected across the three HSP70 genes. Analyses revealed that alleles G, T and C at the SNPs HSPA1A +1911 C/G, HSPA1A +438 C/T and HSPA1L +2437 T/C, respectively, were associated with protection from serious hypersensitivity reactions to CBZ, with the associated alleles falling on a common haplotype. We were unable to detect the presence of population stratification in our patients and controls. CONCLUSIONS: Our data show that HSP70 gene variants are associated with serious CBZ hypersensitivity reactions, but whether this is causal or reflects LD with another gene within the MHC requires further study.

Adolescent↗

PubMed2004

Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites.

Despite the theoretical evidence of the utility of single-nucleotide polymorphisms (SNPs) for linkage analysis, no whole-genome scans of a complex disease have yet been published to directly compare SNPs with microsatellites. Here, we describe a whole-genome screen of 157 families with multiple cases of rheumatoid arthritis (RA), performed using 11,245 genomewide SNPs. The results were compared with those from a 10-cM microsatellite scan in the same cohort. The SNP analysis detected HLA*DRB1, the major RA susceptibility locus (P=.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the microsatellite scan. In addition, four loci were detected at a nominal significance level (P<.05) in the SNP linkage analysis; these were not observed in the microsatellite scan. We demonstrate that variation in information content was the main factor contributing to observed differences in the two scans, with the SNPs providing significantly higher information content than the microsatellites. Reducing the number of SNPs in the marker set to 3,300 (1-cM spacing) caused several loci to drop below nominal significance levels, suggesting that decreases in information content can have significant effects on linkage results. In contrast, differences in maps employed in the analysis, the low detectable rate of genotyping error, and the presence of moderate linkage disequilibrium between markers did not significantly affect the results. We have demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allows loci to be defined more precisely and provides a partial scaffold for association studies, substantially reducing the resource requirement for gene-mapping studies.

Arthritis, Rheumatoid↗

PubMed2004

Oral daily ibandronate prevents bone loss in early postmenopausal women without osteoporosis.

UNLABELLED: Oral daily ibandronate was investigated for the prevention of bone loss in postmenopausal women without osteoporosis (n = 653). BMD at the lumbar spine and hip were significantly increased (3.1% and 1.8%, respectively; p < or = 0.0001 versus placebo) with 2.5 mg ibandronate after 24 months. Oral ibandronate is a promising option for the prevention of postmenopausal bone loss. INTRODUCTION: Further strategies to manage patients most at risk from developing postmenopausal osteoporosis are required. The objectives of this multicenter, double-blind, randomized, placebo-controlled study were to examine the efficacy, tolerability, and optimal dose of oral daily ibandronate in the prevention of bone loss in postmenopausal women. MATERIALS AND METHODS: In total, 653 women (mean bone mineral density [BMD] T-score > -2.5 at the lumbar spine), who had been postmenopausal for at least 1 year, were allocated to one of four strata based on time since menopause and baseline lumbar spine BMD. Women were randomized to receive calcium (500 mg daily) plus either placebo (n = 162) or ibandronate 0.5 mg (n = 162), 1 mg (n = 166), or 2.5 mg (n = 163) as once-daily oral treatment for 2 years. The primary endpoint was the mean percent change in lumbar spine BMD with ibandronate versus placebo. RESULTS AND CONCLUSIONS: After 2 years, oral daily ibandronate produced a dose-related and sustained maintenance or increase in BMD at the lumbar spine and hip (total hip, femoral neck, trochanter), together with a dose-related reduction in the rate of bone turnover. The greatest nominal increases in spinal and hip BMD were observed with the 2.5-mg dose, which produced statistically significant BMD gains compared with placebo at 6 months and all subsequent time-points at the spine and hip (3.1% and 1.8% increase in lumbar spine and total hip BMD, respectively, versus placebo; p < or = 0.0001 after 24 months). Oral daily ibandronate was well tolerated with an incidence of upper gastrointestinal adverse events similar to placebo. No safety concerns were identified. In summary, oral daily ibandronate 2.5 mg decreases bone turnover, preserves or increases BMD in the spine and proximal femur, and is well tolerated. Oral ibandronate provides a promising option for the prevention of bone loss in postmenopausal women.

Aged↗

PubMed2003

Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations.

BACKGROUND: Influenza causes lower respiratory tract complications (LRTCs), particularly bronchitis and pneumonia, in both otherwise healthy adults and those with underlying conditions. The aim of this study was to assess the effect of oseltamivir treatment on the incidence of LRTCs leading to antibiotic treatment and hospitalizations following influenza illness. METHODS: We analyzed prospectively collected data on LRTCs and antibiotic use from 3564 subjects (age range, 13-97 years) with influenzalike illness enrolled in 10 placebo-controlled, double-blind trials of oseltamivir treatment. RESULTS: In adults and adolescents with a proven influenza illness, oseltamivir treatment reduced overall antibiotic use for any reason by 26.7% (14.0% vs 19.1% with placebo; P<.001) and the incidence of influenza-related LRTCs resulting in antibiotic therapy by 55% (4.6% vs 10.3% with placebo; P<.001). In those subjects considered at increased risk of complications, 74 (18.5%) of 401 placebo recipients developed an LRTC leading to antibiotic use compared with 45 (12.2%) of 368 oseltamivir recipients (34.0% reduction; P =.02). Hospitalization for any cause occurred in 18 (1.7%) of 1063 placebo recipients compared with 9 (0.7%) of 1350 oseltamivir-treated patients (59% reduction; P =.02). In contrast, among subjects with an influenzalike illness but without a confirmed influenza infection, the incidence of LRTCs (6.7% vs 5.3%), overall antibiotic use (19.7% vs 19.3%), or hospitalizations (1.7% vs 1.9%) was similar between placebo and oseltamivir recipients, respectively. CONCLUSION: Oseltamivir treatment of influenza illness reduces LRTCs, antibiotic use, and hospitalization in both healthy and "at-risk" adults.

Acetamides↗