12 research outputs found
Specific human leukocyte antigen DQ influence on expression of antiislet autoantibodies and progression to type 1 diabetes
Human leukocyte antigen (HLA) DQ haplotypes have the strongest genetic
association with type 1 diabetes (T1DM) risk. OBJECTIVE: The objective of the
study was to analyze whether HLA DQ alleles influence the development of
antiislet autoantibodies, the progression to T1DM among autoantibody-positive
relatives, or both. DESIGN: The Diabetes Prevention Trial-1 screened more than
90,000 nondiabetic relatives of patients for cytoplasmic islet-cell autoantibody
(ICA) expression between 1994 and 2002. SETTING: The study was conducted in the
general community. PARTICIPANTS: The Diabetes Prevention Trial-1 found 2817
ICA-positive relatives who were tested for biochemical autoantibodies (GAD65,
ICA512, and insulin) and HLA-DQ haplotypes, and 2796 of them were followed up for
progression to diabetes for up to 8 yr (median, 3.6 yr). MAIN OUTCOME MEASURE:
Progression to T1DM was measured. RESULTS: High-risk DQ haplotypes and genotypes
were associated with a higher percentage of relatives expressing multiple
biochemical autoantibodies and higher T1DM risk (e.g., respectively, 59 and 36%
at 5 yr for carriers of the DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype).
The number of autoantibodies expressed significantly increased T1DM risk and
across different DQ genotypes, autoantibody positivity directly correlated with
diabetes risk. However, multivariate analyses indicated that the influence of
most genotypes on T1DM risk was not independent from autoantibody expression,
with the possible exception of DQA1*0102-DQB1*0602. Specific genotypic
combinations conferred 5-yr diabetes risks significantly lower (e.g.
7%-DQA1*0201-DQB1*0201/DQA1*0501-DQB1*0201 and
14%-DQA1*0301-DQB1*0301/DQA1*0501-DQB1*0201) than when those haplotypes were
found in other combinations. CONCLUSION: HLA DQ alleles determine autoantibody
expression, which is correlated with diabetes progression. Among
autoantibody-positive relatives, most HLA DQ genotypes did not further influence
T1DM risk
Dynamic nuclear polarization and spin-diffusion in non-conducting solids
There has been much renewed interest in dynamic nuclear polarization (DNP),
particularly in the context of solid state biomolecular NMR and more recently
dissolution DNP techniques for liquids. This paper reviews the role of spin
diffusion in polarizing nuclear spins and discusses the role of the spin
diffusion barrier, before going on to discuss some recent results.Comment: submitted to Applied Magnetic Resonance. The article should appear in
a special issue that is being published in connection with the DNP Symposium
help in Nottingham in August 200
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)
BACKGROUND: Metoprolol can improve haemodynamics in chronic heart failure, but survival benefit has not been proven. We investigated whether metoprolol controlled release/extended release (CR/XL) once daily, in addition to standard therapy, would lower mortality in patients with decreased ejection fraction and symptoms of heart failure. METHODS: We enrolled 3991 patients with chronic heart failure in New York Heart Association (NYHA) functional class II-IV and with ejection fraction of 0.40 or less, stabilised with optimum standard therapy, in a double-blind randomised controlled study. Randomisation was preceded by a 2-week single-blind placebo run-in period. 1990 patients were randomly assigned metoprolol CR/XL 12.5 mg (NYHA III-IV) or 25.0 mg once daily (NYHA II) and 2001 were assigned placebo. The target dose was 200 mg once daily and doses were up-titrated over 8 weeks. Our primary endpoint was all-cause mortality, analysed by intention to treat. FINDINGS: The study was stopped early on the recommendation of the independent safety committee. Mean follow-up time was 1 year. All-cause mortality was lower in the metoprolol CR/XL group than in the placebo group (145 [7.2%, per patient-year of follow-up]) vs 217 deaths [11.0%], relative risk 0.66 [95% CI 0.53-0.81]; p=0.00009 or adjusted for interim analyses p=0.0062). There were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (79 vs 132, 0.59 [0.45-0.78]; p=0.0002) and deaths from worsening heart failure (30 vs 58, 0.51 [0.33-0.79]; p=0.0023). INTERPRETATION: Metoprolol CR/XL once daily in addition to optimum standard therapy improved survival. The drug was well tolerated