ABSTRACT
Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.8±63.2 vs 204.6±41.8, P=0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10,000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor.
Subject(s)
Amino Acid Substitution/genetics , Coronary Disease/genetics , Mutation , Phospholipases A2/genetics , 1-Alkyl-2-acetylglycerophosphocholine Esterase , Alleles , Coronary Disease/drug therapy , Enzyme Inhibitors/therapeutic use , Genetics, Population , Homozygote , Humans , Phospholipase A2 Inhibitors , Phospholipases A2/metabolism , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , White People/geneticsABSTRACT
OBJECTIVE: To assess the influence of tuberculosis (TB) on the progression of human immunodeficiency virus (HIV) infection in patients without immunological impairment. MATERIAL AND METHODS: In an observational study of retrospective cohorts, the evolution of 28 HIV-infected patients with TB and a CD4 lymphocyte count >500 x 10(6) cells/l was compared with 56 HIV-infected patients without TB. Each case was paired with two controls by CD4 lymphocyte count (+/-50 x 10(6)/l) and date of starting follow-up (+/-6 months). The progression of HIV infection was evaluated as: 1) immunological progression: time to CD4 lymphocyte count <200 x 10(6)/l; 2) clinical progression: time to development of acquired immune-deficiency syndrome (AIDS), excluding TB; 3) survival; and 4) global disease progression: time to the first defined event in 1, 2 and/or 3. The times to these events were estimated using Kaplan Meier curves. RESULTS: There were no significant differences between the cohorts for age, sex and risk group. Faster immunological impairment (RR 2.94; 95%CI 1.46-8.6; P < 0.01), greater progression to AIDS (RR 4.01; 95%CI 1.66-9.69; P < 0.01), lower survival (RR 3.89; 95%CI 1.53-9.87; P < 0.05) and higher global disease progression (RR 2.82; 95%CI 1.57-5.09; P < 0.01) were found in the cohort of TB patients. These associations were still significant after adjustment for CD4 lymphocyte counts. CONCLUSION: The diagnosis of TB in HIV-infected patients with a high initial CD4 lymphocyte count (>500 x 10(6)/l) was related to greater progression to AIDS and shorter survival.
Subject(s)
HIV Infections/immunology , Tuberculosis/immunology , Adult , CD4 Lymphocyte Count , Cohort Studies , Disease Progression , Female , HIV Infections/complications , Humans , Male , Retrospective Studies , Survival Analysis , Treatment Outcome , Tuberculosis/complicationsABSTRACT
Horseradish peroxidase was examined as a function of Ca and substrate binding using infrared spectroscopy in the temperature range of 10-300 K. The Ca complex could be identified by the carboxylate stretches. The amide peak positions indicate that the protein remains stable from room temperature to 10 K. Shifts in these peaks are consistent with increased hydrogen bonding as temperature decreases, but the protein conformation is maintained at cryogenic temperatures. The substrate, benzohydroxamic acid, produced no detectable change in the infrared spectrum, consistent with X-ray crystallography results. With removal of Ca, the protein maintained its overall helicity.
Subject(s)
Horseradish Peroxidase/chemistry , Calcium/chemistry , Protein Conformation , Solvents , Spectrophotometry, Infrared , Substrate Specificity , TemperatureABSTRACT
Resistant starch (RS) was determined in deproteinized and non-deproteinized whole and milled beans (Phaseolus vulgaris) after cooking and freezing. The highest RS values were obtained in the whole bean preparations (3.7-8.7%). Milled and milled and deproteinized beans presented lower RS contents (1.64% and 0.91%, respectively). The results suggest that the presence of protein and the particle size are the main factors affecting the formation of RS.