The objective of this study was to determine whether two vitamin K epoxide reductase complex 1 (VKORC1) polymorphisms contribute to the variability in warfarin response, particularly in African Americans. The effect of the VKORC1 1173C/T and -1639G/A polymorphisms was examined in a prospective cohort study of 338 warfarin users. Subjects carrying an 1173T allele had a lower warfarin maintenance dose compared with subjects with the CC genotype in African Americans (-12.10 mg/week+/-4.93; P=0.02) and Caucasians (-14.41 mg/week+/-3.28; P<0.001). Before reaching maintenance dose, only Caucasians with the T allele had significantly increased risk of international normalized ratio >3 (odds ratio=3.10; 95% confidence interval: 1.73-5.55) compared with Caucasians with the CC genotype. Polymorphisms in the VKORC1 gene are associated with warfarin maintenance dose requirements among both African Americans and Caucasians. However, these polymorphisms may not be as useful in predicting over-anticoagulation among African Americans.

Objectives-The objective of this study was to determine whether clinical, environmental, and genetic factors can be used to develop dosing algorithms for Caucasians and African Americans that perform better than giving empirical 5 mg/day. Methods-From April 2002 through December 2005, 259 warfarin initiators were prospectively followed until they reached maintenance dose.Results-The Caucasian algorithm included 11 variables (R 2 =0.43). This model (51% within 1 mg) performed better compared with 5 mg/day (29% within 5±1 mg). The African American algorithm included 10 variables (R 2 =0.28). This model predicted 37% of doses within 1 mg of the observed dose; a small improvement compared with 5 mg/day (34%). These results were similar to the results we obtained from testing other (published) algorithms.Conclusions-The dosing algorithms in Caucasians explained <45% of the variability and the algorithms in African Americans performed only marginally better than giving 5 mg empirically.

Objective. To compare the incidence and extent of coronary artery calcification (CAC) as measured by electron beam computed tomography (EBCT) in patients with systemic lupus erythematosus (SLE) and controls, and to identify variables associated with CAC in patients with SLE.Methods. Female patients with SLE and matched controls were recruited; EBCT of the coronary arteries was performed, and laboratory values (including the homocysteine concentration, the lipid level, the high- Results. The incidence of CAC was higher in patients with SLE than in controls (P ‫؍‬ 0.009), and patients had a higher mean raw CAC (rCAC) score (87.9 versus 9.6 in controls; P ‫؍‬ 0.02). In particular, more CAC-positive patients than CAC-positive controls had rCAC scores above the 75th percentile (P ‫؍‬ 0.003). Among both patients and controls, those with CAC were ϳ10 years older than those without CAC. In addition to age, a significant determinant of positive CAC status in both groups was the number of cardiovascular risk factors. In patients with SLE, CAC was associated with a higher homocysteine concentration, a lower GFR, and longer disease duration. In controls, the total cholesterol level correlated positively with CAC. When multivariate logistic regression methods were applied to candidate explanatory variables, homocysteine concentration, age, and disease duration (but not the levels of sCD154 or hsCRP) contributed significantly to CAC status. The methylenetetrahydrofolate reductase C677T genotype was not a predictor of hyperhomocysteinemia or CAC status.Conclusion. Among patients with SLE, the homocysteine concentration, the GFR, age, and disease duration were associated with CAC. CAC occurred more frequently and was more extensive in patients with SLE than in controls, suggesting that EBCT could be used to detect premature atherosclerosis in the former group. An elevated homocysteine concentration might identify patients with SLE who are likely to have premature atherosclerosis and who would benefit from evaluation of CAC by EBCT.

CYP2C9 *2 and *3 variants provide predictive information in anticoagulation response. However, these variants may not be useful in African-Americans or as a marker of long-term over-anticoagulation once a stable dose is reached.

Warfarin sodium is a vitamin K antagonist that is plagued by large variability in patient response, including higher dose requirements among African Americans. Polymorphisms in the gene encoding apolipoprotein E (APOE) may partly explain this variability by altering transport of vitamin K to the liver. In a prospective cohort study of 232 individuals (52.2% Caucasian and 47.8% African American) initiating warfarin therapy, the weekly maintenance dose was significantly higher for African Americans than for Caucasians (mean 42.9 versus mean 36.9 mg, P=0.018), and the epsilon4 allele was more common among African Americans (37.8 versus 26.4% for Caucasians). In multivariable analyses, the presence of the epsilon4 allele was associated with a statistically significantly higher warfarin dose among African Americans (median 45.0 mg in epsilon4 carriers versus 35.0 mg in non-epsilon4 carriers, P=0.014) but not Caucasians (38.1 versus 35.0 mg, P=0.60). In addition, warfarin maintenance dose increased among African Americans according to genotype previously associated with differential hepatic chylomicron clearance (epsilon2/epsilon2 or epsilon2/epsilon3: 30.0 mg; epsilon3/epsilon3: 35.0 mg; epsilon3/epsilon4 or epsilon4/epsilon4: 45.0 mg; P=0.012), although the epsilon4/epsilon4 genotype was rare and not clearly associated with higher doses. The association of APOE with warfarin dosing was independent of CYP2C9 and VKORC1 polymorphisms. APOE polymorphisms thus may be important determinants of warfarin maintenance dose and could explain at least some of the observed racial differences in dose requirements.

New antibiotics are urgently required by human medicine as pathogens emerge with developed resistance to almost all antibiotic classes. Pioneering approaches, methodologies and technologies have facilitated a new era in antimicrobial discovery. Innovative culturing techniques such as iChip and co-culturing methods which use 'helper' strains to produce bioactive molecules have had notable success. Exploiting antibiotic resistance to identify antibacterial producers performed in tandem with diagnostic PCR based identification approaches has identified novel candidates. Employing powerful metagenomic mining and metabolomic tools has identified the antibiotic'ome, highlighting new antibiotics from underexplored environments and silent gene clusters enabling researchers to mine for scaffolds with both a novel mechanism of action and also few clinically established resistance determinants. Modern biotechnological approaches are delivering but will require support from government initiatives together with changes in regulation to pave the way for valuable, efficacious, highly targeted, pathogen specific antimicrobial therapies.

No abstract

Substantial evidence suggests that a low folate/high homocysteine phenotype is pathogenic. We analyzed the impact of the thymidylate synthase (TYMS) 3'UTR ins/del polymorphism on folate and homocysteine levels and assessed the relationship between the TYMS 3'UTR ins/del polymorphism and key genetic and lifestyle variables. Among non-smokers only, the TYMS 3'UTR ins/del polymorphism was significantly associated with red blood cell folate (RBC folate; P=0.002) and homocysteine (P=0.03) concentrations. Median RBC folate concentration was much higher for TYMS 3'UTR del/del subjects (434 microg/l) compared with either ins/ins (282 microg/l) or ins/del (298 microg/l) subjects. The median homocysteine concentration for del/del homozygotes was considerably lower compared with either ins/ins homozygotes or ins/del heterozygotes. A possible additive effect for the impact of the TYMS 3'UTR del/del and MTHFR 677CC genotypes on RBC folate concentration was also observed. Our findings suggest that the TYMS 3'UTR del/del genotype is a significant determinant of elevated RBC folate concentration in a non-smoking population of northwestern European adults and that this genotype confers protection against diseases for which a low folate/high homocysteine phenotype appears to be an etiologic component.