Translational research : the journal of laboratory and clinical medicine
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Tens of millions of patients diagnosed with vivax malaria cannot safely receive primaquine therapy against repeated attacks caused by activation of dormant liver stages called hypnozoites. Most of these patients lack access to screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency, a highly prevalent disorder causing serious acute hemolytic anemia with primaquine therapy. We optimized CuCl inhibition of G6PD in normal red blood cells (RBCs) to assess G6PD diagnostic technologies suited to point of care in the impoverished rural tropics. ⋯ At G6PD activity ≤40% of normal (n = 112), CSG test was not inferior to FST in detecting G6PD deficiency (P = 0.003), with 96% vs 90% (P = 0.19) sensitivity and 75% and 87% (P = 0.01) specificity, respectively. The CSG test costs less, requires no specialized equipment, laboratory skills, or cold chain for successful application, and performs as well as the FST standard of care for G6PD screening. Such a device may vastly expand access to primaquine therapy and aid in mitigating the very substantial burden of morbidity and mortality imposed by the hypnozoite reservoir of vivax malaria.
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India tops the list of countries with sickle cell disease (SCD) with an estimated 44,000 live births in 2010 and a prevalence of 10%-33%. In the present study, the first from India, we have investigated the effect of genetic variants in the BCL11A, the HMIP (HBS1L-MYB intergenic polymorphism) locus, in addition to the HBB locus, which are known to be associated with fetal hemoglobin (HbF) levels, a major modulator of the disease phenotype. The present study was conducted on 240 individuals with SCD and 60 with sickle cell trait. ⋯ The highest difference was seen in the Xmn1 single-nucleotide polymorphism, which accounted for 11% of the trait variance, the BCL11A rs11886868 for 3.65%, whereas the HMIP rs9399137 for 3.8%. The present study indicates the BCL11A, HMIP, and β-globin region to be associated with increased HbF levels in Indian patient. Further interrogation of these genotypes with respect to pain crisis is warranted in this population, which may help in prognostication, as also a genome-wide association study, which may help uncover new loci controlling HbF levels.
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The identification of individuals with severe liver fibrosis among patients with chronic liver disease is of major importance when evaluating prognosis, potential risk for complications, and when deciding treatment strategies. Although percutaneous liver biopsy is still considered a "gold standard" for staging of liver fibrosis, attempts to find reliable noninvasive markers of liver fibrosis are frequent. Inflammation is essential for the progression of fibrosis. ⋯ Regarding the performance in predicting severity of fibrosis, suPAR was essentially as good as other commonly used noninvasive fibrosis scoring systems. The results in HCV confirm previous observations. However, this is the first study to investigate suPAR as a biomarker in NAFLD, and the results indicate that suPAR may constitute a severity marker related to fibrosis and prognosis rather than reflecting inflammation.
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Warfarin is a widely used anticoagulant whose active S-enantiomer is primarily metabolized by the CYP2C9 enzyme. The CYP2C9*2 and CYP2C9*3 alleles are associated with lower warfarin dose requirement and decreased enzyme activity. In contrast, we previously identified a novel single-nucleotide polymorphism (SNP) (rs7089580A > T) in CYP2C9 that is associated with higher warfarin dose requirement in African Americans (AAs). ⋯ Our findings indicate that rs7089580 is associated with higher S-warfarin clearance and CYP2C9 expression and may help explain the higher dose requirement of warfarin in AAs. Furthermore, rs7089580 is in complete linkage disequilibrium with the promoter SNP rs12251841 in AAs, which may provide a biologically plausible explanation for the observed effect on CYP2C9 expression levels. Given the many clinically relevant substrates of CYP2C9, identifying polymorphisms that affect expression levels and metabolism across ethnicities is essential for individualization of doses with a narrow therapeutic index.
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Aging is one of the prime risk factors for the development of cancer. Expression patterns of epigenetic regulators, including histone modification levels, are altered during aging of normal cells, a phenomenon referred to as epigenetic drift. Furthermore, it is known that epigenetic mechanisms are involved in the development of cancer. ⋯ The prognostic value reverses with advancing age, high nuclear expression associated with good clinical outcome in young adults, and, in contrast, with worse clinical outcome in elderly patients. In conclusion, for the first time, we demonstrated prognostic impact of epigenetic biomarkers that reverses with advancing age. This new insight supports the hypothesis that CRC biology is different in young vs elderly patients and emphasizes the importance of focusing on age-related effects in CRC.