Polymorphisms in VKORC1 have more impact than CYP2C9 polymorphisms on early warfarin International Normalized Ratio control and bleeding rates

Poor warfarin control with resultant high International Normalized Ratios (INRs) and bleeding events is most common during the first months of treatment. The effects of genetic polymorphisms at the vitamin K epoxide reductase [VKORC1] and cytochrome P450 2C9 [CYP2C9] loci have been increasingly acknowledged as contributory factors of enhanced warfarin sensitivity. In our prospective, blinded study, 557 patients (49·1% male, mean age 65·4 years, range 18-91 years) commencing warfarin (target INR 2·5) were genotyped and monitored through the first 3 months of anticoagulation. Homozygosity for the -1639 G>A single nucleotide functional promoter polymorphism of the VKORC1 gene (genotype AA; 14·5% of cases) was associated with a significantly shortened time to therapeutic INR ≥ 2 (P < 0·01), reduced stable warfarin dose (P < 0·01), and an increased number of INRs > 5 (P < 0·001) and occurrence of bleeding events (P < 0·01) during the first month, as compared to the GG genotype. CYP2C9 genetic variations *2 and *3 were not associated with significant effect on these factors. Neither VKORC1 nor CYP2C9 polymorphisms influenced these parameters beyond the first month of treatment. These findings imply possible benefits of assessing VKORC1 polymorphisms prior to anticoagulation, particularly as a low dose induction regime in VKORC1 AA individuals appears to reduce the incidence of high INRs.     

First provincial survey of Angiostrongylus cantonensis in Guangdong Province, China

The rat lungworm Angiostrongylus cantonensis is a zoonotic nematode with a wide distribution. We report the first provincial survey of the prevalence of A. cantonensis infection among wild rodents and snails in Guangdong Province, China. A total of 2929 Pomacea canaliculata and 1354 Achatina fulica were collected from fields in 22 survey sites with a larval infection rates ranging from 0-26.6% to 0-45.4%. In addition, 114 Cipangopaludina sp and 252 Bellamya sp were bought from markets; larvae were found only in Bellamya snails from two survey sites with an infection rate of 1.4% (1/70) and 3.3% (3/91), respectively. Four hundred and ninety-one rodents were captured in nine sites (Rattus norvegicus, R. flavipectus, Suncus murinus, Mus musculus, Bandicota indica, R. losea and R. rattus). Adult worms were found in R. norvegicus, R. flavipectus and Bandicota indica. Our survey revealed a wide distribution of A. cantonensis and its intermediate hosts P. canaliculata and A. fulica in Guangdong. The prevalence of A. cantonensis in wild snails and rats poses a substantial risk for angiostrongyliasis in humans.     

Elevated TRIB2 with NOTCH1 activation in paediatric/adult T-ALL

TRIB2 is a potent oncogene, elevated in a subset of human acute myeloid leukaemias (AML) with a mixed myeloid/lymphoid phenotype and NOTCH1 mutations. Although rare in AML, activating NOTCH1 mutations occur in 50% of all T cell acute lymphoblastic leukaemias (T-ALL). TRIB2 is a NOTCH1 target gene that functions in the degradation of key proteins and modulation of MAPK signalling pathways, implicated in haematopoietic cell survival and proliferation. This study showed that TRIB2 expression level is highest in the lymphoid compartment of normal haematopoietic cells, specifically in T cells. Analysis of TRIB2 expression across 16 different subtypes of human leukaemia demonstrated that TRIB2 expression was higher in ALL phenotypes versus all other phenotypes including AML, chronic lymphocytic leukaemia (CLL), myelodysplastic syndrome (MDS) and chronic myeloid leukaemia (CML). A T cell profile was distinguished by high TRIB2 expression in normal and malignant haematopoiesis. High TRIB2 expression was seen in T-ALL with normal karyotype and correlated with NOTCH signalling pathways. High TRIB2 expression correlated with NOTCH1/FBXW7 mutations in a paediatric T-ALL cohort, strongly linking NOTCH1 activation and high TRIB2 expression in paediatric T-ALL. The relationship between TRIB2 and T cell signalling pathways uniquely identifies leukaemia subtypes and will be useful in the advancement of our understanding of T cell and ALL biology.     

Summary report from the Human Immunodeficiency Virus and Aging Consensus Project: treatment strategies for clinicians managing older individuals with the human immunodeficiency virus

By 2015, most of the people living with the human immunodeficiency virus (HIV) in the United States will be aged 50 and older. Many will have known their HIV status for at least a decade, and most will have received antiretroviral therapy for some, if not all, of the time since testing positive. As these individuals advance in years, they frequently acquire diseases more commonly associated with aging than with HIV. This represents a unique challenge for today's medical providers. Although these individuals may appear considerably older than their chronological age, they are typically too young to see a geriatrician. An HIV specialist, although knowledgeable in the nuances of antiretroviral therapy, may be less comfortable managing multiple age-related illnesses. Similarly, a geriatrician experienced in managing multiple, age-related conditions may be less familiar with adjusting HIV-related therapies. In this era of caring for older adults with HIV, these two medical disciplines are finding they have much to learn from each other.     

A functional polymorphism in the promoter region of the IL1B gene is associated with risk of multiple myeloma

The cytokine interleukin-1β (IL1B) is important for anti-tumour immune response. Genetic variation may modify the expression of IL1B and thereby influence the risk of disease. We investigated genetic variations with functional importance in the IL1B and NFKB1 genes in 348 population-based samples of multiple myeloma (MM) and a random sample of 1700 individuals. Carriers of the variant T-allele IL1B C-3737T and carriers of the TGT haplotype were at lower risk of MM [relative risk (RR) 0·58 (95% confidence interval (CI) = 0·41-0·84) and RR 0·59 (95%CI 0·40-0·85), respectively]. No association with risk of MM was found for the NFKB1- 94 ins/del polymorphism.     

PAI-1, progress in understanding the clinical problem and its aetiology

Plasminogen activator inhibitor-1 (PAI-1, also known as SERPINE1) is a member of the serine protease inhibitor (SERPIN) superfamily and is the primary physiological regulator of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Although the principal function of PAI-1 is the inhibition of fibrinolysis, PAI-1 possesses pleiotropic functions besides haemostasis. In the quarter century since its discovery, a number of studies have focused on improving our understanding of PAI-1 functions in vivo and in vitro. The use of Serpine1-deficient mice has particularly enhanced our understanding of the functions of PAI-1 in various physiological and pathophysiological conditions. In this review, the results of recent studies on PAI-1 and its role in clinical conditions are discussed.     

Experimental African trypanosomiasis: lack of effective CD1d-restricted antigen presentation

BALB/c mice are highly susceptible to African trypanosomiasis, whereas C57BL/6 mice are relatively resistant. Other investigators have reported that the synthesis of IgG antibodies to purified membrane form of variant surface glycoprotein (mfVSG) of Trypanosoma brucei is CD1 restricted. In this study, we examine the role of the CD1d/NKT cell pathway in susceptibility and resistance of mice to infection by African trypanosomes. Administration of anti-CD1d antibodies to Trypanosoma congolense-infected BALB/c mice neither affects the parasitemia nor the survival time. Correspondingly, CD1d(-/-) and CD1d(+/+) BALB/c mice infected with T. congolense or T. brucei show no differences in either parasitaemia or survival time. The course of disease in relative resistant C57BL/6 mice infected with T. congolense is also not affected by the absence of CD1d. Parasitaemia, survival time, and plasma levels of IgG2a and IgG3 parasite-specific antibodies in infected CD1d(-/-) C57BL/6 are not different from those of infected CD1d(+/+) C57BL/6 mice. We conclude that CD1d-restricted immune responses do not play an important role in susceptibility/resistance of mice infected with virulent African trypanosomes. We speculate that virulent trypanosomes have an evasion mechanism that prevents the induction of a parasite-specific, CD1d-restricted immune response by the host.     

GABRG1 and GABRA2 variation associated with alcohol dependence in African Americans

Background: GABRG1 and GABRA2, genes that encode the γ1 and α2 subunits, respectively, of the GABA‐A receptor, are located in a cluster on chromosome 4p. Association of alcohol dependence (AD) with markers located at the 3′ region of GABRA2 has been replicated in several studies, but recent studies suggested the possibility that the signal may be attributable to the adjacent gene, GABRG1, located 90 kb distant in the 3′ direction. Owing to strong linkage disequilibrium (LD) in European Americans (EAs), the origin, or origins, of the association signal is very difficult to discern, but our previous population‐based study suggested that decreased LD across the GABRG1–GABRA2 region in African Americans (AAs) may be useful for fine mapping and resolution of the association signal in that population. Methods: To examine these associations in greater detail, we genotyped 13 single nucleotide polymorphisms (SNPs) spanning GABRG1 and GABRA2 in 380 AAs with AD and in 253 AA controls. Results: Although there was no association between any individual SNP and AD, a highly significant difference was shown between AD subjects and controls in the frequency of a 3‐SNP GABRA2 haplotype (global p = 0.00029). A similar level of significance was obtained in 6‐SNP haplotypes that combined tagging SNPs from both genes (global p = 0.00994). High statistical significance was also shown with a 6‐SNP haplotype (T‐G‐C‐G‐T‐A), p = 0.0033. The T‐G‐C‐G‐T‐A haplotype contains the most significant GABRA2 3‐SNP haplotype (p = 0.00019), G‐T‐A. Conclusions: These findings reflect the interrelationship between these 2 genes and the likelihood that risk loci exist in each of them. Study of an AA population allowed evaluation of these associations at higher genomic resolution than is possible in a EA population, owing to the much lower LD across these loci in AAs.     

Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia

The myelodysplastic syndromes (MDS) are heterogeneous and can evolve into acute myeloid leukaemia (AML). Rare familial cases are reported in which five disease genes have been identified to date (RUNX1, CEBPA, TERC, TERT and GATA2). Here we report the genetic categorization of 27 families with familial MDS/AML. All of these families were screened for RUNX1, CEBPA, TERC, TERT and GATA2 as well as TET2 and NPM1. Five of the 27 families had telomerase mutations; one had a RUNX1 mutation, while none were found to have TET2, CEBPA or NPM1 mutations. We identified four families with heterozygous GATA2 mutations, each associated with a different phenotype. While one of these mutations is novel, three have been previously reported: one has been described in dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency and one is in a family that has been reported in a series with primary lymphoedema with a predisposition to AML (Emberger syndrome). In summary, genetic characterization was shown in 10 (four GATA2, three TERT, two TERC, one RUNX1) of these families; however 17 remain uncharacterized, highlighting marked genetic heterogeneity in familial MDS/AML and the scope for further functional pathways that could give rise to this group of disorders.