KIR content genotypes associate with carriage of hepatitis B surface antigen, e antigen and HBV viral load in Gambians.

BACKGROUND: Hepatocellular carcinoma (HCC) causes over 800,000 deaths worldwide annually, mainly in low income countries, and incidence is rising rapidly in the developed world with the spread of hepatitis B (HBV) and C (HCV) viruses. Natural Killer (NK) cells protect against viral infections and tumours by killing abnormal cells recognised by Killer-cell Immunoglobulin-like Receptors (KIR). Thus genes and haplotypes encoding these receptors may be important in determining both outcome of initial hepatitis infection and subsequent chronic liver disease and tumour formation. HBV is highly prevalent in The Gambia and the commonest cause of liver disease. The Gambia Liver Cancer Study was a matched case-control study conducted between September 1997 and January 2001 where cases with liver disease were identified in three tertiary referral hospitals and matched with out-patient controls with no clinical evidence of liver disease. METHODS: We typed 15 KIR genes using the polymerase chain reaction with sequence specific primers (PCR-SSP) in 279 adult Gambians, 136 with liver disease (HCC or Cirrhosis) and 143 matched controls. We investigated effects of KIR genotypes and haplotypes on HBV infection and associations with cirrhosis and HCC. RESULTS: Homozygosity for KIR group A gene-content haplotype was associated with HBsAg carriage (OR 3.7, 95% CI 1.4-10.0) whilst telomeric A genotype (t-AA) was associated with reduced risk of e antigenaemia (OR 0.2, 95% CI 0.0-0.6) and lower viral loads (mean log viral load 5.2 vs. 6.9, pc = 0.022). One novel telomeric B genotype (t-ABx2) containing KIR3DS1 (which is rare in West Africa) was also linked to e antigenaemia (OR 8.8, 95% CI 1.3-60.5). There were no associations with cirrhosis or HCC. CONCLUSION: Certain KIR profiles may promote clearance of hepatitis B surface antigen whilst others predispose to e antigen carriage and high viral load. Larger studies are necessary to quantify the effects of individual KIR genes, haplotypes and KIR/HLA combinations on long-term viral carriage and risk of liver cancer. KIR status could potentially inform antiviral therapy and identify those at increased risk of complications for enhanced surveillance

Relationship Between Non-Hodgkin's Lymphoma and Blood Levels of Epstein-Barr Virus in Children in North-Western Tanzania: A Case Control Study.

Non-Hodgkin's Lymphomas (NHL) are common in African children, with endemic Burkitt's lymphoma (BL) being the most common subtype. While the role of Epstein-Barr Virus (EBV) in endemic BL is known, no data are available about clinical presentations of NHL subtypes and their relationship to Human Immunodeficiency Virus (HIV) infection and Epstein Barr Virus (EBV) load in peripheral blood of children in north-western, Tanzania. A matched case control study of NHL subtypes was performed in children under 15 years of age and their respective controls admitted to Bugando Medical Centre, Sengerema and Shirati district designated hospitals in north-western, Tanzania, between September 2010 and April 2011. Peripheral blood samples were collected on Whatman 903 filter papers and EBV DNA levels were estimated by multiplex real-time PCR. Clinical and laboratory data were collected using a structured data collection tool and analysed using chi-square, Fisher and Wilcoxon rank sum tests where appropriate. The association between NHL and detection of EBV in peripheral blood was assessed using conditional logistic regression model and presented as odds ratios (OR) and 95% confidence intervals (CI). A total of 35 NHL cases and 70 controls matched for age and sex were enrolled. Of NHLs, 32 had BL with equal distribution between jaw and abdominal tumour, 2 had large B cell lymphoma (DLBCL) and 1 had NHL-not otherwise specified (NHL-NOS). Central nervous system (CNS) presentation occurred only in 1 BL patient; 19 NHLs had stage I and II of disease. Only 1 NHL was found to be HIV-seropositive. Twenty-one of 35 (60%) NHL and 21 of 70 (30%) controls had detectable EBV in peripheral blood (OR = 4.77, 95% CI 1.71 - 13.33, p = 0.003). In addition, levels of EBV in blood were significantly higher in NHL cases than in controls (p = 0.024). BL is the most common childhood NHL subtype in north-western Tanzania. NHLs are not associated with HIV infection, but are strongly associated with EBV load in peripheral blood. The findings suggest that high levels of EBV in blood might have diagnostic and prognostic relevance in African children

HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients

Effect of partial replacement of wheat with peanut flour on the chemical, sensory and microbial quality of bread

Background: Consumption of bread is continually growing despite the high cost of wheat importation. There is a dire need to reduce the dependence on wheat through partial replacement of wheat with indigenous crops as well as improving the nutritional value of carbohydrate based foods.Objectives: The objectives of this study were to assess the chemical, sensory and microbiological qualities of bread fortified with peanut flour.Materials and Methods: Four samples of bread were formulated by blending wheat flour with partially defatted peanut flour at various ratios of 100:0, 90:10, 80:20 and 70:30 (Wheat: Peanut). The 100:0 ratio (Wheat: Peanut) served as control. The proximate composition, pro-vitamin A, sensory properties and the microbiological qualities were evaluated using standard methods of analysis. The data obtained were subjected to statistical analysis.Results: The Proximate composition result showed that ash, fibre, fat and protein contents increased as the proportion of peanut flour increased in the blend  formulation from 0.50% to 1.35%, 0.48% to 2.84%, 4.40% to 12.70% and  9.019% to 18.16% respectively. Carbohydrate content decreased with increase in the proportion of peanut flour from 53.37% to 36.10%. Pro-vitamin A content increased in a dose dependent manner (0.49mg/100g to 12.20mg/100g). Sensoryevaluation results indicated that all the bread had high sensory ratings for all the parameters evaluated. The total viable count of the bread samples during ten days of storage ranged from 1.80x102 cfu/g to 4.8x105 cfu/g. Fungal count ranged from 1.2x102 cfu/g to 5.0x103 cfu/g. Some species of fungi and bacteria were isolated after ten days of  storage.Conclusion: Substitution of wheat flour with peanut flour up to 30% produced a more nutritionally adequate,organoleptically acceptable and microbiologically shelf stable bread.Keywords: Bread, Peanut, Fortification, Microbial Quality

Dose-dependent influence of genetic polymorphisms on DNA damage induced by styrene oxide, ethylene oxide and gamma-radiation.

Styrene oxide (SO), ethylene oxide (EO) and gamma-radiation (G) are agents with a well-described metabolism and genotoxicity. EPHX1 and GSTs play an important role in the detoxification of electrophiles and oxidative stress. Enzymes involved in base excision repair (hOGG1, XRCC1), in rejoining single strand breaks (XRCC1) and in repair of cross-links and chromosomal double strand breaks (XRCC3) might have an impact on genotoxicity as well. In this study we assessed the dose-dependent effect of genetic polymorphisms in biotransforming (EPHX (Tyr113/His113 and His139/Arg139), GSTP1 (Ile105/Val105), GSTM1 and GSTT1) and DNA repair enzymes (hOGG1 (Ser326/Cys326), XRCC1 (Arg194/Trp194, Arg280/His280, Arg399/Gln399), XRCC3 (Thr241/Met241)) on the induced genotoxicity. Peripheral blood mononuclear cells from 20 individuals were exposed to 3 doses per agent (+control). Genotoxicity was evaluated by measuring comet tail length (TL) and micronucleus frequencies in binucleated cells (MNCB). Dose-dependent DNA damage was found for all agents and end-points, with the exception of MNCB induced by EO. Repeated measure ANOVA revealed a significant contribution of hOGG1 and XRCC3 genotypes to the inter-individual variability of TL and MNCB in cells exposed to EO and G. Homozygous hOGG1326 wild cells showed significantly lower EO-induced TL than the heterozygous cells. Significantly higher TL and MNCB were found in EO-exposed cells carrying the XRCC3(241)Met variant and the influence on TL was more pronounced at higher dose. In G-irradiated cells, TL was significantly higher in the hOGG1326 homozygous wild types compared with mutated genotypes. The influence of hOGG1326 on TL was borderline dose-dependent. We conclude that the influence of genetic polymorphisms of enzymes involved in DNA repair on induced genotoxicity depends on exposure dose

Are genetic polymorphisms in OGG1, XRCC1 and XRCC3 genes predictive for the DNA strand break repair phenotype and genotoxicity in workers exposed to low dose ionising radiations?

Identification of higher risk individuals carrying genetic polymorphisms responsible for reduced DNA repair capacity has substantial preventive implications as these individuals could be targeted for cancer prevention. We have conducted a study to assess the predictivity of the OGG1, XRCC1 and XRCC3 genotypes and the in vitro single strand break repair phenotype for the induction of genotoxic effects. At the population level, a significant contribution of the OGG1 genotypes to the in vitro DNA strand break repair capacity was found. At an individual level, the OGG1 variants Ser/Cys and Cys/Cys genotypes showed a slower in vitro DNA repair than the Ser/Ser OGG1genotype. A multivariate analysis performed with genotypes, age, cumulative dose, exposure status and smoking as independent variables indicated that in the control population, repair capacity is influenced by age and OGG1 polymorphisms. In the exposed population, DNA damage is greater in older men and in smokers. Repair capacity is slower in individuals with Ser/Cys or Cys/Cys OGG1 genotypes compared to those with the Ser/Ser OGG1 genotype. Micronuclei (MN) frequencies increased with age and the cumulative dose of γ-rays. Analysis of the total population revealed that genetic polymorphisms in XRCC1 resulted in higher residual DNA (RDNA) values and the Met/Met variant of XRCC3 resulted in an increased frequency of micronuclei. The analysis confirms that MN frequencies are reliable biomarkers for the assessment of genetic effects in workers exposed to ionising radiation (IR). A combined analysis of the three genotypes, OGG1, XRCC1 and XRCC3 polymorphisms is advised in order to assess individual susceptibility to ionising radiation. As an alternative or complement, the in vitro DNA strand break repair phenotype which integrates several repair pathways is recommended. Smokers with OGG1 polymorphisms who are exposed to ionising radiation represent a specific population requiring closer medical surveillance because of their increased mutagenic/carcinogenic risk. © 2004 Elsevier B.V. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe