Hepatocellular carcinoma and polymorphisms in carcinogen-metabolizing and DNA repair enzymes in a population with aflatoxin exposure and hepatitis B virus endemicity.

High rates of hepatocellular carcinoma (HCC) in The Gambia, West Africa, are primarily due to a high prevalence of chronic hepatitis B virus infection and heavy aflatoxin exposure via groundnut consumption. We investigated genetic polymorphisms in carcinogen-metabolizing (GSTM1, GSTT1, HYL1*2) and DNA repair (XRCC1) enzymes in a hospital-based case-control study. Incident HCC cases (n = 216) were compared with frequency-matched controls (n = 408) with no clinically apparent liver disease. Although the prevalence of variant genotypes was generally low, in multivariable analysis (adjusting for demographic factors, hepatitis B virus, hepatitis C virus, and TP53 status), the GSTM1-null genotype [odds ratio (OR), 2.45; 95% confidence interval (95% CI), 1.21-4.95] and the heterozygote XRCC1-399 AG genotype (OR, 3.18; 95% CI, 1.35-7.51) were significantly associated with HCC. A weak association of the HYL1*2 polymorphism with HCC was observed but did not reach statistical significance. GSTT1 was not associated with HCC. The risk for HCC with null GSTM1 was most prominent among those with the highest groundnut consumption (OR, 4.67; 95% CI, 1.45-15.1) and was not evident among those with less than the mean groundnut intake (OR, 0.64; 95% CI, 0.20-2.02). Among participants who had all three suspected aflatoxin-related high-risk genotypes [GSTM1 null, HLY1*2 (HY/HH), and XRCC1 (AG/GG)], a significant 15-fold increased risk of HCC was observed albeit with imprecise estimates (OR, 14.7; 95% CI, 1.27-169). Our findings suggest that genetic modulation of carcinogen metabolism and DNA repair can alter susceptibility to HCC and that these effects may be modified by environmental factors.     

Mortality Risk Factors for Middle East Respiratory Syndrome Outbreak,South Korea, 2015

As of July 15, 2015, the South Korean Ministry of Health and Welfare had reported 186 case-patients with Middle East respiratory syndrome in South Korea. For 159 case-patients with known outcomes and complete case histories, we found that older age and preexisting concurrent health conditions were risk factors for death.     

Prospective study of cytomegalovirus seropositivity and risk of mortality from diabetes

Cytomegalovirus (CMV) infects 40 % of the world population and has been suggested to be associated with diabetes; however, no prospective study has ever examined diabetes mortality associated with the infection. A cohort of 14,404 non-diabetic adult participants aged 17–90 years from the Third National Health and Nutrition Examination Survey (1988–1994) was prospectively followed for mortality through 2006. CMV immunoglobulin G was measured by enzyme-linked immunosorbent assay and immunofluorescence assay. Diabetes death was assessed with death records from the National Death Index. Cox proportional hazards modeling was used to determine diabetes mortality risk associated with CMV infection, adjusting for socio-demographics, diabetes risk factors, and comorbidities. At baseline, 76.8 % of subjects were CMV seropositive, and after an average follow-up of 13.7 years, diabetes mortality rate per 10,000 person-years was 6.8 (95 % CI 5.7, 8.0). Among seropositive participants, the diabetes death rate (8.4, 95 % CI 7.0, 9.9) was more than four times the rate in seronegative ones (2.0, 95 % CI 1.1, 3.6) (P value for the difference <0.001). In the adjusted Cox proportional hazards analysis, CMV seropositivity more than doubled the risk of diabetes mortality (HR 2.06, 95 % CI 1.05, 4.06). CMV infection may thus predict future mortality from diabetes in non-diabetic people.     

Ser-249 p53 mutations in plasma DNA of patients with hepatocellular carcinoma from The Gambia

BACKGROUND: A selective mutation, an arginine-to-serine substitution in codon 249, of the p53 gene has been identified as a "hotspot" mutation in hepatocellular carcinoma (HCC). This mutation occurs in populations that are exposed to aflatoxins and have a high prevalence of hepatitis B virus carriers. We evaluated whether this mutation could be detected in cell-free DNA isolated from the plasma of subjects from The Gambia to detect this mutation that is strongly associated with HCC. METHODS: Fifty-three patients with HCC, 13 patients with cirrhosis, and 53 control subjects were prospectively recruited from The Gambia. Sixty patients, of non-African origin, with various liver pathologies were also selected from France. DNA was extracted and purified from 200-microL aliquots of plasma. The Ser-249 p53 mutation was detected by restriction endonuclease digestion of polymerase chain reaction products from exon 7 and was confirmed by direct sequencing of the amplified DNA. RESULTS: The Ser-249 p53 mutation was detected in plasma DNA from 19 (36%) of the 53 patients with HCC, two (15%) of the 13 patients with cirrhosis, and three (6%) of the 53 control subjects. This mutation was not detected in any plasma DNA from the European patients. The adjusted odds ratio for having the mutation was 16.4 (95% confidence interval = 3.0-90.5) for patients with HCC compared with the control subjects. CONCLUSION: The Ser-249 p53 mutation in plasma DNA is strongly associated with HCC in Gambian patients. This mutation was also detected at a much lower prevalence in plasma DNA from Gambian patients with cirrhosis and in Gambian control subjects, findings that may lead to the earlier detection of HCC. Use of the Ser-249 p53 mutation should facilitate further molecular epidemiologic studies on the development of HCC.     

Effect of whey proteins, their oligopeptide hydrolysates and free amino acid mixtures on growth and nitrogen retention in fed and starved rats

The effects of alimentary whey proteins given, as whole proteins (WP), controlled trypsin and chymotrypsin hydrolysate oligopeptides (WPH), or a free amino acid mixture (AAM), on growth, nitrogen retention, and steatorrhea were assessed in 24 Wistar rats (250 to 300 g) after 72 hr of starvation and 24 to 96 hr of realimentation and in 24 controls. The three diets had the same caloric, nitrogen, vitamin, and mineral contents. Rats had free access to the liquid diets. Only rats which ate the whole diet (90 cal) were included in the study. No differences in steatorrhea and fecal nitrogen were observed. The absorption rate was over 95% on the three diets. In contrast, weight gain was statistically better on WPH (+9% after 96 hr of realimentation) than on WP (+5%) or AAM (+2%). This was associated with a statistically higher nitrogen retention at all time periods studied, which was a result of a significant lower nitrogen urinary excretion. Similar results were obtained in controls. This better growth was a result of a better protein synthesis and lower ureagenesis.     

RIP links TLR4 to Akt and is essential for cell survival in response to LPS stimulation

Receptor-interacting protein (RIP) has been reported to associate with tumor necrosis-associated factor (TRAF)2 and TRAF6. Since TRAF2 and TRAF6 play important roles in CD40 signaling and TRAF6 plays an important role in TLR4 signaling, we examined the role of RIP in signaling via CD40 and TLR4. Splenocytes from RIP(-/-) mice proliferated and underwent isotype switching normally in response to anti-CD40-IL-4 but completely failed to do so in response to LPS-IL-4. However, they normally up-regulated TNF-alpha and IL-6 gene expression and CD54 and CD86 surface expression after LPS stimulation. RIP(-/-) splenocytes exhibited increased apoptosis and impaired Akt phosphorylation after LPS stimulation. These results suggest that RIP is essential for cell survival after TLR4 signaling and links TLR4 to the phosphatidylinositol 3 kinase-Akt pathway.     

Dépistage tardif de l’infection à VIH à la clinique des maladies infectieuses de Fann,Dakar : circonstances de diagnostic,itinéraire thérapeutique des patients et facteurs déterminants

Background and methodology

The delay in the diagnosis of HIV infection is a major obstacle to optimal care for this disease. To deal with this problem, we conducted this study among newly diagnosed HIV patients hospitalized in the Fann University Hospital Infectious Diseases Clinic in Dakar. The epidemiological, clinical, biological and outcome aspects are described and patient history reviewed. A qualitative socio-anthropological study was made to understand and describe the logic of the decision processes in the patient's search for treatment.

Results

One hundred patients were included, with a mean age of 39.5 ± 11.1 years and a sex-ratio: 1.08. The transmission was mainly heterosexual (90%), and chronic diarrhea (64%) and/or chronic cough (66%) were the principal symptoms leading to diagnosis. The mean delay before diagnosis was 5 ± 4.27 months. The major opportunistic diseases were tuberculosis (44 cases) and infectious diarrhea (23 cases). Most patients were diagnosed at the AIDS stage (97%) and the death rate was 30% among hospitalized patients after admission. Sixty-eight percent of patients had consulted at least three times, generally a “traditional practitioner”, at first and 43% had been hospitalized at least once. The qualitative investigation revealed that the “representation” or the “feeling of severity” of the disease were the principal justifications for consulting the “traditional practitioner” or the physician, respectively.

Conclusion

Better information for health workers and global population is necessary for an earlier diagnosis of HIV infection in Dakar.