An LC-MS-MS method for the determination of cyclizine in human serum

Cyclizine is a piperazine derivative with anti-emetic activity that is useful in the prevention and treatment of nausea and vomiting associated with motion sickness. A liquid chromatography-tandem mass spectrometry (LC-MS-MS) method is presented for the quantitation of cyclizine in serum. Sample pretreatment involved liquid-liquid extraction of 200 μl of serum with dichloromethane after the addition of 100 μl each of ammonium hydroxide and internal standard solutions. The extracts were analyzed by HPLC on a Luna ® C18 reversed-phase column and an ion-trap mass spectrometer with an electrospray interface. A limit of detection of 1 ng/ml was determined which allowed for the reliable measurement of cyclizine in the serum of human subjects. The method was found to be linear over the calibration range of 2.5-100 ng/ml. The applicability of this method was demonstrated by the analysis of serum obtained from a human volunteer following administration of a single 50 mg cyclizine hydrochloride tablet. The reported method was observed to have the necessary sensitivity, selectivity, precision and accuracy for monitoring cyclizine concentrations in human subjects following oral administration

Golestan cohort study of oesophageal cancer: feasibility and first results

To investigate the incidence of oesophageal cancer (EC) in the Golestan province of North-East Iran, we invited 1349 rural and urban inhabitants of Golestan province aged 35–80 to undergo extensive lifestyle interviews and to provide biological samples. The interview was repeated on a subset of 130 participants to assess reliability of questionnaire and medical information. Temperature at which tea was consumed was measured on two occasions by 110 subjects. Samples of rice, wheat and sorghum were tested for fumonisin contamination. An active follow-up was carried out after 6 and 12 months. A total of 1057 subjects (610 women and 447 men) participated in this feasibility study (78.4% participation rate). Cigarette smoking, opium and alcohol use were reported by 163 (13.8%), 93 (8.8%) and 39 (3.7%) subjects, respectively. Tobacco smoking was correlated with urinary cotinine (κ=0.74). Most questionnaire data had κ >0.7 in repeat measurements; tea temperature measurement was reliable (κ=0.71). No fumonisins were detected in the samples analysed. During the follow-up six subjects were lost (0.6%), two subjects developed EC (one dead, one alive); in all, 13 subjects died (with cause of death known for 11, 84.6%). Conducting a cohort study in Golestan is feasible with reliable information obtained for suspected risk factors; participants can be followed up for EC incidence and mortality

Higher urine 1-hydroxy pyrene glucuronide (1-OHPG) is associated with tobacco smoke exposure and drinking maté in healthy subjects from Rio Grande do Sul, Brazil

BACKGROUND: The highest rates of esophageal squamous cell carcinoma (ESCC) in Brazil occur in Rio Grande do Sul, the most southern state, which has incidence rates of 20.4/100,000/year for men and 6.5/100,000/year for women. Exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs) through tobacco smoke and other sources may increase the risk of ESCC. The aims of the current study were to investigate the degree and sources of PAH exposure of the inhabitants of this region of southern Brazil. METHODS: Two hundred healthy adults (half smokers, half non smokers, half male and half female) were recruited, given a standardized questionnaire, and asked to provide a urine sample for measurement of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite). Urine 1-OHPG concentrations were measured using immunoaffinity chromatography and synchronous fluorescence spectroscopy and urine cotinine was measured using a dipstick test. We examined factors associated with 1-OHPG concentration using Wilcoxon tests and multiple linear regression. RESULTS: Urine 1-hydroxypyrene glucuronide (1-OHPG) was successfully measured on 199 subjects. The median (interquartile range) of urine 1-OHPG in the 199 participants was 2.09 pmol/mL (0.51, 5.84). Tobacco smoke exposure and maté drinking were statistically significantly associated with higher urine 1-OHPG concentrations in the multivariate linear regression model. CONCLUSION: Tobacco smoke and maté both contribute to high levels of benzo[a]pyrene exposure in the people of southern Brazil. This high PAH exposure may contribute to the high rates of ESCC observed in this population. The increased urine 1-OHPG concentrations associated with maté suggest that contaminants, not just thermal injury, may help explain the increased risk of ESCC previously reported for maté consumption

TRIM5α and TRIM22 are differentially regulated according to HIV-1 infection phase and compartment.

CAPRISA, 2014.The antiviral role of TRIM E3 ligases in vivo is not fully understood. To test the hypothesis that TRIM5α and TRIM22 have differential transcriptional regulation and distinct anti-HIV roles according to infection phase and compartment, we measured TRIM5α, TRIM22, and type I interferon (IFN-I)-inducible myxovirus resistance protein A (MxA) levels in peripheral blood mononuclear cells (PBMCs) during primary and chronic HIV-1 infection, with chronic infection samples being matched PBMCs and central nervous system (CNS)-derived cells. Associations with biomarkers of disease progression were explored. The impact of IFN-I, select proinflammatory cytokines, and HIV on TRIM E3 ligase-specific expression was investigated. PBMCs from individuals with primary and chronic HIV-1 infection had significantly higher levels of MxA and TRIM22 than did PBMCs from HIV-1-negative individuals (P < 0.05 for all comparisons). PBMCs from chronic infection had lower levels of TRIM5α than did PBMCs from primary infection or HIV-1-uninfected PBMCs (P = 0.0001 for both). In matched CNS-derived samples and PBMCs, higher levels of MxA (P = 0.001) and TRIM5α (P = 0.0001) in the CNS were noted. There was a negative correlation between TRIM22 levels in PBMCs and plasma viral load (r = -0.40; P = 0.04). In vitro, IFN-I and, rarely, proinflammatory cytokines induced TRIM5α and TRIM22 in a cell type-dependent manner, and the knockdown of either protein in CD4(+) lymphocytes resulted in increased HIV-1 infection. These data suggest that there are infection-phase-specific and anatomically compartmentalized differences in TRIM5α and TRIM22 regulation involving primarily IFN-I and specific cell types and indicate subtle differences in the antiviral roles and transcriptional regulation of TRIM E3 ligases in vivo

Diet and esophageal cancer risk in the Eastern Cape Province of South Africa.

A multicenter hospital-based case-control study comprising 670 incident cases of esophageal cancer (EC) and 1188 controls, frequency-matched for age and sex, was conducted to evaluate the role of diet on EC development in the Eastern Cape Province, South Africa. A locally relevant lifestyle and dietary questionnaire was used. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were computed using unconditional multivariable logistic regression. Individually, maize or sorghum consumption vs. never or rare consumption were not associated with EC (P > 0.1). Males and females consuming green leafy vegetables 5-7 days/wk had 38% (P = 0.04) and 50% (P = 0.007) reduced odds of developing EC, respectively, compared with consumption ≤1 day/wk. A similar reduction in odds was observed with fruit consumption. Principal component factor analysis revealed 3 distinct dietary patterns. In females, high vs. low consumption of Pattern 1 (sorghum, green leafy vegetables, green legumes, fruits, meat) was inversely associated with EC development (OR = 0.54; 95% CI: 0.34-0.89), whereas for Pattern 2 (maize, wild greens-imifino, dry beans) the odds were elevated (OR = 1.67; 95% CI: 1.04-2.67). Compared with low adherence, high adherence to Pattern 3 (wheat-based products) reduced the odds by 35% for both sexes. This study provides further evidence on the role of diet in minimizing EC risk in this population

Tobacco and alcohol as risk factors for oesophageal cancer in a high incidence area in South Africa

BACKGROUND: The Eastern Cape Province of South Africa, which includes the former Transkei has high rates of squamous cell oesophageal cancer (OC), thought to be caused mainly by nutritional deficiencies and fungal contamination of staple maize. A hospital-based case-control study was conducted at three of the major referral hospitals in this region to measure, among other suspected risk factors, the relative importance of tobacco smoking and alcohol consumption for the disease in this population. METHODS: Incident cases (n=670) of OC and controls (n=1188) were interviewed using a structured questionnaire which included questions on tobacco and alcohol-related consumption. Odds ratios (ORs) with 95% confidence intervals for each of the risk factors were calculated using unconditional multiple logistic regression models. RESULTS: A monotonic dose-response was observed across the categories of each tobacco-related variable in both sexes. Males and females currently smoking a total of >14g of tobacco per day were observed to have over 4-times the odds of developing OC (males OR=4.36, 95% CI 2.24-8.48; females OR=4.56, 95% CI 1.46-14.30), with pipe smoking showing the strongest effect. Similar trends were observed for the alcohol-related variables. The quantity of ethanol consumed was the most important factor in OC development rather than any individual type of alcoholic beverage, especially in smokers. Males and females consuming >53g of ethanol per day had approximately 5-times greater odds in comparison to non-drinkers (males OR=4.72, 95% CI 2.64-8.41; females OR=5.24, 95% CI 3.34-8.23) and 8.5 greater odds in those who smoked >14g tobacco daily. The attributable fractions for smoking and alcohol consumption were 58% and 48% respectively, 64% for both factors combined. CONCLUSION: Tobacco and alcohol use are major risk factors for OC development in this region. IMPACT: This study provides evidence for further reinforcement of cessation of smoking and alcohol consumption to curb OC development.South African Medical Research Council, The Rockefeller Foundation, Cancer Council NSW and UICC are acknowledged for their financial support of this study

Biomarkers of exposure to fumonisin mycotoxins: A review

ArticleThe investigation of adverse health effects associated with fungal mycotoxins requires the measurement of human exposure. Most frequently, this exposure is estimated from contamination levels of raw foodstuffs, which are the primary source of toxin exposure, and data on food consumption patterns. However, variations in food preparation methods, food intake, contamination level, intestinal absorption, toxin distribution and excretion lead to individual variations in toxin exposure that are more readily measured with a biomarker. Fumonisin biomarkers have been sought in the measurement of levels of the toxin in physiological samples such as serum, urine, faeces, hair and nails. However, due to the low bioavailability of fumonisin, these samples pose a variety of analytical challenges and also still require validation as biomarkers. The most widely researched fumonisin biomarkers have been those related to the disruption of de novo sphingolipid biosynthesis, namely elevated levels of the sphingoid base, sphinganine, or of its ratio with sphingosine. Elevation of these parameters in humans would potentially provide a biomarker of biochemical effect. A number of investigations into the possible elevation of sphinganine (or its ratio with sphingosine) in human blood and urine have generally failed to correlate with estimates of fumonisin exposure. The sphingoid bases occur naturally in human blood and urine such that their levels have normal ranges, which can be influenced by dietary factors other than fumonisin ingestion. The lower exposures from human diets, as compared with doses in experimental animals, have made detection of changes in these sphingoid biomarkers problematic

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01 octobre 18421842/10/01 (A5)-1842/10/01