An efficient new route to dihydropyranobenzimidazole inhibitors of HCV replication.

A class of dihydropyranobenzimidazole inhibitors was recently discovered that acts against the hepatitis C virus (HCV) in a new way, binding to the IRES-IIa subdomain of the highly conserved 5' untranslated region of the viral RNA and thus preventing the ribosome from initiating translation. However, the reported synthesis of these compounds is lengthy and low-yielding, the intermediates are troublesome to purify, and the route is poorly structured for the creation of libraries. We report a streamlined route to this class of inhibitors in which yields are far higher and most intermediates are crystalline. In addition, a key variable side chain is introduced late in the synthesis, allowing analogs to be easily synthesized for optimization of antiviral activity

Association between the plasma/whole blood lead ratio and history of spontaneous abortion: a nested cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Blood lead has been associated with an elevated risk of miscarriage. The plasmatic fraction of lead represents the toxicologically active fraction of lead. Women with a tendency to have a higher plasma/whole blood Pb ratio could tend towards an elevated risk of miscarriage due to a higher plasma Pb for a given whole blood Pb and would consequently have a history of spontaneous abortion.</p> <p>Methods</p> <p>We studied 207 pregnant Mexico City residents during the 1^sttrimester of pregnancy, originally recruited for two cohorts between 1997 and 2004. Criteria for inclusion in this study were having had at least one previous pregnancy, and having valid plasma and blood Pb measurements. Pb was measured in whole blood and plasma by inductively coupled plasma mass spectrometry using ultra-clean techniques. History of miscarriage in previous pregnancies was obtained by interview. The incidence rate of spontaneous abortion was defined as the proportion of previous pregnancies that resulted in miscarriage. Data were analyzed by means of Poisson regression models featuring the incidence rate of spontaneous abortion as the outcome and continuous or categorized plasma/blood Pb ratios as predictor variables. All models were adjusted for age and schooling. Additionally, logistic regression models featuring inclusion in the study sample as the outcome were fitted to assess potential selection bias.</p> <p>Results</p> <p>The mean number of miscarriages was 0.42 (range 0 to 4); mean Pb concentrations were 62.4 and 0.14 μg/L in whole blood and plasma respectively. Mean plasma/blood Pb ratio was 0.22%. We estimated that a 0.1% increment in the plasma/blood Pb ratio lead was associated to a 12% greater incidence of spontaneous abortion (p = 0.02). Women in the upper tertile of the plasma/blood Pb ratio had twice the incidence rate of those in the lower tertile (p = 0.02). Conditional on recruitment cohort, inclusion in the study sample was unrelated to observable characteristics such as number of abortions, number of pregnancies, blood Pb levels, age schooling, weight and height.</p> <p>Conclusion</p> <p>Women with a large plasma/whole blood Pb ratio may be at higher risk of miscarriage, which could be due to a greater availability of placental barrier-crossing Pb.</p

Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis

Background B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance. Results We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0–15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while differentially expressed genes include, among others, multiple genes related to WNT signaling as well as the miRNAs miR-150-5p and miR-155-5p. Conclusions Our findings demonstrate the presence in prediagnostic blood of future CLL patients, more than 10 years before diagnosis, of CLL-like cells which evolve as preclinical disease progresses, and point to early molecular alterations with a pathogenetic potential

Lead exposure in adult males in urban Transvaal Province, South Africa during the apartheid era

Human exposure to lead is a substantial public health hazard worldwide and is particularly problematic in the Republic of South Africa given the country’s late cessation of leaded petrol. Lead exposure is associated with a number of serious health issues and diseases including developmental and cognitive deficiency, hypertension and heart disease. Understanding the distribution of lifetime lead burden within a given population is critical for reducing exposure rates. Femoral bone from 101 deceased adult males living in urban Transvaal Province (now Gauteng Province), South Africa between 1960 and 1998 were analyzed for lead concentration by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Of the 72 black and 29 white individuals sampled, chronic lead exposure was apparent in nearly all individuals. White males showed significantly higher median bone lead concentration (ME = 10.04 µg·g−1), than black males (ME = 3.80 µg·g−1) despite higher socioeconomic status. Bone lead concentration covaries significantly, though weakly, with individual age. There was no significant temporal trend in bone lead concentration. These results indicate that long-term low to moderate lead exposure is the historical norm among South African males. Unexpectedly, this research indicates that white males in the sample population were more highly exposed to lead

Influence of Socioeconomic Status Trajectories on Innate Immune Responsiveness in Children

Lower socioeconomic status (SES) is consistently associated with poor health, yet little is known about the biological mechanisms underlying this inequality. In children, we examined the impact of early-life SES trajectories on the intensity of global innate immune activation, recognizing that excessive activation can be a precursor to inflammation and chronic disease.Stimulated interleukin-6 production, a measure of immune responsiveness, was analyzed ex vivo for 267 Canadian schoolchildren from a 1995 birth cohort in Manitoba, Canada. Childhood SES trajectories were determined from parent-reported housing data using a longitudinal latent-class modeling technique. Multivariate regression was conducted with adjustment for potential confounders.SES was inversely associated with innate immune responsiveness (p=0.003), with persistently low-SES children exhibiting responses more than twice as intense as their high-SES counterparts. Despite initially lower SES, responses from children experiencing increasing SES trajectories throughout childhood were indistinguishable from high-SES children. Low-SES effects were strongest among overweight children (p<0.01). Independent of SES trajectories, immune responsiveness was increased in First Nations children (p<0.05) and urban children with atopic asthma (p<0.01).These results implicate differential immune activation in the association between SES and clinical outcomes, and broadly imply that SES interventions during childhood could limit or reverse the damaging biological effects of exposure to poverty during the preschool years

Signs of oral dryness in relation to salivary flow rate, pH, buffering capacity and dry mouth complaints

<p>Abstract</p> <p>Background</p> <p>This study aimed to investigate the signs of oral dryness in relation to different salivary variables and to correlate subjective complaints of oral dryness with salivary flow rate.</p> <p>Methods</p> <p>312 unmedicated healthy individuals belonging to three age groups, (6–11, 12–17, and 18–40 years) were examined clinically for signs of oral dryness. Resting and stimulated saliva were collected to determine flow rate, pH and buffering capacity. A questionnaire was used to obtain information on subjective sensation of dry mouth.</p> <p>Results</p> <p>Dry lip and dry mucosa were present in 37.5% and 3.2% of the sample respectively. The proportion of subjects who complained of oral dryness (19%) showed a stimulated salivary flow rate significantly lower than non complainers. Dry lip was significantly related to low resting flow rate but pH and buffering capacity did not show any significant relation to dry lip. Dry mucosa was not related to any of the above mentioned parameters.</p> <p>Conclusion</p> <p>The finding that the stimulated salivary flow rate was reduced in subjects complaining of dry mouth is of great clinical relevance, since the reduction is expected to be reflected in compromising various salivary functions.</p

Gender Differences in Public and Private Drinking Contexts: A Multi-Level GENACIS Analysis

This multi-national study hypothesized that higher levels of country-level gender equality would predict smaller differences in the frequency of women’s compared to men’s drinking in public (like bars and restaurants) settings and possibly private (home or party) settings. GENACIS project survey data with drinking contexts included 22 countries in Europe (8); the Americas (7); Asia (3); Australasia (2), and Africa (2), analyzed using hierarchical linear models (individuals nested within country). Age, gender and marital status were individual predictors; country-level gender equality as well as equality in economic participation, education, and political participation, and reproductive autonomy and context of violence against women measures were country-level variables. In separate models, more reproductive autonomy, economic participation, and educational attainment and less violence against women predicted smaller differences in drinking in public settings. Once controlling for country-level economic status, only equality in economic participation predicted the size of the gender difference. Most country-level variables did not explain the gender difference in frequency of drinking in private settings. Where gender equality predicted this difference, the direction of the findings was opposite from the direction in public settings, with more equality predicting a larger gender difference, although this relationship was no longer significant after controlling for country-level economic status. Findings suggest that country-level gender equality may influence gender differences in drinking. However, the effects of gender equality on drinking may depend on the specific alcohol measure, in this case drinking context, as well as on the aspect of gender equality considered. Similar studies that use only global measures of gender equality may miss key relationships. We consider potential implications for alcohol related consequences, policy and public health