Predicting PCB concentrations in cow milk: validation of a fugacity model in high-mountain pasture conditions

A fugacity model reported in the literature was applied to a high - altitude pasture in the Italian Alps. The model takes into account three compartments (digestive tract, blood and fat tissues) in unsteady-state conditions using food as the contamination source. Disregarding biotransformation inside cow tissues, the predicted concentrations of 14 polychlorinated biphenyls (PCBs) in milk were in good agreement with the observed data, especially for congeners known for their resistance to biotransformation (e.g., CB-138 and 153). In contrast, the predicted concentrations were clearly overestimated for congeners with high biotransformation susceptibilities. Therefore data measured in milk and faeces were used to calculate the first-order-biotransformation rate constants in dairy cows. The PCB absorption efficiency observed for pasture conditionswas lower than that observed in the cowshed. The final version of the model included biotransformation and observed PCB absorption andwas able to predict PCB concentrations in cow milkwith mean differences between the predicted and measured data below \ub120% for most congener

Geographic Clusters of Primary Biliary Cirrhosis

Genetic and environmental factors have been widely suggested to contribute to the pathogenesis of primary biliary cirrhosis (PBC), an autoimmune disease of unknown etiology leading to destruction of small bile ducts. Interestingly, epidemiologic data indicate a variable prevalence of the disease in different geographical areas. The study of clusters of PBC may provide clues as to possible triggers in the induction of immunopathology. We report herein four such unique PBC clusters that suggest the presence of both genetic and environmental factors in the induction of PBC. The first cluster is represented by a family of ten siblings of Palestinian origin that have an extraordinary frequency of PBC (with 5/8 sisters having the disease). Second, we describe the cases of a husband and wife, both having PBC. A family in which PBC was diagnosed in two genetically unrelated individuals, who lived in the same household, represents the third cluster. Fourth, we report a high prevalence of PBC cases in a very small area in Alaska. Although these data are anedoctal, the study of a large number of such clusters may provide a tool to estimate the roles of genetics and environment in the induction of autoimmunity

Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial

Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin. In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1·5 μg/kg plus ribavirin 800–1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400–1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00423670. Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 [54%, 95% CI 44–64], p=0·013 for PRB28; 58/103 [56%, 44–66], p=0·005 for PR4/PRB24; 69/103 [67%, 57–76], p<0·0001 for PRB48; and 77/103 [75%, 65–83], p<0·0001 for PR4/PRB44; vs 39/104 [38%, 28–48] for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]). Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group. In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone. Merck

Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs

While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues

Four species of non-biting midges (Chironomidae) new for Cyprus

Four species of Chironomidae new for Cyprus are reported. These are: Procladius choreus, Rheocricotopus tirolus, Chironomus salinarius and Paratendipes nudisquama. Except Rheocricotopus tirolus all species are widespread in Europe. Rheocricotopus tirolus was up to now recorded mainly from northern and central part of the continent, however it was also found on Iberian Peninsula and North Africa

Predicting pesticide fate in the hive (part 2): development of a dynamic hive model

A new hive model is proposed for the assessment of the distribution and fate of pesticides in the hive ecosystem. Based on the chemical used, the model draws a dynamic picture of pesticide contamination in the hive, calculating contamination trends and concentration levels in the various hive components (e.g. bees, wax and honey). The proposed model is validated using empirical data on tau-fluvalinate residues in bees, wax and honey. It predicts with good approximation both the trends over time and the contamination levels of the pesticide in the various hive components. We have developed most of the parameters and equations used in this model. Although they will require further experimental testing, they provide realistic predictions that are consistent with the experimental data. The proposed model is a useful tool for predictive purposes and improves our understanding of contamination phenomena in the hive

Increased alanine concentration is associated with exposure to fenitrothion but not carbamates in Chironomus riparius larvae

Chironomus riparius Meigen were exposed to three different insecticides, the organophosphorous fenitrothion and the carbamates carbaryl and carbofuran (0, 1, 10, and 100 mu g/L) for 24h as fourth-instar larvae. Acetylcholinesterase (AChE), naphtylacetate esterase (NAE), p-nitrophenylacetate esterase (PNPAE), glutathione-S-transferase (GST), and a number of metabolites (alanine, pyruvate, lactate, trehalose, aspartate, oxalacetate) were measured to determine which was the most valuable biochemical biomarker of exposure. ACNE activity was significantly reduced by all three insecticides, PNPAE by fenitrothion, carbofuran and carbaryl, whereas NAE activity was stimulated by carbaryl and unaffected by fenitrothion and carbofuran. Metabolites analysis revealed a strong accumulation of alanine in larvae exposed to fenitrothion, but not in larvae exposed to carbamates. This accumulation was accompanied by a significant increase of lactate and a significant decrease of pyruvate and trehalose. No variations were observed with carbofuran and carbaryl. No change of aspartate concentration was detected. We conclude that the association of alanine accumulation with a significant inhibition of ACNE activity can be used as a valuable biochemical biomarker of exposure