The role of metabolism in the developmental toxicity of polycyclic aromatic hydrocarbon-containing extracts of petroleum substances

In vitro assays presently used for prenatal developmental toxicity (PDT) testing only assess the embryotoxic potential of parent substances and not that of potentially embryotoxic metabolites. Here we combined a biotransformation system, using hamster liver microsomes, with the ES-D3 cell differentiation assay of the embryonic stem cell test (EST) to compare the in vitro PDT potency of two 5-ring polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (BaP) and dibenz[a,h]anthracene (DBA), and dimethyl sulfoxide extracts from five PAH-containing petroleum substances (PS) and a gas-to-liquid base oil (GTLb), with and without bioactivation. In the absence of bioactivation, DBA, but not BaP, inhibited the differentiation of ES-D3 cells into beating cardiomyocytes in a concentration-dependent manner. Upon bioactivation, BaP induced in vitro PDT, while its major metabolite 3-hydroxybenzo[a]pyrene was shown to be active in the EST as well. This means BaP needs biotransformation to exert its embryotoxic effects. GTLb extracts tested negative in the EST, with and without bioactivation. The PS-induced PDT in the EST was not substantially changed following bioactivation, implying that metabolism may not play a crucial role for the PS extracts under study to exert the in vitro PDT effects. Altogether, these results indicate that although some PAH require bioactivation to induce PDT, some do not and this latter appears to hold for the (majority of) the PS constituents responsible for the in vitro PDT of these complex substances.     

Intake of dietary iron is low in patients with Crohn's disease: a case-control study

Patients with Crohn's disease (CD) often experience Fe deficiency (ID) and frequently alter their diet to relieve abdominal symptoms. The present study set out to assess whether patients with CD have dietary habits that lead to low Fe intakes and/or reduced bioavailable Fe compared with control subjects. Patients with asymptomatic CD were matched to controls (n 91/group). Dietary intakes of Fe and contributions from different food groups were compared using a 7 d food diary. Promoters and inhibitors of non-haem Fe absorption were investigated and a recently published algorithm was applied to assess bioavailable Fe. Fewer patients than controls met the reference nutrient intake for Fe (32% CD patients v. 42% controls). Overall, patients had significantly lower mean Fe intakes (by 2.3 mg/d) and Fe density (by 0.26 mg/MJ (1.1 mg/1000 kcal)) compared with controls (both P<0.001). Differences were mainly due to a preference among CD patients for low-fibre non-Fe fortified cereals, particularly breakfast cereals. In particular, control subjects had higher Fe intakes than matched CD subjects for men (P<0.001) and women less than 50 years (P=0.03). Intakes of both ascorbic acid (P<0.001) and phytic acid (P<0.01), but not animal tissue (P=1.0), were lower in patients with CD, but these had no overall effect on the predicted percentage of bioavailable Fe. Thus total bioavailable Fe was reduced in patients with CD due to lower intakes (P<0.01). Dietary Fe intakes are low in CD patients, which may contribute to an increased risk of ID and anaemia. Changing dietary advice may compromise perceived symptoms of the disease so the need for Fe supplementation should be carefully considered.     

Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays

A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.     

Optimal oxygen concentration during induction of general anesthesia

BACKGROUND: The use of 100% oxygen during induction of anesthesia may produce atelectasis. The authors investigated how different oxygen concentrations affect the formation of atelectasis and the fall in arterial oxygen saturation during apnea. METHODS: Thirty-six healthy, nonsmoking women were randomized to breathe 100, 80, or 60% oxygen for 5 min during the induction of general anesthesia. Ventilation was then withheld until the oxygen saturation, assessed by pulse oximetry, decreased to 90%. Atelectasis formation was studied with computed tomography. RESULTS: Atelectasis in a transverse scan near the diaphragm after induction of anesthesia and apnea was 9.8 +/- 5.2 cm2 (5.6 +/- 3.4% of the total lung area; mean +/- SD), 1.3 +/- 1.2 cm2 (0.6 +/- 0.7%), and 0.3 +/- 0.3 cm2 (0.2 +/- 0.2%) in the groups breathing 100, 80, and 60% oxygen, respectively (P < 0.01). The corresponding times to reach 90% oxygen saturation were 411 +/- 84, 303 +/- 59, and 213 +/- 69 s, respectively (P < 0.01). CONCLUSION: During routine induction of general anesthesia, 80% oxygen for oxygenation caused minimal atelectasis, but the time margin before unacceptable desaturation occurred was significantly shortened compared with 100% oxygen.     

Antimicrobial susceptibility and molecular typing of multiple Chlamydiaceae species isolated from genital infection of women in Egypt

This study investigated the existence of vaginal Chlamydia infection and the prevalence of the disease in symptomatic gynecologically diseased women in Egypt. In addition, the antibiotics penicillin, tetracycline, and erythromycin were evaluated for their in vitro antichlamydial activity of the isolated strains. Vaginal swabs (n=160) were collected from females gynecologically diseased using cotton swabs. Samples were tested for Chlamydia by Vero cells tissue culture, chicken embryo, Gimenez staining, direct fluorescein-conjugated monoclonal antibody staining, and immunoperoxidase. Polymerase chain reaction (PCR) analyses conducted for the presence of chlamydial DNA was used to detect its specific DNA by the omp2 gene. PCR analyses conducted for the presence of chlamydial DNA revealed that 112/160 (70%) were positive for Chlamydiaceae. The specific DNA defined by the omp2 gene identified them as Chlamydia trachomatis (17/112, 15.2%), Chlamydophila psittaci (56/112, 50.0%), and Chlamydophila abortus (40/112, 35.7%). The antibiotics penicillin, tetracycline, and erythromycin at different concentrations were effective in inactivating the viability of Chlamydiaceae isolates.     

Multiple task demands in action disorganization syndrome

We present novel evidence for specific, disruptive effects of multi-step task demands on the production of everyday life tasks in two patients with Action Disorganization Syndrome (ADS). Experiment 1 demonstrated that the patients were impaired at carrying out everyday life tasks but improved when they instructed the examiner to perform the tasks. Experiments 2 and 3 showed that the patients improved in their own performance when the demands were reduced - by eliminating the need to use their own task schema (Experiment 2) and by reducing the need for error monitoring (Experiment 3). Experiment 4 reduced sequential effects in task performance further by having patients perform the same individual actions as before but now out of the task context. The data indicate that ADS patients are vulnerable to multiple demands made during the performance of everyday life tasks and show abnormal, disruptive effects of three specific factors: (i) using a self-driven schema, (ii) error monitoring and (iii) the activation of prior actions from the same task. The implications for understanding ADS are discussed.