CYP2A5-mediated activation and early ultrastructural changes in the olfactory mucosa: studies on 2,6-dichlorophenyl methylsulfone.

2,6-Dichlorophenyl methylsulfone (2,6-diClPh-MeSO2) is a potent olfactory toxicant reported to induce endoplasmic reticulum (ER) stress, caspase activation, and extensive cell death in mice. The aim of the present study was to examine cytochrome P450 (P450)-dependent bioactivation, nonprotein sulfhydryl (NP-SH) levels, and early ultrastructural changes in mouse olfactory mucosa following an i.p. injection of 2,6-diClPh-MeSO2 (32 mg/kg). A high covalent binding of 2,6-diClPh-14C-MeSO2 in olfactory mucosa S9 fraction was observed, and the CYP2A5/CYP2G1 substrates coumarin and dichlobenil significantly decreased the binding, whereas the CYP2E1 substrate chlorzoxazone had no effects. An increased bioactivation was detected in liver microsomes of mice pretreated with pyrazole, known to induce CYP2A4, 2A5, 2E1, and 2J, and addition of chlorzoxazone reduced this binding. 2,6-DiClPh-14C-MeSO2 showed a marked covalent binding to microsomes of recombinant yeast cells expressing mouse CYP2A5 or human CYP2A6 compared with wild type. One and 4 h after a single injection of 2,6-diClPh-MeSO2, the NP-SH levels in the olfactory mucosa were significantly reduced compared with control, whereas there was no change in the liver. Ultrastructural studies revealed that ER, mitochondria, and secretory granules in nonneuronal cells were early targets 1 h after injection. We propose that lesions induced by 2,6-diClPh-MeSO2 in the mouse olfactory mucosa were initiated by a P450-mediated bioactivation in the Bowman's glands and depletion of NP-SH levels, leading to disruption of ion homeostasis, organelle swelling, and cell death. The high expression of CYP2A5 in the olfactory mucosa is suggested to play a key role for the tissue-specific toxicity induced by 2,6-diClPh-MeSO2.     

Brain Iron and Zinc Contents of German Patients with Alzheimer Disease

Our first project aimed to determine the average values of Fe and Zn in normal German human brain (5 individuals, 10 brain parts). Determinations were carried out by instrumental neutron activation analysis in Berlin. Quality control measurements were performed using National Institute of Standard Technology standard reference materials. The present results show non-homogeneous distribution of Fe and Zn in normal human brain. Our second goal was to study the possible elemental concentration changes in German patients with Alzheimer disease (5 subjects, 10 brain regions). Fe and Zn values are found to be significantly changed in some AD brain regions compared to the controls. Another object of this work was to extend the method for the determination of elemental concentration not only in whole brain samples (high fat content) but - applying two types of solvent extraction - in lipid fraction and in brain tissue without lipid.     

Weekly docetaxel and capecitabine is not effective in the treatment of advanced gastric cancer: a phase II study.

BACKGROUND: Capecitabine and docetaxel have demonstrated preclinical antitumor synergy and activity in advanced gastric cancer. We assessed the clinical activity and the toxicity of weekly docetaxel in combination with capecitabine in untreated patients with advanced gastric cancer. PATIENTS AND METHODS: A total of 38 patients were treated with docetaxel 36 mg/m2 on days 1, 8, and 15 i.v., plus capecitabine, 625 mg/m2 bid per os on days 5 to 18 repeated every 4 weeks. RESULTS: All patients were assessable for response to treatment and for toxicity. Major responses were observed in eight patients (21%), with three patients achieving a CR (7.8%) and five showing a PR (13%). The median time to progression was 5.4 months and the overall survival was 7.7 months. The safety profile of this schedule was acceptable with a low rate of myelossuppression, diarrhoea and hand-foot syndrome. CONCLUSIONS: The combination of docetaxel and capecitabine at the doses and schedule investigated in this study is safe, but does not show significant activity in untreated patients with advanced gastric cancer.     

Evaluation of the micronucleus test in vitro using chinese hamster cells: Results of four chemicals weakly positive in the in vivo micronucleus test

A rapid and simple procedure for the micronucleus test (MNT) in vitro using Chinese hamster ovary (CHO) cells was established in our laboratory. The assay is intended to quickly screen chromosomal aberrations in vitro within the framework of industrial genotoxicity studies. To test the sensitivity of the assay in the experiments described here, four substances, classified as noncarcinogens but reported as weak inducers of micronuclei (MN) in bone-marrow cells of mice, were evaluated in the MNT in vitro. Of the four compounds, ascorbic acid, phenol, and 2,6-diaminotoluene proved to be genotoxic in the MNT in vitro. Titanium dioxide, which could not be dissolved in the culture medium, did not induce MN. The MNT in vitro proved to be quick and relatively simple and to yield highly reproducible results when testing the four chemicals. © 1995 Wiley-Liss, Inc.     

The impact of diagnostic labelling in population-based research into cerebral palsy

This study explores and quantifies the impact on the estimation of prevalence rates and aetiological hypotheses of inclusion and exclusion of different diagnostic labels and types of cerebral palsy (CP). The study was based on data from a CP register which had been established in the English North East Thames Regional Health Authority (NETRHA). As a deliberate policy, no definition of CP was given to notifiers and no inclusion or exclusion criteria were specified. Clinical information, including known malformations, genetic disorders, and features that made the diagnosis doubtful, was requested. Rates and relative risks for different inclusion and exclusion criteria were calculated. The crude rate of CP as defined above was 1.6/1000 (95%CI 1.5,1.7). "Exclusion of all cases with a known or potentially causal" association reduced this rate to 1.2/1000 (95%CI 1.0, 1.3). Comparison with an intensively investigated sample from Germany and Sweden showed that more of the same causal associations (or diagnostic labels) were found, particularly where MRI studies had been carried out. Future comparative studies in CP will need to be very precise in specifying inclusions and exclusions and in estimating the effects they will have on monitoring trends over time and aetiological hypotheses.     

Motor and Sensory Impairments in Children with Intractable Epilepsy

During a 3-year period (1988–1991), 72 children with severe intractable epilepsy were studied. A standardized protocol for assessment of motor and sensory function was designed for school age children. Function was quantified on a 4-point scale on 47 items, including gross motor function, balance, coordination, strength, range of motion (ROM), velocity, fine motor function, sensation, perception, and neurologic tests. Classification of handicaps according to World Health Organization (WHO) definitions was performed. Videotape documentation completed the assessment. Evaluation of treatment services showed that provision of rehabilitation services had been insufficient and provided only for children with additional major movement disorders, mainly cerebral palsy (CP) cases. To minimize the handicap in children with severe epilepsy, it is essential to clarify the total sensorimotor impairment pattern, including balance, co-ordination, and perceptual capacity. Impairments in these functions are, as shown in this study, frequent and exist independent of major disabilities such as mental retardation or cerebral palsy. When several neuroimpairments were identified, a multiplicative rather than an additive effect on the total handicap was evident.     

Poor sleepers who do not complain of insomnia: Myths and realities about psychological and lifestyle characteristics of older good and poor sleepers

Psychological adjustment, lifestyle, and sleep parameters were investigated in 634 older community residents. Participants were divided into three categories: good sleepers, poor sleepers experiencing high distress, and poor sleepers experiencing minimal distress. Results indicate that (1) highly distressed poor sleepers manifested an anxious, depressed, negative cognitive-affective set; (2) many coped well with age related changes in sleep quality—they resembled good sleepers in the relative absence of psychological maladjustment they displayed; (3) the three groups had similar lifestyles, but they differed in the cognitive-affective evaluation of their activities, (4) the insomnia complaint is itself multifaceted and is comprised of three distinct elements—difficulty sleeping, distress, and daytime fatigue; (5) sleep practices (e.g., naps, bedtimes) are not implicated in chronic poor sleep; and (6) many commonly held assumptions about sleep disruptions in older individuals are myth rather than reality. Implications for better understanding and treating insomnia in older individuals are discussed.This article was prepared during the tenure of grants from the Conseil Québécois de la recherche sociale, Health and Welfare Canada, and the Direction générale de l'enseignement collégial. We are grateful for the generous support of these organizations. In addition, we would like to thank the dedicated members of our research team: Sally Bailes, Ann Gay, Jason Lavers, John Martos, Kathleen McAdams, Vicki Tagalakis, and most especially, Harriet Lennox for their substantial contribution to this research.Dawson College.Sir Mortimer B. Davis—Jewish General Hospital.Concordia University.McGill University.