Changes in neurobiological parameters in the hippocampus after exposure to trimethyltin

The effects of trimethyltin (TMT) on neurotransmitters, morphological changes and physiological activity of the hippocampus were studied. A single injection of TMT (8 mg/kg) decreased the high affinity uptake of glutamate (HA-Glu), which is a marker for glutamergic nerve terminals, after 7 days. The maximal reduction of HA-Glu was 42% and was obtained on postinjection day 21. Glutamate decarboxylase (GAD) and choline acetyltransferase (ChAT), markers for GABAergic and cholinergic structures, were not affected. The electrical activity of the hippocampus recorded through chronically implanted electrodes was altered by day three postinjection. The amplitude of the hippocampal electrographic record gradually decreased and the EEG ceased to be correlated with the rats' behavioral state. Fink-Heimer staining showed degenerating neurons within the subiculum, CA1, ventral CA3 and CA4 hippocampal subfields. TMT (3 mg/kg) injected once a week for three weeks decreased the HA-Glu significantly 21 days after the first injection. The HA-Glu was reduced by a maximum of 68%. The activity of ChAT was slightly increased only at day 35 postinjection while the GAD activity was not significantly reduced over a 21 day period beginning on day 14. Fink-Heimer staining showed degeneration of nerve cells within the CA1, ventral CA3 and CA4 hippocampal subfields. Both injection schedules produced degenerating neurons in the entorhinal cortex. The neurons of the dorsal CA3 region and the granule cells of the dentate gyrus were not lesioned by either TMT injection. The relationship between the behavioral, physiological and neurochemical changes induced by TMT will be discussed.     

Glycine--an important neurotransmitter and cytoprotective agent

BACKGROUND: Glycine, the simplest of the amino acids, is an essential component of important biological molecules, a key substance in many metabolic reactions, the major inhibitory neurotransmitter in the spinal cord and brain stem, and an anti-inflammatory, cytoprotective, and immune modulating substance. MATERIAL AND METHODS: Based on available literature, we discuss some of the important biological properties of glycine. In addition, we describe some clinical disorders where glycine plays a central role, either as an essential structural element, or through its metabolism or receptors. RESULTS: The past few years have witnessed a broadening of glycine research. The traditional prime interest in aspects related to its role as an inhibitory neurotransmitter in the central nervous system has been expanded to equally emphasize other organs and tissues. With the demonstration of glycine-gated chloride channels on neurons in the central nervous system, on most leukocytes, and subsequently on other cells as well, a unifying mechanism of action accounting for many of the widespread effects of glycine has been found. CONCLUSIONS: Glycine is a simple, easily available, and inexpensive substance with few and innocuous side-effects. The diversity of biological activities is well documented in the literature. Despite this, glycine has only gained a modest place in clinical medicine.     

Effects of early intake of fruit or vegetables in relation to later asthma and allergic sensitization in school-age children

AIM: To assess the associations between nutrition supplements in infancy and later asthma and allergy in school-age children, and to explore the impact of environmental factors in early life. METHODS: Five hundred and two children underwent clinical examination, skin prick test and a second parentally completed questionnaire within 2 y of a cross-sectional questionnairebased study, including 4585 primary school children (6-16 y old) in 1994 from urban Oslo (37%), the mountainous area of Hallingdal (42%), and the industrial, coastal area of Odda (21%). The children were selected from the 1994 survey on the basis of reported diagnosed asthma (n=166), wheeze in the last 12 mo (n=155) and no asthma/no wheeze (n=181). Questions were related to nutrition and environmental exposure in early life. Possible associations between allergic sensitization or asthma at school age and exposures were estimated by logistic regression analysis, adjusting for potential confounders. RESULTS: Daily intake of fresh fruit or vegetables, but not extra vitamins or cod liver oil supplements, in infancy decreased the risk of asthma (adjusted odds ratio (aOR) 0.57 (95% confidence interval (CI): 0.37-0.88). Early supplements of cod liver oil and extra vitamins were associated with increased allergic sensitization (aOR 1.78 (95% CI: 1.03-3.07) and 1.71 (95% CI: 1.01-2.88), respectively). A significantly higher prevalence of allergic sensitization was found in children living in Hallingdal compared to Odda, while the latter children, on the other hand, had the highest prevalence of house dust mite allergy (p = 0.001 vs Hallingdal and p = 0.04 vs Oslo). CONCLUSION: The present study suggests that the early introduction of daily fresh fruit or vegetables may decrease the risk of asthma after 1 y of life, whereas allergic sensitization at school age seemed to increase with extra vitamin and cod liver oil supplements during infancy. Living area influenced allergic sensitization, with differences between coastal and inland areas.     

Shunt revisions in children--can they be avoided? Experiences from a population-based study

Background: Shunt failure is by far the most frequent problem in children with shunts, and most of them will experience this condition at some point in their lives. In order to identify causes of shunt failure, and to compare multi-component and one-piece shunt systems, we analyzed retrospectively all pediatric shunt procedures in our Department during an 11-year period. The study does not deal with shunt infections. Methods: We reviewed the records of all pediatric shunting procedures between January 1986 and December 1996. Results: The study included 161 children operated for hydrocephalus with a total of 431 procedures. The procedures included 124 (29%) primary insertions, 10 (2%) reinsertions and 297 (69%) revisions; 206 (69%) of the revisions were due to shunt failures, of which 74 (36%) were caused by the failure of the surgical technique (misplaced ventricular catheters, disconnected shunts, or misplaced peritoneal catheters). Conclusions: Improvement of the surgical technique may reduce the incidence of shunt failures and revisions. The results obtained in a small department like ours do not seem to differ substantially from those obtained in more specialized departments with a larger patient group. Practical measures that may reduce the risk of shunt failures are suggested.     

Lack of association with the CD28/CTLA4/ICOS gene region among Norwegian multiple sclerosis patients

Chromosome region 2q33 encodes several regulators of the immune system, among these the CD28, CTLA4, and ICOS molecules. Involvement of these genes in multiple sclerosis (MS) is not yet clear. We investigated six microsatellites and three SNPs in a relatively large and clinically well characterised Norwegian MS cohort. No associations were observed for any of the markers analysed in 575 MS patients and 551 controls. Associations were neither found when stratifying the material for the HLA-DRB1*1501, DQB1*0602 haplotype, gender, age at onset, disease course nor familial aggregation. In conclusion, this study could not confirm association with the CD28/CTLA4/ICOS gene region.     

Organic solvent-induced cell death in rat cerebellar granule cells: structure dependence of c10 hydrocarbons and relationship to reactive oxygen species formation

Previously, increased formation of reactive oxygen species (ROS) has been demonstrated in cultured rat cerebellar granule cells (CGCs) exposed to t-butylcyclohexane, n-decane, and n-butylbenzene (Dreiem et al. Relationship between lipophilicity of C6-10 hydrocarbon solvents and their ROS-inducing potency in rat cerebellar granule cells. Neurotoxicology 2002;23:701-9). In the present paper, we have studied the effects of these hydrocarbons on the viability of CGCs. Cell death was assessed by measurement of lactate dehydrogenase (LDH) release and trypan blue staining. t-butylcyclohexane and n-butylbenzene induced cell death in rat CGCs in a time-dependent and concentration-dependent manner. In contrast, n-decane did not cause release of LDH from rat CGCs even at 1mM. Morphological studies revealed apoptotic morphology characterized by cell shrinkage and chromatin condensation after exposure to low concentrations of t-butylcyclohexane and n-butylbenzene. However, there was no internucleosomal DNA fragmentation and no protection by the pan-caspase inhibitor Boc-D-FMK or the protein synthesis inhibitor cycloheximide. This indicates that cell death after t-butylcyclohexane and n-butylbenzene exposure is an intermediate between classical apoptosis and necrosis. Treatment with the antioxidant alpha-tocopherol ameliorated hydrocarbon-induced cell death, indicating involvement of reactive oxygen species in the mechanism of hydrocarbon toxicity. The significance of ROS formation in relation to cell death is discussed.     

Plasmacytoid dendritic cells activate allergen-specific TH2 memory cells: modulation by CpG oligodeoxynucleotides

BACKGROUND: Plasmacytoid dendritic cells (PDCs) accumulate in the nasal mucosa of allergic rhinitis patients, but their function in upper airway allergy has not been determined. CpG oligodeoxynucleotides, potent adjuvants in immunotherapeutic strategies in animal models, are especially effective at activating PDCs. These cells are therefore potential targets for immunomodulation in humans. OBJECTIVE: In this study, PDCs were compared with CD11c+ dendritic cells (DCs), a very potent antigen-presenting cell type, for their capacity to induce allergen-dependent activation of TH2 memory cells. Then, we investigated whether CpG-activated PDCs were able to modulate the allergen-specific TH2 memory response. METHODS: DCs were isolated from patients with upper airway allergy and cocultured with autologous CD4+ T cells with or without grass pollen extract and CpG. In some experiments cells were restimulated with allergen-pulsed monocyte-derived DCs. T-cell activation was measured by their proliferative response and cytokine production. RESULTS: PDCs stimulated allergen-dependent T-cell proliferation and TH2 cytokine production as efficiently as CD11c+ DCs. CpG-activated PDCs inhibited allergen-dependent proliferation of TH2 memory cells and markedly increased IFN-gamma production in PDC/T-cell cocultures; the former effect depended on the CpG-induced IFN-alpha/beta production by the PDCs. CONCLUSION: Our results demonstrated that PDCs efficiently drive allergen-dependent TH2 memory responses, suggesting that they play an active role in the allergic reaction. However, in the presence of CpG, PDCs were responsible for increased production of the TH1-related cytokines IFN-alpha and IFN-gamma, indicating that mucosal PDCs may be targets for CpG-based immunotherapeutic strategies against airway allergy.     

Thiophene is toxic to cerebellar granule cells in culture after bioactivation by rat liver enzymes

Several compounds that are not neurotoxic by themselves can cause toxic effects in vivo after enzymatic bioactivation. Thiophene is an industrial solvent known to produce degeneration primarily of the granule cells in the cerebellum when administered to animals in vivo. The mechanism for thiophene toxicity is not known, although it has been suggested that thiophene metabolism may lead to formation of oxidative intermediates that could function as the ultimate toxicants. In the present work we have used rat cerebellar granule cells (CGCs) in culture combined with rat liver postmitochondrial (S9) fraction as a source of biotransformation enzymes to test the toxicity of thiophene in vitro. The results demonstrate that thiophene is toxic to rat cerebellar granule cells in culture only after biotransformation. Furthermore, the toxic effects were reduced by cytochrome P450 (CYP) inhibitors and by scavengers of reactive molecules (alpha-tocopherol, reduced glutathione, and phenyl-N-tert-butylnitrone). These findings support the hypothesis that thiophene requires metabolism to produce the ultimate toxicant, and that the cytochrome P450 enzyme system is involved in the metabolism.     

Minnesota leisure time activity questionnaire and doubly labeled water in adolescents

PURPOSES: To validate the energy expenditure estimated from The Minnesota Leisure Time Physical Activity Questionnaire (MLTPAQ) with total energy expenditure (TEE) measured by doubly labeled water (DLW), and to present and examine the validity of an extended version of the MLTPAQ with additional questions about inactivity during leisure time (eMLTPAQ), in a sample of Swedish 15-yr-old adolescents. METHODS: Thirty-five 15-yr-old adolescents were interviewed using the eMLTPAQ. In addition to anthropometry, indirect calorimetry was measured to assess basal metabolic rate, and TEE was assessed by the DLW method over a 14-d period. RESULTS: Energy expenditure calculated from MLTPAQ correlated well with TEEDLW (r=0.49, P<0.01), and the correlation increased when including questions about inactivity (r=0.73, P<0.01). However, eMLTPAQ underestimated TEE in 34 of the 35 students, with a mean difference between the methods of 2.8 MJ.d(-1) (95% limits of agreement: -0.1 to 5.6 MJ.d(-1)), which mainly was explained by a relative high intensity in the time which remained unreported. CONCLUSION: eMLTPAQ is valid in ranking adolescents energy expenditure and in describing patterns of leisure time physical activities.