Transient enriched housing before amyloidosis onset sustains cognitive improvement in Tg2576 mice

Levels of educational and occupational attainment, as components of cognitive reserve, may modify the relationship between the pathological hallmarks and cognition in Alzheimer's disease (AD). We examined whether exposure of a Tg2576 transgenic mouse model of AD to environmental enrichment (EE) at a specific period during the amyloidogenic process favored the establishment of a cognitive reserve. We found that exposure to EE during early adulthood of Tg2576 mice—before amyloidogenesis has started—reduced the severity of AD-related cognitive deficits more efficiently than exposure later in life, when the pathology is already present. Interestingly, early-life exposure to EE, while slightly reducing forebrain surface covered by amyloid plaques, did not significantly impact aberrant inhibitory remodeling in the hippocampus of Tg2576 mice. Thus, transient early-life exposure to EE exerts long-lasting protection against cognitive impairment during AD pathology. In addition, these data define the existence of a specific life time frame during which stimulatory activity most efficiently builds a cognitive reserve, limiting AD progression and favoring successful aging.     

Prevalence of peanut allergy in primary-school children in Montreal, Canada

BACKGROUND: Peanut allergy is receiving increasing attention. Only one study has estimated the prevalence in North America, but it did not corroborate history with diagnostic testing. OBJECTIVE: We estimated the prevalence of peanut allergy in Montreal by administering questionnaires regarding peanut ingestion to children in kindergarten through grade 3 in randomly selected schools. METHODS: Respondents were stratified as follows: (1). peanut tolerant, (2). never-rarely ingest peanut, (3). convincing history of peanut allergy, and (4). uncertain history of peanut allergy. Groups 2, 3, and 4 underwent peanut skin prick tests (SPTs), and if the responses were positive in groups 2 or 4, measurement of peanut-specific IgE were undertaken. Children in group 3 with a positive SPT response were considered allergic to peanut without further testing. Children in groups 2 and 4 with peanut-specific IgE levels of less than 15 kU/L underwent oral peanut challenges. RESULTS: Of the 7768 children surveyed, 4339 responded, 94.6% in group 1. The prevalence of peanut allergy was 1.50% (95% CI, 1.16%-1.92%). When multiple imputation was used to incorporate data on those responding to the questionnaire but withdrawing before testing, the estimated prevalence increased to 1.76% (95% CI, 1.38%-2.21%). When data regarding the peanut allergy status of nonresponders (as declared to the school before the study) were also incorporated, the estimated prevalence was 1.34% (95% CI, 1.08%-1.64%). CONCLUSION: Our prevalence study is the first in North America to corroborate history with confirmatory testing and the largest worldwide to incorporate these techniques. We have shown that, even with conservative assumptions, prevalence exceeds 1.0%.     

Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance

PURPOSE: Although single nucleotide polymorphisms (SNP) of the dihydropyrimidine dehydrogenase gene (DPYD) have been reported, which affect enzyme activity and the severity of 5-fluorouracil (5-FU) toxicity, no pretherapeutic detection has thus far been developed. We investigated 22 DPYD gene SNPs, their respective incidence, their link with grade 3 to 4 toxic side effects, and their management in practice: 9 were looked for in 487 patients, whereas 13 others were investigated in 171 patients. PATIENTS AND METHODS: SNPs were detected before 5-FU-based treatment in WBC using a Pyrosequencing method. Close clinical and biological follow-up was done. RESULTS: Five different SNPs were found in 187 patients (IVS14 + 1G>A, 2846A>T, 1679T>G, 85T>C, -1590T>C). Three hundred patients had no SNP. Forty-four patients had grade 3 to 4 toxic side effects in either the first or second cycle. Sixty percent of patients with either IVS14 + 1G>A or 2846A>T SNPs and the only patient with 1679T>G SNP experienced early grade 3 to 4 toxicity, compared with 0%, 5.5%, and 15% of those with either -1590T>C, 85T>C SNP, or no SNP, respectively. In cases with grade 3 to 4 toxicity, treatment either had to be quickly stopped, or could be safely continued with an individual dose adjustment. Sensitivity, specificity, and positive and negative predictive values of the detection of these three major SNPs as toxicity predictive factors were 0.31, 0.98, and 0.62 and 0.94, respectively. CONCLUSION: Pretreatment detection of three DPYD SNPs could help to avoid severe toxic side effects. This approach is suitable for clinical practice and should be compared or combined with pharmacologic approaches. In the case of dihydropyrimidine dehydrogenase deficiency, 5-FU administration often can be safely continued with an individual dose adjustment.     

Characterization of drug-specific T cells in lamotrigine hypersensitivity

BACKGROUND: Lamotrigine is associated with hypersensitivity reactions, which are most commonly characterized by skin rash. An immune etiology has been postulated, though the nature of this is unclear. OBJECTIVES: The aim of this study was to characterize the role of T cells in lamotrigine hypersensitivity. METHODS: A lymphocyte transformation test was performed on 4 hypersensitive patients. Lymphocytes from 3 of 4 lamotrigine-hypersensitive patients proliferated when stimulated with lamotrigine. T-cell clones were generated from one patient to further characterize the nature of the T-cell involvement. Cells were characterized in terms of their phenotype, functionality, and mechanisms of antigen presentation and cytotoxicity. RESULTS: Of the 44 drug-specific T-cell clones generated, most were CD4(+) with occasional CD8(+) cells. All clones expressed the alphabeta T-cell receptor; several Vbeta 5.1(+) or 9(+) T-cell clones were generated. All clones also expressed the skin-homing receptor cutaneous lymphocyte antigen. Lamotrigine-stimulated T cells were cytotoxic and secreted perforin, IFN-gamma, IL-5, and macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, RANTES, and I-309. Lamotrigine was present on HLA-DR and HLA-DQ by antigen-presenting cells in the absence of drug metabolism and processing. The T-cell receptor of certain clones could accommodate analogs of lamotrigine, but no cross-reactivity was seen with other anticonvulsants. CONCLUSIONS: Our data provide evidence that T cells are involved in the pathogenesis of some lamotrigine-hypersensitivity reactions. The identification of drug-specific cells that express cutaneous lymphocyte antigen and type 1 cytokines after T-cell receptor activation is consistent with the clinical symptoms. Furthermore, identification of large numbers of Vbeta 5.1(+) T cells suggests that polymorphisms within T-cell receptor genes might act as determinants of susceptibility.     

Maternal Alcohol Use During Pregnancy Causes Systemic Oxidation of the Glutathione Redox System

Background: Increased systemic oxidant stress contributes to a variety of maternal complications of pregnancy. Although the antioxidant glutathione (GSH) and its oxidized component glutathione disulfide (GSSG) have been demonstrated to be significantly altered in the adult alcoholic, the effects of maternal alcohol use during pregnancy on oxidant stress in the postpartum female remain under investigation. We hypothesized that maternal alcohol use would increase systemic oxidant stress in the pregnant female, evidenced by an oxidized systemic GSH redox potential. Methods: As a subset analysis of a larger maternal language study, we evaluated the effects of alcohol consumption during pregnancy on the systemic GSH redox status of the postpartum female. Using an extensive maternal questionnaire, postpartum women where queried regarding their alcohol consumption during pregnancy. Any drinking, the occurrence of drinking >3 drinks/occasion, and heavy drinking of >5 drinks/occasion during pregnancy were noted. Using HPLC, maternal plasma samples were analyzed for GSH, oxidized GSSG and the redox potential of the GSH/GSSG antioxidant pair calculated. Results: Maternal alcohol use occurred in 25% (83/321) of our study sample. Two in ten women reported consuming >3 drinks/occasion during pregnancy, while 1 in 10 women reported consuming alcohol at >5 drinks/occasion. Any alcohol use during pregnancy significantly decreased plasma GSH (p < 0.05), while alcohol at >3 drinks/occasion or >5 drinks/occasion significantly decreased plasma GSH concentration (p < 0.05), increased the percent of oxidized GSSG (p < 0.05), and substantially oxidized the plasma GSH redox potential (p < 0.05). Conclusions: Alcohol use during pregnancy, particularly at levels >3 drinks/occasion, caused significant oxidation of the systemic GSH system in the postpartum women. The clinical ramifications of the observed alcohol‐induced oxidation of the GSH redox system on high risk pregnancies or on the exposed offspring require more accurate identification and further investigation.