Sequence of changes in rat buccal mucosa induced by zinc deficiency

In weanling rats, after receiving a zinc-deficient diet (less than 1 ppm) for 4 wk, the buccal mucosa appears hyperplastic. This study determines changes at earlier stages of the lesion. After 9 days of deficiency, the keratin layer had partially converted to parakeratosis and thickened, and the size of the capillary bed was increased. After 18 days, the keratin layer was fully parakeratotic and thickened further. The cellular layer was thickened. The mitotic rate was doubled and rete ridges were convoluted. After 27 days, the keratin and cellular layers were further thickened, and the mitotic rate remained elevated. The rete ridges were further convoluted. The number of mast cells was doubled and the size of the vascular bed had increased further. These findings suggest early and late interactions between the epithelium and lamina propria. After four days on a control diet following 27 days of zinc deficiency, the mucosa returned normal.     

A neonatal swine model for peanut allergy.

BACKGROUND: Peanut allergy represents a significant health threat in the United States. The factors contributing to the severity of the allergic response and the immunopathogenic mechanisms underlying peanut allergy remain to be completely characterized. As yet, no animal model has been developed that will completely mimic the physical, immunologic, and histologic features of food allergy. OBJECTIVE: The purpose of this investigation was to develop a neonatal pig model of peanut allergy that would mimic the allergic symptoms and the immunologic and histologic profile of human peanut allergy. METHODS: Newborn piglets sensitized intraperitoneally with peanut extract and cholera toxin were orally challenged repeatedly with peanut meal. Physical symptoms, including emesis, lethargy, diarrhea, and respiratory distress, were monitored to determine the allergic response. Immunologic assessment was conducted through use of skin testing and the antigenic response to peanut proteins. Histologically, tissues derived from the esophagus, stomach, small intestine, and colon were assessed for morphologic changes after the oral challenge. RESULTS: Peanut-sensitized pigs responded with physical symptoms that mimicked those seen in double-blinded, placebo-controlled oral food challenges to peanuts in children and adults. Skin testing suggested an IgE-mediated response; this was confirmed by a negative passive cutaneous anaphylaxis response of heat-treated sera obtained from peanut-sensitized animals. Damage to villi of the small intestine was similar to that seen in endoscopically obtained tissue specimens from certain food-allergic individuals. CONCLUSION: The neonatal pig model of peanut allergy mimics the physical and immunologic characteristics of peanut allergy in human beings. The model will be useful for determining IgE-mediated mechanisms and conducting endoscopic histologic assessment of tissues and immunotherapeutic intervention strategies with repeated allergen challenges.     

Increased serotonin2 and beta-adrenergic receptor binding in the frontal cortices of suicide victims

A statistically significant 28% increase in the mean (+/- SD) number of serotonin2 receptors (127.8 +/- 13.4 vs 99.6 +/- 11.1 fmol/mg of protein) and a 73% increase in beta-adrenergic receptor binding (14.5 +/- 1.5 vs 8.4 +/- 1.5 fmol/mg) was found in the frontal cortices of violent suicide victims compared with matched controls. No significant differences were found in the number of serotonin1 binding sites (109.5 +/- 13.4 vs 99.9 +/- 8.8 fmol/mg). We have previously reported a reduced density of presynaptic tritiated imipramine binding sites on serotonergic nerve terminals in the frontal cortices of suicide victims. These data support the hypothesis that suicide completed by violent methods is associated with reduced presynaptic serotonergic activity that has generated compensatory upregulation of the postsynaptic serotonin2 receptor sites. The increase observed in beta-adrenergic binding suggests that there may also be a concomitant reduction in presynaptic noradrenergic activity associated with suicide. If antidepressant pharmacotherapies specifically downregulate cortical beta-adrenergic and/or serotonin2 receptors in depressed subjects, as has been demonstrated in animal studies, and since these effects would be in the opposite direction of the receptor changes found in suicide victims, they may account for the therapeutic action of antidepressants on suicidal behavior and depressive disorders.     

Technical considerations in the application of intensity-modulated radiotherapy as a concomitant integrated boost for locally-advanced cervix cancer.

The technical aspects of IMRT applied to cervix cancer are discussed in this paper, as well as issues related to tumor delineation, target volume definitions, inverse planning, and IMRT delivery. A theoretical example illustrating how IMRT can accurately mimic dose distributions obtained using conventional planning plus HDR brachytherapy is also shown. The notion of clinical optimization parameters is introduced to account for the radiation delivery variables, which affect the overall treatment time. This is especially relevant to the possible introduction of intrafractional movement and resulting inaccuracy, as well as facility efficiency.     

Phase I study of the anthrapyrazole biantrazole: clinical results and pharmacology

Summary In a phase I study the anthrapyrazole biantrazole (Warner-Lambert Company) was given to 41 patients with tumour refractory to existing therapy. The drug was given i.v. weekly for 3 weeks, with a 3-week interval between courses. At the 1st week a full pharmacokinetic study was performed, and at weeks 2 and 3, blood samples were taken at 1 and 6 h following treatment to check for drug accumulation. Biantrazole pharmacokinetics were linear with respect to the AUC (r=0.924) over the full range of doses studied (4–36 mg/m²) but exhibited large inter-patient variations at each dose level. Elimination was triphasic, comprising two rapid early phases and a long terminal half-life (mean, 14.1±7.8 h). There was no evidence of drug accumulation over the 3-week treatment period. Approximately 12% of the parent drug was excreted unchanged in the urine together with two non-circulating, more water-soluble metabolites. Biantrazole was well tolerated but did cause moderate emesis at doses of >18 mg/m² and mild alopecia. The dose-limiting side effect was leucopenia, with no other major toxicity being observed. One patient developed biventricular failure that was not clearly related to biantrazole administration. On the present schedule, the recommended dose of biantrazole is 24 mg/m². No response were seen in this patient population. Authors: on behalf of the EORTC Early Clinical Trials Group and the CRC Phase I/II Trials Committee     

Induction of DT-diaphorase by anticarcinogenic sulfur compounds in mice

The effects of the dietary administration of four anticarcinogenic sulfur compounds on the activity of DT-diaphorase, a protective enzyme in quinone and quinoneimine detoxification, have been investigated in female CD-1 mice. Bisethylxanthogen, disulfiram, sodium diethyldithiocarbamate, and benzylisothiocyanate, administered at 0.5% of the diet (by weight) for 14 days, each induced significant increases in DT-diaphorase specific activities in cytosol fractions of lung, kidney, urinary bladder, proximal small intestine, and colon. Cytosolic DT-diaphorase of the fore-stomach was elevated in response to bisethylxanthogen, disulfiram, and benzylisothiocyanate. The increases in cytosolic DT-diaphorase activities in organs of mice fed 0.5% bisethylxanthogen were similar in magnitude to those observed previously in response to 0.75% butylated hydroxyanisole. Liver cytosol DT-diaphorase specific activity was enhanced sevenfold by 0.5% bisethylxanthogen, twofold by 0.5% benzylisothiocyanate, and 2.6-fold by 1% disulfiram but was not significantly increased by disulfiram or sodium diethyldithiocarbamate at 0.5% of the diet. Diets containing 0.5% bisethylxanthogen or 0.5% benzylisothiocyanate also elevated microsomal DT-diaphorase specific activities in several organs. Even at the tenfold-lower concentration of 0.05% of the diet, bisethylxanthogen induced significant increases in DT-diaphorase specific activities in cytosol fractions of liver, lung, kidney, and small intestine and in liver and kidney microsomes. The protective function of DT-diaphorase in limiting free-radical formation and oxidative damage to cells suggests that the induction of this enzyme contributes to the anticarcinogenic effects of the four sulfur compounds studied.