A mathematical model for intracellular effects of toxins on DNA adduction and repair

The process by which certain classes of toxins compounds or their metabolites may react with DNA to alter the genetic information contained in subsequent generations of cells or organisms are a major component of hazard associated with exposure to chemicals in the environment. Many classes of chemicals may form DNA adducts and there may or may not be a defined mechanism to remove a particular adduct from DNA independent of replication. Many compounds and metabolites that bind DNA also readily bind existing proteins; some classes of toxins and DNA adducts have the capacity to inactivate a repair enzyme and divert the repair process competitively. This paper formulates an intracellular dynamic model for one aspect of the action of toxins that form DNA adducts, recognizing a capacity for removal of those adducts by a repair enzyme combined with reaction of the toxin and/or the DNA adduct to inactivate the repair enzyme. This paper model illustrates the possible saturation of repair enzyme capacity by the toxin dosage and shows that bistable behavior can occur, with the potential to induce abrupt shifts away from steady state equilibria. The model suggests that bistable behavior, dose and variation between individuals or tissues may combine under certain conditions to amplify the biological effect of dose observed as DNA adduction and its consequences as mutation. A model recognizing stochastic phenomena also indicates that variation in within-cell toxin concentration may promote jumps between stable equilibria.     

Prognostic factors for disease progression in advanced Hodgkin''s disease: an analysis of patients aged under 60 years showing no progression in the first 6 months after starting primary chemotherapy

Cell and tissue concentrations of NO2- and NO3- are important indicators of nitric oxide synthase activity and crucial in the regulation of many metabolic functions, as well as in nonenzymatic nitric oxide release. We adapted the capillary electrophoresis technique to quantify NO2- and NO3- levels in single identified buccal neurons and ganglia in the opisthobranch mollusc Pleurobranchaea californica, a model system for the study of the chemistry of neuron function. Neurons were injected into a 75-microm separation capillary and the NO2- and NO3- were separated electrophoretically from other anions and detected by direct ultraviolet absorbance. The limits of detection for NO2- and NO3- were <200 fmol (<4 microM in the neurons under study). The NO2- and NO3- levels in individual neurons varied from 2 mM (NO2-) and 12 mM (NO3-) in neurons histochemically positive for NADPH-diaphorase activity down to undetectable levels in many NADPH-diaphorase-negative cells. These results affirm the correspondence of histochemical NADPH-diaphorase activity and nitric oxide synthase in molluscan neurons. NO2- was not detected in whole ganglion homogenates or in hemolymph, whereas hemolymph NO3- averaged 1.8 +/- 0.2 x 10(-3) M. Hemolymph NO3- in Pleurobranchaea was appreciably higher than values measured for the freshwater pulmonate Lymnaea stagnalis (3.2 +/- 0.2 x 10(-5) M) and for another opisthobranch, Aplysia californica (3.6 +/- 0.7 x 10(-4) M). Capillary electrophoresis methods provide utility and convenience for monitoring NO2-/NO3- levels in single cells and small amounts of tissue.     

A phase II study of topotecan administered five times daily in patients with advanced gastric cancer

CASE REPORT: Arginine hydrochloride is used both diagnostically to test for growth hormone deficiency and therapeutically for treatment of metabolic alkalosis. We describe a 21-month-old girl who developed cardiopulmonary arrest following an accidental overdose of arginine hydrochloride. The patient developed acute metabolic acidosis and transient, but severe, hyponatremia. Thirty-six hours after successful resuscitation, she developed fatal central pontine and extrapontine myelinolysis. Unlike previous reports of arginine-toxicity, our patient showed no evidence of hyperkalemia. This case illustrates a previously unreported mechanism of arginine hydrochloride toxicity.     

Assessment and surgical treatment of basal cell skin cancer

The conspicuously high rate of BCC in the population mandates that clinicians have a clear understanding of the tumor's patterns of presentation and behavior. Goals of any form of treatment include establishment of the proper diagnosis and eradication of the lesion with a reasonable aesthetic result.     

Drug and environmental factors associated with adverse pregnancy outcomes. Part II: Improvement with folic acid

OBJECTIVE: To provide a comprehensive review of periconceptional folic acid supplementation and factors affecting folate supplementation trials. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, spina bifida, and anencephaly. STUDY SELECTION: Relevant animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included: type of study, folate dosing, dietary folate intake, serum and red blood cell folate concentrations, type of defect(s) studied, vitamin usage, parental risk factors, factors affecting trial results. DATA SYNTHESIS: Nine key factors have been identified that affect outcomes of folic acid supplementation trials. Daily doses of 0.8 mg decreased the occurrence and doses of 4 mg decreased the recurrence of neural tube defects in randomized clinical trials. Since lower folic acid doses were effective in nonrandomized trials, research is needed to determine the lowest effective dosage. Other benefits involving pregnancy outcome are suggested. CONCLUSIONS: Women of childbearing age should take a daily folic acid supplement to reduce the risk of pregnancies resulting in infants with a neural tube defect and other potential adverse pregnancy outcomes. Further health benefits from folic acid supplementation are reviewed in Part III of this series.     

Timing of computed tomography in acute diverticulitis

OBJECTIVE: Studies on brain serotonin metabolism in human and nonhuman primates have indicated that dysfunction of serotonin transmission may play a role in the biological vulnerability to dependence on alcohol. Among young men, low sensitivity to alcohol intoxication predicts subsequent alcohol abuse and dependence. METHOD: The authors used single photon emission computed tomography and the radioligand [(I)123]beta-CIT ([(I)123]methyl 3beta-(4-iodophenyl) tropane-2-carboxylate) to measure the availability of serotonin transporters in 11 male rhesus monkeys, and the monkeys were genotyped for a functional polymorphism of the serotonin transporter gene. The 11 monkeys had experienced parental separation after birth; their behavior and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in CSF had been assessed regularly. RESULTS: In the 5-year-old monkeys, there was a significant negative correlation between beta-CIT binding to serotonin transporters in the brainstem and 5-HIAA concentrations in CSF. Animals with greater beta-CIT binding and low CSF 5-HIAA concentrations displayed greater aggressiveness and were less sensitive to alcohol-induced intoxication. The genetic constitution of the serotonin transporter promoter gene did not significantly contribute to the availability of brainstem serotonin transporters as measured by beta-CIT binding. CONCLUSIONS: In adult nonhuman primates who underwent early developmental stress, variables indicating a low serotonin turnover rate were associated with behavior patterns similar to those predisposing to early-onset alcoholism among humans.