Phineas gauged: decision-making and the human prefrontal cortex.

Poor social judgment and decision-making abilities have often been attributed to people who have suffered injury to the ventromedial prefrontal cortex (VMPFC). However, few laboratory tests of decision-making have been conducted on these patients. The exception to this is the Iowa Gambling Task which has often, but not always, demonstrated differential performance between patients and controls.

4-hydroperoxycyclophosphamide--purged peripheral blood stem cells for autologous transplantation in patients with acute myeloid leukemia.

We have performed a phase I dose escalation of 4-Hydroperoxycyclophosphamide (4HC) purging of autologous peripheral blood progenitor cells (PBPCs) to improve the outcome of autologous transplantation for patients with myeloid leukemia. Peripheral blood stem cells were mobilized after cytosine arabinoside of 2 g/m(2) every 12 hours x 8 doses with etoposide of 40 mg/kg total dose infused over 4 days, followed by growth factor support. The preparative regimen included Busulfan of 1 mg/kg orally every 6 hours x 16 doses, followed by etoposide of 60 mg/kg x 1 day (the patient with chronic myeloid leukemia received cyclophosphamide of 60 mg/kg/d x 2 days in lieu of etoposide).

Camptothecin analogs in malignant gliomas: comparative analysis and characterization.

Object: The authors compared and characterized several new classes of camptothecin (CPT) analogs (a total of 22 drugs) directed against human and murine glioma cell lines in vitro, trying to identify CPT analogs that can be used for local therapy in future clinical trials. Camptothecin is a naturally occurring alkaloid that inhibits the DNA-replicating enzyme topoisomerase I. Moreover, CPT and its analogs have shown promising antitumor activity against both systemic and intracranial neoplasms.

Use of ab initio calculations to predict the biological potency of carboxylesterase inhibitors.

Carboxylesterases are important enzymes responsible for the hydrolysis and metabolism of numerous pharmaceuticals and xenobiotics. These enzymes are potently inhibited by trifluoromethyl ketone containing (TFK) inhibitors. We demonstrated that the ketone hydration state was affected by the surrounding chemical moieties and was related to inhibitor potency, with inhibitors that favored the gem-diol conformation exhibiting greater potency.

Metabolic oxidation of carcinogenic arylamines by p450 monooxygenases: theoretical support for the one-electron transfer mechanism.

N-oxidation by cytochrome p450 enzymes is an initial step in the metabolic activation of aromatic amine compounds. Once metabolized, these compounds are converted to DNA-reactive species which can exhibit potent mutagenic and/or carcinogenic activity. The precise mechanism of p450 enzyme oxidation is not completely understood, although various theories, involving either one-electron transfer, two-electron transfer or addition-rearrangement, have been debated.

Molecular modeling-based analysis of interactions in the RFC-dependent clamp-loading process.

Replication and related processes in eukaryotic cells require replication factor C (RFC) to load a molecular clamp for DNA polymerase in an ATP-driven process, involving multiple molecular interactions. The detailed understanding of this mechanism is hindered by the lack of data regarding structure, mutual arrangement, and dynamics of the players involved. In this study, we analyzed interactions that take place during loading onto DNA of either the PCNA clamp or the Rad9-Rad1-Hus1 checkpoint complex, using computationally derived molecular models.

The dynamics, structure, and conformational free energy of proline-containing antifreeze glycoprotein.

Recent NMR studies of the solution structure of the 14-amino acid antifreeze glycoprotein AFGP-8 have concluded that the molecule lacks long-range order. The implication that an apparently unstructured molecule can still have a very precise function as a freezing inhibitor seems startling at first consideration. To gain insight into the nature of conformations and motions in AFGP-8, we have undertaken molecular dynamics simulations augmented with free energy calculations using a continuum solvation model.

Experimental and simulation studies of heat flow and heterocyclic amine mutagen/carcinogen formation in pan-fried meat patties.

Heterocylic amine (HA) compounds formed in the cooking of certain foods have been shown to be bacterial mutagens and animal carcinogens, and may be a risk factor for human cancer. To help explain the variation observed in HA formation under different cooking conditions, we have performed heat-flow simulations and experiments on the pan-frying of beef patties. The simulations involve modeling the heat flow within a meat patty using empirically derived thermal transport coefficients for the meat.

Modified guanines representing O(6)-alkylation by the cyclophosphamide metabolites acrolein and chloroacetaldehyde: synthesis, stability, and ab initio studies.

Alkylation of DNA by acrolein and/or chloroacetaldehyde may result in the mutations that lead to the therapy-induced leukemia associated with cyclophosphamide (and ifosfamide) treatment. O(6)-(n-Propanalyl)guanine (O(6)-PAG) and O(6)-(ethanalyl)guanine (O(6)-EAG) were synthesized for use as authentic standards in investigations of DNA alkylation by acrolein and chloroacetaldehyde, respectively. Preparation of the O-methyl oximes of these aldehydes aided in confirming the structural assignments of O(6)-PAG and O(6)-EAG.

The effects of frontal lobe lesions on goal achievement in the water jug task.

Patients with prefrontal cortex lesions are impaired on a variety of planning and problem-solving tasks. We examined the problem-solving performance of 27 patients with focal frontal lobe damage on the Water Jug task. The Water Jug task has never been used to assess problem-solving ability in neurologically impaired patients nor in functional neuroimaging studies, despite sharing structural similarities with other tasks sensitive to prefrontal cortex function, including the Tower of Hanoi, Tower of London, and Wisconsin Card Sorting Task (WCST).

Extended quantitative structure-activity relationships for 80 aromatic and heterocyclic amines: structural, electronic, and hydropathic factors affecting mutagenic potency.

The mutagenic/carcinogenic heterocyclic amines formed during the cooking of protein foods have been determined to be probable or possible human carcinogens. As part of a comprehensive study of the food mutagens, our laboratory has produced a series of quantitative structure-activity relationships (QSARs) of aromatic and heterocyclic amines, to attempt to elucidate the mechanisms of mutagenesis/carcinogenesis. Amines are genotoxically active only after activation by a series of reactions converting the parent compound to an electrophilic derivative, which is postulated to be a nitrenium ion that covalently binds to and damages DNA.

Isophosphoramide Mustard and Its Mechanism of Bisalkylation.

To investigate the mechanism(s) of bisalkylation by isophosphoramide mustard (IPM), IPM-beta,beta,beta',beta'-d(4) was synthesized and the products of its reaction with thiosulfate (at pD 7.0) were analyzed by NMR. By both (1)H and (13)C NMR, the distribution of deuterium in the products was consistent with bisalkylation through sequential aziridinyl intermediates [(NCH(2)CD(2)S):(NCD(2)CH(2)S) = 53:47].

Immunoreactivity of organic mimeotopes of the E2 component of pyruvate dehydrogenase: connecting xenobiotics with primary biliary cirrhosis.

In primary biliary cirrhosis (PBC), the major autoepitope recognized by both T and B cells is the inner lipoyl domain of the E2 component of pyruvate dehydrogenase. To address the hypothesis that PBC is induced by xenobiotic exposure, we took advantage of ab initio quantum chemistry and synthesized the inner lipoyl domain of E2 component of pyruvate dehydrogenase, replacing the lipoic acid moiety with synthetic structures designed to mimic a xenobiotically modified lipoyl hapten, and we quantitated the reactivity of these structures with sera from PBC patients. Interestingly, antimitochondrial Abs from all seropositive patients with PBC, but no controls, reacted against 3 of the 18 organic modified autoepitopes significantly better than to the native domain.

Impact of HIV-1 infection in South Africa.

In a prospective study, 60% of admissions to an academic hospital were infected with HIV. HIV infected children were younger, less likely to have been referred, more likely to have pneumonia and candidiasis, and had more health service attendances. This impact may be alleviated by appropriate primary and secondary level health care.

Prevalence of HIV and HIV-related diseases in the adult medical wards of a tertiary hospital in Durban, South Africa.

Our objective was to determine the prevalence of HIV and the distribution of HIV-related diseases among adult, medical inpatients. Consecutive admissions were recruited and a single ELISA assay was used to determine HIV infection. Demographic and clinical details were extracted from clinical records.

Generation of dual resistance to 4-hydroperoxycyclophosphamide and methotrexate by retroviral transfer of the human aldehyde dehydrogenase class 1 gene and a mutated dihydrofolate reductase gene.

The genetic transfer of drug resistance to hematopoietic cells is an attractive approach to overcoming myelosuppression caused by high-dose chemotherapy. Because cyclophosphamide (CTX) and methotrexate (MTX) are commonly used non-cross-resistant drugs, generation of dual drug resistance in hematopoietic cells that allows dose intensification may increase anti-tumor effects and circumvent the emergence of drug-resistant tumors. We constructed a retroviral vector containing both a human cytosolic ALDH-1 cDNA and a human doubly mutated DHFR cDNA (Phe22/Ser31; termed F/S in the description of constructs) to generate increased resistance to both CTX and MTX.

Radiolabeled guanine derivatives for the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase: 6-(4-[(18)F]Fluoro-benzyloxy)-9H-purin-2-ylamine and 6-(3-[(131)I]Iodo-benzyloxy)-9H-purin-2-ylamine.

Two radiolabeled analogues of 6-benzyloxy-9H-purin-2-ylamine (O(6)-benzylguanine; BG) potentially useful in the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase (AGT) were synthesized. Fluorine-18 labeling of the known 6-(4-fluoro-benzyloxy)-9H-purin-2-ylamine (FBG; 6) was accomplished by the condensation of 4-[(18)F]fluorobenzyl alcohol with 2-aminopurin-6-yltrimethylammonium chloride (4) or 2-amino-6-chloropurine in average decay-corrected radiochemical yields of 40 and 25%, respectively. Unlabeled 6-(3-iodo-benzyloxy)-9H-purin-2-ylamine (IBG; 7) was prepared from 4 and 3-iodobenzyl alcohol.

Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity.

The mutagenic/carcinogenic heterocyclic amines formed during the cooking of protein foods have been determined to be a potential risk to human health. Therefore, mitigation measures are beginning to be studied. A recent finding is that the induction of mutation in Salmonella by these amines can be inhibited by the addition of flavonoids to the assay.

Sexually transmitted infections and HIV in a rural community in the Lesotho highlands.

Objectives: To conduct a knowledge, attitude, and practice (KAP) study and to determine the prevalence of sexually transmitted diseases (STDs), including HIV, in a community residing in remote, rural Lesotho.

Methods: In 1995 a cross sectional, community based epidemiological study was conducted on a population of 7500 people living in 89 villages. A total of 29 villages were randomly selected and a systematic sample of houses within villages was obtained.

Exceptionally pyramidalized olefins: A theoretical study of the cyclopropenyl fused tricycles Tricyclo.

RHF, MP2, and TCSCF ab initio theory and B3LYP, B3PW91, and SVWN density functional theory were used to study the series of cyclopropenyl-fused tricycles 9-12. In each of 9-12, the cyclopropenyl double bond is exceptionally pyramidalized (butterfly angle psi approximately 41-50 degrees ) with both endo and exo bent isomers. In the norbornyl systems (9 and 10), the endo bent isomers are more stable than the exo bent isomers, whereas in the bicyclo[2.

Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study.

Object: The gene therapy paradigm of intratumoral activation of ganciclovir (GCV) following transduction of tumor cells by retroviral vectors bearing the thymidine kinase (tk) gene has produced dramatic remissions of malignant gliomas in animal models. In human trials, although the technique has been deemed safe, little antitumor effect has been demonstrated. To evaluate the basis of this inefficacy in human gliomas, the authors conducted a gene-marking trial involving neuropathological and biochemical studies of treated tumor specimens.

Neuropsychological function in solvent-exposed South African paint makers.

Neuropsychological and neurological function were investigated in 228 organic solvent exposed paint manufacturing workers in two factories. Solvent exposure was expressed as both American Conference of Governmental Industrial Hygienists 1990 Threshold Limit Value equivalents and total hydrocarbon parts per million. The World Health Organization (WHO) neurobehavioral core test battery, the Neurobehavioural Evaluation System--2 (NES-2), and the UNISA Neuropsychological Assessment Procedure (UNAP) were used to measure outcomes, and a Vibratron II was used to measure peripheral vibration sensation.

Heterocyclic amine formation and the impact of structure on their mutagenicity.

The occurrence and formation of heterocyclic amines in foods is discussed in light of the consistent finding of a new class of imidazopyridines. In addition, a quantitative structure-activity relationship will be presented correlating the potency of these imidazopyridines to predicted chemical properties. Although no strong linear correlation is found between the potency and the chemical properties, a low dipole moment is found to be a qualitative predictor of high mutagenic potency.