RESUMO
AIM: The outcome of surgery for colorectal cancer in each unit in the UK is collated by the National Bowel Cancer Audit Project (NBOCAP). In 2008-2009 our unit had a raw 30-day postoperative mortality close to the national average, but when it was nationally adjusted it appeared to be an outlier. The purpose of this study was to identify reasons for this disparity. METHOD: All records were obtained for patients undergoing surgery for colorectal cancer over the 2 years. Data submitted to NBOCAP to determine adjusted rates were compared with actual data. RESULTS: There were major discordances between submitted and actual data for American Society of Anesthesiology grades and timing of surgery. This explained why the unit appeared to be an outlier. CONCLUSION: There is increasing emphasis on outcome of health service delivery, which has important implications. Submission of correct data is essential if objective comparison is to be made on which to base decisions on service delivery among units and within health regions.
Assuntos
Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Mortalidade Hospitalar , Avaliação de Processos e Resultados em Cuidados de Saúde , Humanos , Reino Unido/epidemiologiaRESUMO
OBJECTIVES: Aboriginal people are under-represented in epidemiological research, largely due to past failures to engage and recruit Aboriginal communities, research fatigue and the use of culturally inappropriate methods. A qualitative study was undertaken in rural and urban Aboriginal communities in north-eastern and south-western Ontario to identify culturally congruent public health research methodologies. STUDY DESIGN: A qualitative participatory research study using focus group discussions. METHODS: This study employed a participatory research framework to elicit methodological suggestions for conducting public health research with Aboriginal communities during focus groups with healthcare providers from six diverse Aboriginal health organizations in Ontario, Canada. RESULTS: Continuing requests for participation in health research studies have led to community exhaustion. Discussions explored appropriate methods to obtain community approval and support for a study, the need for cultural sensitivity training for researchers, the value of conducting studies of interest and benefit to the community, advantages and disadvantages of qualitative and quantitative studies, the benefit of both Aboriginal and non-Aboriginal ethics reviews, the importance of safeguarding trusted information, types of incentives that may enhance study participation, suggestions to improve the collection of questionnaire information and biological specimens, how to resolve contentious issues and dissemination of study results. CONCLUSION: In order to successfully engage Aboriginal people in health studies, researchers need to build rapport with communities, have a community presence, be respectful and collaborative, utilize incentives, and employ flexible and adaptive methodologies of reasonable length. Oral interviews are preferred to self-completed information. The use of more mixed methods methodologies was suggested when quantitative data collection is necessary. Communities expect presentations about research findings.
Assuntos
Pesquisa Participativa Baseada na Comunidade , Indígenas Norte-Americanos , Saúde Pública/tendências , Competência Cultural , Grupos Focais , Humanos , Ontário , População Rural , População UrbanaRESUMO
The 490 quinone, a natural sulfhydryl-arylating reagent from the mushroom, Agaricus bisporus, markedly inhibited L1210 murine leukemia DNA polymerase alpha while resulting in little inhibition of DNA polymerase beta from this source. This quinone was more strongly inhibitory than p-chloromercuri-benzoate or N-ethylmaleimide and was less readily neutralized by sulfhydryl-containing molecules such as dithioerythritol. Preliminary experiments indicate that DNA protects DNA polymerase alpha from inhibition by the 490 quinone. The inhibition of DNA synthesis by quinone 490 may contribute significantly to the cytotoxicity of this compound and to the potential of gamma-L-glutaminyl-4-hydroxybenzene as an antitumor agent.
Assuntos
DNA Polimerase II/antagonistas & inibidores , DNA Polimerase I/antagonistas & inibidores , Leucemia L1210/tratamento farmacológico , Inibidores da Síntese de Ácido Nucleico , Reagentes de Sulfidrila/farmacologia , Animais , Antineoplásicos , Sítios de Ligação , Cloromercurobenzoatos/farmacologia , DNA Polimerase I/metabolismo , DNA Polimerase II/metabolismo , DNA de Neoplasias/biossíntese , Ditiotreitol/farmacologia , Avaliação Pré-Clínica de Medicamentos , Etilmaleimida/farmacologia , Leucemia L1210/enzimologia , Leucemia L1210/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Reagentes de Sulfidrila/metabolismo , Reagentes de Sulfidrila/uso terapêuticoRESUMO
A stable phenol, gamma-L-glutaminyl-4-hydroxybenzene (GHB), is oxidized by tyrosinase in the gill tissues of the mushroom Agaricus bisporus to a quinone and a second oxidation product which together suppress mitochondrial energy production and the synthesis of proteins and nucleic acids in the zygote, thus establishing dormancy in the spores. Brief incubation of cultured murine L1210 leukemia and B-16 melanoma cells with muM concentrations of the purified quinone notably prolonged survival times or blocked tumor growth in histocompatible mice inoculated i.p. with high concentrations of the exposed cells. The instability of the quinone precluded in vivo administration. The short incubation of cultured B-16 melanoma cells with mM concentrations of GHB markedly prolonged survival times or abolished tumor growth in histocompatible C57BL/6J mice inoculated i.p. with 5 X 10(6) exposed cells. This response did not occur with L1210 leukemia cells, which lack the enzyme tyrosinase. The survival times of mice bearing B-16 melanoma, but not of those with L1210 leukemia, were slightly prolonged by a single injection and were significantly extended by daily i.p. injections of GHB. Normal C57BL/6J mice, given GHB i.p. as single or multiple 400-mg/kg doses, manifested no systemic toxicity but showed depigmentation of the hair after 2 to 3 weeks. These studies provide evidence that GHB exerts cytotoxicity specifically for cells that by their content of tyrosinase convert the phenol to the quinone. This targeted response minimizes systemic toxocity and underscores the potential therapeutic application of this agent to melanocarcinoma.
Assuntos
Agaricales/fisiologia , Antimetabólitos Antineoplásicos , Glutamina/análogos & derivados , Melanoma/tratamento farmacológico , Fenóis/farmacologia , Animais , Células Cultivadas , Metabolismo Energético/efeitos dos fármacos , Glutamina/farmacologia , Leucemia L1210/tratamento farmacológico , Leucemia L1210/metabolismo , Masculino , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Monofenol Mono-Oxigenase/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Quinonas/farmacologia , Esporos Fúngicos/fisiologiaRESUMO
The quinone intermediates resulting from tyrosinase-mediated oxidation of tyrosine were evaluated as sulfhydryl reagent inhibitors of purified calf thymus DNA polymerase alpha in order to determine which of these might be cytotoxic. Dopachrome and an oxidation product of 2,4,5-trihydroxyphenylalanine were relatively ineffective as inhibitors of DNA polymerase alpha. On the other hand, a dopaquinone analogue, 4-(2-N-acetylaminoethyl)-1,2-benzoquinone, synthesized from N-acetyl dopamine, was demonstrated to have marked affinity for this sulfhydryl enzyme. This property was shared by 1,2-benzoquinone. These studies point to dopaquinone as a significant toxic metabolite in melanin biosynthesis.
Assuntos
Melaninas/biossíntese , Quinonas/farmacologia , Animais , Bovinos , Di-Hidroxifenilalanina/análogos & derivados , Di-Hidroxifenilalanina/metabolismo , Técnicas In Vitro , Monofenol Mono-Oxigenase/metabolismo , Inibidores da Síntese de Ácido Nucleico , Fenilalanina/metabolismo , Quinonas/metabolismo , Reagentes de Sulfidrila , Tirosina/metabolismoRESUMO
gamma-L-Glutaminyl-4-hydroxybenzene is converted by the tyrosinase of the common mushroom, Agaricus bisporus, to the toxic, dormancy-inducing metabolite 2-hydroxy-4-imino-2,5-cyclohexadiene-1-one. Hydroxylation of gamma-L-glutaminyl-4-hydroxybenzene by mammalian tyrosinase was monitored by determining tritium water release from gamma-L-glutaminyl-[3,5-(3)H[4-hydroxybenzene and occurred at only 25% of the rate found with tyrosine. The dihydroxy product of the hydroxylation reaction, gamma-L-glutaminyl-3,4-dihydroxybenzene, was not oxidized by the mammalian enzyme. Therefore, oxidation of gamma-L-glutaminyl-4-hydroxybenzene to sulfhydryl-reactive quinones by mammalian tyrosinase is an unlikely explanation for the hair depigmentation and inhibition of melanocarcinoma growth observed following administration of this compound. Cleavage of gamma-L-glutaminyl-4-hydroxybenzene by gamma-glutamyl transpeptidase releasing p-aminophenol was demonstrated. p-Aminophenol was an active depigmenting and melanocytotoxic compound. N2-Methyl-gamma-L-glutaminyl-4-hydroxybenzene was synthesized, differing from gamma-L-glutaminyl-4-hydroxybenzene only by the presence of a methylated amide linkage. This chemical modification resulted in a compound resistant to cleavage by gamma-glutamyl transpeptidase and lacking in melanocytotoxic activity. gamma-Glutamyl transpeptidase cleavage is proposed as the route for transformation of gamma-L-glutaminyl-4-hydroxybenzene into an active inhibitor of melanocytes.
Assuntos
Glutamina/análogos & derivados , Melanócitos/enzimologia , Aminofenóis/metabolismo , Animais , Bovinos , Ativação Enzimática , Glutamina/metabolismo , Hidroxilação , Levodopa/metabolismo , Melanoma/enzimologia , Camundongos , Monofenol Mono-Oxigenase/metabolismo , Trítio , gama-Glutamiltransferase/metabolismoRESUMO
The neurotoxicity of the gamma-diketone 3,4-dimethyl-2,5-hexanedione(DMHD) was studied to determine the distribution of the neuropathologic changes and the temporal sequence during the intoxication period and following five and 15 weeks of recovery. Intoxication with 3,4-dimethyl-2,5-hexanedione at a daily dose of 0.25 mmoles/kg led to a profound clinical neuropathy, resulting in paralysis of all four limbs after 12-15 days. The cumulative toxic dose for this gamma-diketone was 3-4 mmoles/kg, indicating that dimethyl substitution increased the neurotoxicity of gamma-diketones by a factor of 20-30. The neuropathy was characterized histologically by giant axonal swellings in the proximal axon of the lower motor neuron in a distribution similar to IDPN (beta,beta'-iminodipropionitrile)-neuropathy, with swellings in the anterior horn, intraspinal anterior root, and the proximal anterior root. These swellings developed from six to 12 days of intoxication and were still evident after 15 weeks of recovery. The fact that dimethyl substitution of 2,5-hexanedione accelerated the neuropathy and was characterized by proximal axonal swellings has two important implications: 1) that formation of pyrrole derivatives may be an important step in the pathogenesis of gamma-diketone neuropathies, and 2) that the neurofilament neuropathies may represent a continuum of toxic neuropathies in which the rate of action of the neurotoxin ultimately determines the proximo-distal location of the axonal swellings.
Assuntos
Axônios/ultraestrutura , Hexanonas/efeitos adversos , Cetonas/efeitos adversos , Doenças do Sistema Nervoso Periférico/patologia , Animais , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ratos , Ratos EndogâmicosRESUMO
Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mammals causes damage to the nigrostriatal dopaminergic pathway similar to that observed in Parkinson disease (PD). Reactive oxygen species (ROS) are thought to be involved in the pathogenesis of MPTP-mediated dopaminergic neurodegeneration. To further clarify the role of superoxide anion radical (*O2-) and to study the possible involvement of hydroperoxides in MPTP-mediated neurodegeneration, MPTP neurotoxicity was induced in mice deficient in either CuZn superoxide dismutase (SOD), a scavenger enzyme for *O2-, or cellular glutathione peroxidase (GSHPx-1), a scavenger enzyme for hydroperoxides. Littermate control and homozygous deficient mice were injected intraperitoneally with a total cumulative dose of 0, 75, or 150 mg/kg of MPTP delivered over 5 d. All mice were killed 5 d after the last injection and the brains were processed for immunohistological analysis for tyrosine hydroxylase (TH) in the striatum and the substantia nigra pars compacta (SNc), as well as for direct measurements of dopamine concentrations in the striatum. The intensity of TH immunoreactivity in the striatum was evaluated by measuring the relative optical density (OD) with NIH IMAGE, and expressed as Log (OD of striatum)/Log (OD of white matter). Degeneration of TH-containing neurons was assessed by counting TH-positive neurons in the SNc. We found that this MPTP exposure protocol produced dose-dependent depletion of TH immunoreactivity and dopamine in the striatum in littermate control mice and both strains of knockout mice; however. reduction in TH immunoreactivity and dopamine content were significantly greater in CuZn-SOD or GSHPx-1 deficient mice compared with littermate controls. MPTP exposure did not significantly alter the number of TH-positive neurons in the SNc in littermate control or knockout mice. These data suggest that some of the deleterious effects of MPTP on striatal dopaminergic nerve terminals are mediated by both *O2- and hydroperoxides, and that they occur prior to dopaminergic neurodegeneration in the SNc. The similarity between the MPTP model and PD raises the possibility that both types of ROS may play a significant role in the early pathogenesis of dopaminergic neurodegeneration in PD.
Assuntos
Glutationa Peroxidase/genética , Intoxicação por MPTP/enzimologia , Intoxicação por MPTP/patologia , Superóxido Dismutase/genética , Animais , Morte Celular , Corpo Estriado/enzimologia , Corpo Estriado/patologia , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/enzimologia , Neurônios/patologia , Estresse Oxidativo/fisiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/enzimologia , Doença de Parkinson Secundária/patologia , Substância Negra/enzimologia , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/análiseRESUMO
Exposure to the gamma-diketone, 2,5-hexanedione (HD), results in the accumulation of neurofilaments within the distal axon and is associated with acceleration of neurofilament transport within the proximal axon. The epsilon-amino groups of lysyl residues react with HD forming pyrrole adducts, followed by pyrrole-mediated protein crosslinking. Both reaction steps have been proposed as mechanisms causing neurofilament accumulation and acceleration of transport. In order to assess the importance of these steps on neurofilament transport, we compared transport in the optic system of rats exposed to HD and 3-acetyl-2,5-hexanedione (AcHD), a non-toxic analog of HD which forms pyrroles but does not crosslink proteins. Control, HD-treated, and AcHD-treated rats received intraoptic injections of [35S]-methionine and were exposed to saline, HD, or AcHD by intraperitoneal injections before and during the period of neurofilament transport. Neurofilament triplet proteins in the optic nerve and tract were identified by polyacrylamide gel electrophoresis followed by fluorography. The rate of neurofilament transport was accelerated in HD-treated animals over that of controls. However, despite higher levels of protein-bound pyrroles in AcHD-treated animals, the rate of transport was indistinguishable from that of controls. These findings indicate that pyrrole formation alone is not sufficient to cause acceleration of neurofilament transport.
Assuntos
Hexanonas/farmacologia , Proteínas de Neurofilamentos/metabolismo , Pirróis/metabolismo , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Transporte Biológico/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Hexanonas/sangue , Hexanonas/metabolismo , Masculino , Ratos , Ratos EndogâmicosRESUMO
Administration of 3,3'-iminodipropionitrile (IDPN) to rats results in massive accumulation of tangled neurofilaments in the proximal axons of large neurons, such as in dorsal root ganglia (DRG) and ventral horns of the lumbar spinal cord (LSC). Clinically, rats develop hyperexcitability, circling, head bobbing, and retropulsion. The ultimate toxicant and the molecular mechanism are not known. In a study designed to explore potential activation and detoxification pathways, dose-related differences in location and severity of lesions were observed in rats treated with IDPN or deuterium substituted analogs, 2,2,2',2'-tetradeuterio-IDPN (2-d-IDPN) or 3,3,3',3'-tetradeuterio-IDPN (3-d-IDPN). The compounds or saline were administered intraperitoneally to three rats per group at dose levels of 3.0, 1.5, 1.0, and 0.0 mmole/kg/day for 3 days. One week after the initial dose, tissues from DRG and LSC were collected, prepared and evaluated histologically in zones extending from areas adjacent to the cell bodies, distally toward the DRG stalk or toward the lumbar spinal roots. In the low dose IDPN group, DRG and LSC lesions were most prominent in distal zones. As dosage increased, the lesions progressed in severity and in proximity to the cell bodies. At the high dose, lesions were prominent in all zones. The same general pattern occurred with both analogs, although 2-d-IDPN was less potent than IDPN and 3-d-IDPN was more potent than IDPN. The differences in potency from the secondary isotopic effect of deuterium suggest that the 3-position is important in detoxification while the 2-position is important in the bioactivation of IDPN.
Assuntos
Axônios/fisiologia , Gânglios Espinais/patologia , Atividade Motora/efeitos dos fármacos , Neurônios/patologia , Neurotoxinas/toxicidade , Nitrilas/toxicidade , Medula Espinal/patologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Axônios/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Deutério , Relação Dose-Resposta a Droga , Gânglios Espinais/efeitos dos fármacos , Filamentos Intermediários/efeitos dos fármacos , Filamentos Intermediários/ultraestrutura , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Brainstem Lewy bodies (LB) are neuronal inclusions that are closely related to Parkinson's disease (PD). The filamentous component of LB from patients with PD contains biochemically altered neurofilaments (NF). Herein we have tested the hypothesis that the oxidized products of catechols may covalently crosslink NF. Neurofilaments were incubated in the presence of oxidized L-dopa, dopamine, or dopac and then analyzed by SDS-PAGE and protein staining or immunoblotting with monoclonal antibodies specific for neurofilament subunit proteins. Oxidized catechols yielded the same pattern of NF protein crosslinking as known covalent crosslinking agents. Coincubation of NF and catechols with N alpha-acetyl-L-lysine (NAL) produced strong reactivity on immunoblots probed with a polyclonal antiserum specific for NAL crosslinked to protein (antiserum 1400/3). Crosslinking of NAL to model proteins by oxidized dopac was followed by antibody capture assays using antiserum 1400/3. Increasing immunoreactivity was observed for 0.01 to 1.0 mM dopac and was augmented by Cu2+, Fe2+, Fe3+, Mn2+, or Mn3+ up to 0.1 mM. These results show that the products of catechol oxidation can covalently crosslink neurofilaments, that the crosslinking mechanism can involve lysine, and that copper, iron, and manganese ions can accelerate catechol-mediated protein crosslinking.
Assuntos
Catecóis/farmacologia , Corpos de Lewy/metabolismo , Proteínas de Neurofilamentos/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Tronco Encefálico/metabolismo , Catecóis/metabolismo , Reagentes de Ligações Cruzadas/metabolismo , Dopamina/metabolismo , Levodopa/metabolismo , Lisina/análogos & derivados , Lisina/farmacologia , Oxirredução , SuínosRESUMO
Apolipoprotein E (APOE) genotype and advancing aging are interacting ri sk factors in the expression of late onset and sporadic Alzheimer's Disease (AD). We tested the hypothesis that 2 products of lipid peroxidation, malondialdehyde (MDA) and 4 hydroxy-2-nonenal (HNE), covalently modify APOE and alter its metabolism. In vitro, both HNE and MDA crosslinked purified APOE3 and APOE4. HNE was a more potent crosslinker than MDA, and purified APO3 was more susceptible to crosslinking by HNE than was purified APOE4. In P19 neuroglial cultures, oxidative stress with lipid peroxidation led to increased intracellular accumulation of anti-HNE and anti-APOE immunoreactive proteins of approximately 50 kDa. Intercellular accumulation of the 50 kDa APOE-immunoreactive protein (APOE-50) was not prevented by cyclohexamide, suggesting formation by post-translational mechanisms. In CSF, a 50 kDa APOE-immunoreactive protein co-migrated with proteins most immunoreactive for HNE and MDA adducts, containing NaB3H4-reducible bonds. These proteins were in CSF from adult subjects (with or without dementia), and in AD patients homozygous for APOE3 or APOE4 alleles. These data suggest that HNE covalently crosslinks APOE in P19 neuroglial cultures to form a 50 kDa protein, and that similar modifications of APOE appear to occur in vivo.
Assuntos
Doença de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , Peroxidação de Lipídeos , Adulto , Reagentes de Ligações Cruzadas , Humanos , Estrutura MolecularRESUMO
Increased catechol thioether formation is associated with Parkinson's disease. In this study, we examined whether catechol thioethers, having a lower oxidation potential than their parent catechols, would cause greater oxidative damage than their parent catechols. We synthesized 5'-S-glutathionyl, cysteinyl, and N-acetylcysteinyl derivatives of dopamine and dopac, encompassing the known catechol thioethers of the mercapturate pathway. Cyclic voltametry studies showed that catechol thioethers had higher reduction potentials than their parent catechols. A higher reduction potential did not correlate with an increase in oxidative damage, measured by metal-catalyzed DNA strand breakage. 5'-S-Glutathionyldopamine and the cysteinyl adducts of dopamine and dopac mediated less oxidative damage than their parent catechols. In contrast, both N-acetylcysteinyl analogs were equipotent to dopamine. Oxygen consumption corresponded to DNA damage except for 5'-S-glutathionyldopamine. The glutathionyl and cysteinyl adducts of dopamine inhibited dopamine-mediated DNA damage indicating that these adducts may have antioxidant properties. 5'-S-Glutathionyldopamine potentiated H2O2-mediated damage whereas 5-S-cysteinyldopamine was inhibitory. Our results show that the ability of catechol thioethers to cause oxidative damage in vitro is not based simply upon the reduction potential but rather, reflects a complex relationship among structures of the parent catechol and thiol adduct, metal catalyst, and oxidant.
Assuntos
Antioxidantes/metabolismo , Catecóis/metabolismo , Oxidantes/metabolismo , Doença de Parkinson/metabolismo , Sulfetos/metabolismo , Dano ao DNA , DNA Bacteriano/genética , Escherichia coli/genética , Consumo de Oxigênio/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
A 66-year-old man with acute monoblastic leukemia developed acute polyneuropathy with quadriplegia, autonomic instability, and respiratory failure while he was in hematologic remission following both systemic and intrathecal chemotherapy. Autopsy revealed dense infiltration of somatic and autonomic peripheral nerves, sparing the meninges. There was a small peripheral infiltrate in one of four dorsal root ganglia, but, otherwise, sensory and autonomic ganglia were normal. The blood-nerve barrier may allow some malignant cells to escape cytotoxic agents. The epineurium and ganglia lack a blood-tissue barrier, and malignant cells could have been eradicated at those sites.
Assuntos
Leucemia Monocítica Aguda/patologia , Neoplasias do Sistema Nervoso Periférico/patologia , Potenciais de Ação , Idoso , Humanos , Leucemia Monocítica Aguda/fisiopatologia , Masculino , Condução Nervosa , Neoplasias do Sistema Nervoso Periférico/fisiopatologia , Tempo de ReaçãoRESUMO
The existence of an X-linked sensorimotor peripheral neuropathy has been debated. We reevaluated the original family, and present data on 13 affected males and 25 obligate or probable heterozygous females, documenting the devastating nature of the disease in the men and the extremely variable degree of clinical involvement in the carriers. Use of DNA probes indicates that the gene lies in the DXYS1-p58-1 region of the X-chromosome.
Assuntos
Ligação Genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Atrofia Muscular/genética , Cromossomo X , Adolescente , Adulto , Criança , Feminino , Seguimentos , Marcadores Genéticos , Neuropatias Hereditárias Sensoriais e Autônomas/fisiopatologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Condução Nervosa , LinhagemRESUMO
Recognition of the deleterious neurological effects of chemicals has evolved from anecdotal observation to studies of illness in persons exposed to high doses. Now, the more subtle effects of exposures to environmental neurotoxicants are being documented: reduction in intelligence, impairment in reasoning ability, shortening of attention span, and alteration of behavior. Substances to which millions of persons are exposed occupationally and in the general environment that can result in such deficits include lead, organophosphorus pesticides, certain chlorinated hydrocarbons, carbon disulfide, solvents, and mercury. The first step in the prevention of neurological impairments due to environmental exposures is to assess the toxicity of chemicals. Fewer than 10% of the 70,000 chemicals in commercial use have been evaluated for neurotoxicity. This knowledge gap needs to be narrowed by building on existing systems of toxicity testing. Concurrent with assessment of chemicals will be tiers of in vivo screening tests to measure functional and structural changes following exposures in vitro. Epidemiologic surveillance of populations at high risk will continue to inform on the ranking of suspect or known neurotoxicants. Research and researchers must become more sophisticated in the development and application of refined biologic markers so the findings can be used to detect absorption of toxicants and early neurological or neurobehavioral dysfunction before disability occurs and to protect human health and the environment.
Assuntos
Exposição Ambiental/efeitos adversos , Doenças do Sistema Nervoso/induzido quimicamente , Biomarcadores , Humanos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/prevenção & controle , Projetos de Pesquisa , Medição de Risco , Testes de ToxicidadeRESUMO
Even though atherosclerotic cardiovascular disease (ACVD) is the number one cause of death in the United States, the effects of environmental toxicants on this process are less well studied than the effects of chemicals on the second leading cause of death, cancer. There is considerable epidemiological evidence that workers exposed to carbon disulfide (CS2) have increased rates of ACVD, and there is conflicting evidence of the atherogenic potential of CS2 from animal studies. Chemical modification, such as oxidation of low-density lipoproteins (LDL), is tightly associated with increased LDL uptake by macrophages and the development of arterial fatty streaks. CS2 has been previously demonstrated to modify several proteins in vitro including LDL, and others in vivo through derivatization and covalent cross-linking. To investigate both the capacity of CS2 to induce arterial fatty deposits by itself, and its ability to enhance the rate of fatty deposit formation induced by a western style, high fat diet, groups of 20 female C57BL/6 mice were exposed to 0, 50, 500, or 800 ppm CS2 by inhalation. Half the animals in each group were placed on an atherogenic high fat diet and half on a control diet (NIH-07). Animals were sacrificed after 1, 4, 8, 12, 16, or 20 weeks of exposure, and the rates of fatty deposit formation under the aortic valve leaflets were evaluated. Exposure of mice on the control diet to 500 and 800 ppm CS2 induced a small but significant increase in the rate of fatty deposit formation over non-exposed controls. A more striking result was observed in the animals on the high fat diet. There was marked enhancement of the rate of fatty deposit formation in mice exposed to 500 and 800 ppm over the animals on the high fat diet alone. In addition, there was a small but significant enhancement in mice exposed to 50 ppm over the rate of fatty deposit formation induced by the high fat diet alone. Analysis of erythrocyte spectrin for protein cross-linking revealed a dose-dependent formation of alpha- and beta-heterodimers in animals on both diets. These data demonstrate that CS2 is atherogenic at high concentrations, but more importantly, suggest that, in conjunction with other risk factors, CS2 at relatively low concentrations can enhance atherogenesis.
Assuntos
Arteriosclerose/induzido quimicamente , Dissulfeto de Carbono/toxicidade , Gorduras na Dieta/efeitos adversos , Metabolismo dos Lipídeos , Administração por Inalação , Animais , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/metabolismo , Arteriosclerose/metabolismo , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eritrócitos/química , Feminino , Células Espumosas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Espectrina/análise , Taxa de Sobrevida , Fatores de TempoRESUMO
In its second year of development, this program blends cognitive and affective approaches to integrating ethics and human values into medical education. The core of this effort is the establishment of direct and continuing relationships between the four advisory deans and their medical student advisees through small groups that continue throughout the four years of medical school. Clinical correlation seminars, lecture/discussions, the humanities, clinical clerkships, and electives are components of this integration process. Both basic science and clinical faculty members have observed positive changes in the degree and depth of participation, discussion, and interest, as well as in the general attitudes of the students.
Assuntos
Currículo , Educação Médica , Ética Médica , Valores Sociais , Pessoal Administrativo , Docentes de Medicina , Humanos , North Carolina , Faculdades de Medicina/organização & administraçãoRESUMO
B6C3F1 mice were exposed to n-hexane 6 h/day, 5 days/week for 13 weeks at concentrations of 0, 500, 1000, 4000, and 10,000 ppm and at 1000 ppm 22 h/day, 5 days/week for 13 weeks (1000C group). Toxicological endpoints assessed included clinical signs, body and organ weight changes, gross and histopathology, neuropathology, and a battery of neurobehavioral tests. All mice survived the treatment. Exposure-related effects of n-hexane included sneezing at 10,000 ppm and body weight gain depression at 1000C and 10,000 ppm. Histopathologic changes included mild inflammatory, erosive and regenerative lesions in the olfactory and respiratory epithelium of the nasal cavity at 1000C, 4000, and 10,000 ppm. The only neurobehavioral parameter affected was a decrease in locomotor activity in female mice at 1000C and 10,000 ppm. In teased fiber preparations of tibial nerve, paranodal axonal swellings were observed at 1000C or at 10,000 ppm, but not in the control groups. The severity of the peripheral nerve lesion was mild. These studies show that n-hexane has minimal toxicity to the nervous system and respiratory system of mice.
Assuntos
Hexanos/toxicidade , Administração por Inalação , Animais , Relação Dose-Resposta a Droga , Feminino , Hexanos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos , Valores de Referência , Fatores Sexuais , Conchas Nasais/efeitos dos fármacos , Conchas Nasais/patologiaRESUMO
Subchdronic administration of S,S,S-tributyl phosphorotrithioate (DEF) caused 3 toxicologic effects in hens, depending upon route of administration. Small delay oral doses (0.5--20 mg/kg) of DEF produced ataxia, which progressed to paralysis and death in some birds. Large daily oral doses (40 and 80 mg/kg) caused a 'late acute' effect 4 days after administration. The clinical signs of the late acute effect were identical to those produced by n-butyl mercaptan (nBM), a hydrolytic product of DEF, and were not relieved by atropine sulfate. The late acute effect of DEF overlapped with the clinical signs of delayed neurotoxicity. These hens died early, and while one hen showed histopathological lesions in peripheral nerves, another showed unequivocal lesions in the central nervous system. Topical application of daily doses of DEF consistently produced delayed neurotoxicity in the absence of late acute poisonining and was characterized by degeneration of the central and peripheral nerve tissues. Orally administered DEF was rapidly metabolized in the gastrointestinal tract to nBM, which apparently caused the late acute toxic effect. Topically administered DEF, which was not subjected to gastrointestinal tract hydrolysis, caused delayed neurotoxicity but did not produce a late acute effect.