RESUMO
Acrylamide (AA) is an important industrial chemical that is neurotoxic in rodents and humans and carcinogenic in rodents. The observation of cancer in endocrine-responsive tissues in Fischer 344 rats has prompted hypotheses of hormonal dysregulation, as opposed to DNA damage, as the mechanism for tumor induction by AA. The current investigation examines possible evidence for disruption of the hypothalamic-pituitary-thyroid axis from 14 days of repeated exposure of male Fischer 344 rats to doses of AA that range from one that is carcinogenic after lifetime exposure (2.5 mg/kg/d), an intermediate dose (10 mg/kg/d), and a high dose (50 mg/kg/d) that is neurotoxic for this exposure time. The endpoints selected include: serum levels of thyroid and pituitary hormones; target tissue expression of genes involved in hormone synthesis, release, and receptors; neurotransmitters in the CNS that affect hormone homeostasis; and histopathological evaluation of target tissues. These studies showed virtually no evidence for systematic alteration of the hypothalamic-pituitary-thyroid axis and do not support hormone dysregulation as a plausible mechanism for AA-induced thyroid cancer in the Fischer 344 rat. Specifically, there were no significant changes in: 1) mRNA levels in hypothalamus or pituitary for TRH, TSH, thyroid hormone receptor alpha and beta, as well 10 other hormones or releasing factors; 2) mRNA levels in thyroid for thyroglobulin, thyroid peroxidase, sodium iodide symporter, or type I deiodinases; 3) serum TSH or T3 levels (T4 was decreased at high dose only); 4) dopaminergic tone in the hypothalamus and pituitary or importantly 5) increased cell proliferation (Mki67 mRNA and Ki-67 protein levels were not increased) in thyroid or pituitary. These negative findings are consistent with a genotoxic mechanism of AA carcinogenicity based on metabolism to glycidamide and DNA adduct formation. Clarification of this mechanistic dichotomy may be useful in human cancer risk assessments for AA.
Assuntos
Acrilamidas/toxicidade , Química Encefálica/efeitos dos fármacos , Hormônios/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Animais , Monoaminas Biogênicas/metabolismo , Contagem de Células , Ciclo Celular/efeitos dos fármacos , DNA Complementar/biossíntese , DNA Complementar/genética , Expressão Gênica/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , RNA/biossíntese , RNA/isolamento & purificação , Ratos , Ratos Endogâmicos F344 , Receptores de Neurotransmissores/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Glândula Tireoide/metabolismo , Glândula Tireoide/patologiaRESUMO
Compulsive drug abuse has been conceptualized as a behavioral state where behavioral stimuli override normal decision making. Clinical studies of methamphetamine users have detailed decision making changes and imaging studies have found altered metabolism and activation in the parietal cortex. To examine the molecular effects of amphetamine (AMPH) on the parietal cortex, gene expression responses to amphetamine challenge (7.5 mg/kg) were examined in the parietal cortex of rats pretreated for nine days with either saline, non-neurotoxic amphetamine, or neurotoxic AMPH dosing regimens. The neurotoxic AMPH exposure [three doses of 7.5 mg/kg/day AMPH (6 h between doses), for nine days] produced histological signs of neurotoxicity in the parietal cortex while a non-neurotoxic dosing regimen (2.0 mg/kg/day x 3) did not. Neurotoxic AMPH pretreatment resulted in significantly diminished AMPH challenge-induced mRNA increases of activity-regulated cytoskeletal protein (ARC), nerve growth-factor inducible protein A (NGFI-A), and nerve growth-factor inducible protein B (NGFI-B) in the parietal cortex while neither saline pretreatment nor non-neurotoxic AMPH pretreatment did. This effect was specific to these genes as tissue plasminogen activator (t-PA), neuropeptide Y (NPY) and c-jun expression in response to AMPH challenge was unaltered or enhanced by amphetamine pretreatments. In the striatum, there were no differences between saline, neurotoxic AMPH, and non-neurotoxic AMPH pretreatments on ARC, NGFI-A or NGFI-B expression elicited by the AMPH challenge. These data indicate that the responsiveness of synaptic plasticity-related genes is sensitive to disruption specifically in the parietal cortex by threshold neurotoxic AMPH exposures.
Assuntos
Anfetamina/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Lobo Parietal/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Animais , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , DNA Complementar/biossíntese , DNA Complementar/genética , Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Lobo Parietal/efeitos dos fármacos , Perfusão , RNA/biossíntese , RNA/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Probabilistic risk assessment is gaining acceptance as the most appropriate way to characterize and communicate uncertainties in estimates of human health risk and/or reference levels of exposure such as benchmark doses. Although probabilistic techniques are well established in the exposure-assessment component of the National Research Council's risk-assessment paradigm, they are less well developed in the dose-response-assessment component. This paper proposes the use of hierarchical statistical models as tools for implementing probabilistic dose-response assessments, in that such models provide a natural connection between the pharmacokinetic (PK) and pharmacodynamic (PD) components of dose-response models. The results show that incorporating internal dose information into dose-response assessments via the coupling of PK and PD models in a hierarchical structure can reduce the uncertainty in the dose-response assessment of risk. However, information on the mean of the internal dose distribution is sufficient; having information on the variance of internal dose does not affect the uncertainty in the resulting estimates of excess risks or benchmark doses. In addition, the complexity of a PK model of internal dose does not affect how the variability in risk is measured via the ultimate endpoint.
Assuntos
Modelos Estatísticos , Relação Dose-Resposta a Droga , Humanos , Probabilidade , Medição de RiscoRESUMO
Genotypic selection methods detect rare sequence changes in populations of DNA molecules. These methods have been used to investigate the chemical induction of mutation and for the detection and diagnosis of cancer. The possible use of genotypic selection for improving current risk assessment practices is based on the premise that the frequency of somatic mutation is of critical importance in understanding and modeling carcinogenesis. If genotypic selection can measure the induction of specific mutations that disrupt normal cell/tissue homeostasis, then it could provide key mechanistic information for cancer risk assessment. For example, genotypic selection data might support a particular low-dose extrapolation method or characterize the relationship between rodent and human cancer risk. Strategies for evaluating the use of genotypic selection in cancer risk assessment include the concept of developing a battery of targets that detect a range of agent-specific effects. Ideal targets to examine by genotypic selection are the oncogene and tumor suppressor gene mutations frequently detected in human tumors because these are thought to represent tumor-initiating events. The most commonly occurring basepair (bp) substitutions within the ras and p53 genes are identified. Also, the battery of genotypic selection methods is defined in terms of the most important mutational specificities to include. In theory, the major basepair substitution mutations induced by 29 of 31 chemical carcinogens could be detected by analyzing three different mutations: G:C-->T:A, G:C-->A:T, and A:T-->T:A. Genotypic selection will have the greatest impact on risk assessment if measurement of spontaneous mutation is possible. Data from phenotypic selection assays suggest this corresponds to detection of mutant fractions of approximately 10(-7), and this would necessitate examining DNA samples containing >10(7) target molecules. Despite its apparent potential, considerable development and validation is needed before genotypic selection data can be applied to cancer risk assessment.
Assuntos
Carcinógenos/toxicidade , Transformação Celular Neoplásica/genética , Análise Mutacional de DNA/métodos , Testes de Mutagenicidade/métodos , Mutação , Animais , Relação Dose-Resposta a Droga , Genes Supressores de Tumor/efeitos dos fármacos , Genótipo , Humanos , Oncogenes/efeitos dos fármacos , Oncogenes/genética , Especificidade de Órgãos , Projetos de Pesquisa , Medição de Risco , Sensibilidade e EspecificidadeRESUMO
The erythrocyte concentrations of the body's chief physiologic methyl donor S-adenosylmethionine (SAM) and of its metabolite and inhibitor S-adenosylhomocysteine (SAH), the plasma concentrations of total homocysteine (tHcy), and the activity of N(5,10) methylenetetrahydrofolate reductase (MTHFR) in lymphocytes were determined in healthy subjects and patients with diabetes mellitus without complications and at various stages of diabetic nephropathy, categorized according to the degree of progression of the disease. These groups were as follows: 1, control; 2, diabetics with no complications; 3, patients with albuminuria; 4, patients with an elevated plasma creatinine; and 5, patients on dialysis. No parameter studied exhibited significant differences between the type 1 and the type 2 diabetics. In control subjects, the blood concentrations of SAM were proportional to the activity of MTHFR; in diabetics, it was not. Consistent with previous observations, progression of nephropathy was accompanied by increased concentrations of tHcy. Increased erythrocyte concentrations of SAH, decreased erythrocyte concentrations of SAM, SAM/SAH ratios, and lymphocyte MTHFR activity also accompanied disease progression. The blood concentrations of SAH paralleled those of tHcy, while the concentrations of SAM showed a bimodal relationship with those of tHcy. These results provide further evidence that alterations in the blood concentrations of SAM and related compounds are abnormal in patients with diabetes, particularly in those with nephropathy. The deficiency of SAM may lead to methyl deficiencies, which may contribute to the high morbidity and mortality in patients with diabetic nephropathy. We have also demonstrated a decrease in lymphocyte MTHFR activity in patients with advanced nephropathy, suggesting that hyperhomocysteinemia in these patients may be due to a generalized metabolic abnormality. Further studies are needed to determine the pathogenesis of these abnormalities and whether they are present in renal failure due to causes other than diabetes or whether they are specific to diabetic nephropathy.
Assuntos
Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/metabolismo , Linfócitos/enzimologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , S-Adenosilmetionina/sangue , Adulto , Albuminúria , Creatinina/sangue , Complicações do Diabetes , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/terapia , Progressão da Doença , Eritrócitos/metabolismo , Feminino , Homocisteína/sangue , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Pessoa de Meia-Idade , Valores de Referência , Análise de Regressão , Diálise Renal , S-Adenosil-Homocisteína/sangueRESUMO
An increasing number of both clinical and experimental studies have shown an association between deficiencies of the dietary sources of physiological methyl groups and cancer formation. The critical metabolic intermediate in a determination of methylation status is S-adenosylmethionine (SAM), the body's chief physiological methyl donor. The present study examined the erythrocyte levels of SAM and of its demethylated metabolite S-adenosylhomocysteine (SAH) in 66 normal subjects (33 men and 33 women), whose blood had been drawn at days 0, 7 and 14 of an experimental period during which they were fed a fixed diet. The plasma levels of homocysteine (HCys) were also determined in the same individuals at the same time points. In addition, the subjects had completed a food frequency questionnaire (FFQ) describing their usual dietary habits before being placed on the dietary regimen. The blood levels of SAM, SAH, and HCys were compared with the dietary intakes of folate, vitamin B(6), fats, and calories, both prior to using the FFQ and during the experimental period. The results indicated that the intraindividual differences were very low, but the interindividual differences were large for the values of SAM, SAH, SAM:SAH ratios, and HCys. Interestingly, the blood levels of SAM and HCys were higher in men than in women and generally showed the expected correlations with folate intake i.e., positive for SAM and negative for HCys. The intakes of folate (276 microg/days) and B(6) (1.87 mg/days) during the 2-week experimental period were relatively low compared with the usual intakes of these vitamins (375 and 2.06 mg/day for folate and B(6), respectively) but correlated well with each other during both periods of the study. Surprisingly, both men and women showed a significant rise in erythrocyte SAM:SAH ratios as a function of age. In addition, the combined results from men and women, even adjusted for gender, showed significant correlations between HCys and both weight and body mass index. On the other hand, during the experimental period of the study, blood SAM levels were inversely correlated with the intakes of both fat and calories when the data for both men and women were combined and adjusted for gender. The blood determinations of SAM and related compounds showed a high degree of reproducibility over time and thus appear to provide a practical marker of methylation status for the assessment of cancer risk from dietary, environmental, and genetic factors.
Assuntos
Dieta , Homocisteína/sangue , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/sangue , Índice de Massa Corporal , Gorduras na Dieta , Eritrócitos , Feminino , Ácido Fólico , Humanos , Masculino , Neoplasias/etiologia , Neoplasias/genética , Piridoxina , Valores de Referência , Fatores de RiscoRESUMO
Target genes in most transgenic systems have higher spontaneous mutation frequencies than do endogenous mammalian genes. Spontaneous mutations in transgenes predominantly arise from three sources: (1) mutations fixed in the animals, (2) mutations arising from replication errors caused by damage to the DNA that may have occurred in vivo or in vitro and then was fixed during amplification of the vector in vitro, and (3) mutations arising during replication of non-revertant phages in non-permissive bacteria. An assay based on single bursts was developed to directly distinguish between the in vivo and in vitro origins of revertants. The size of the aliquot is determined by mutant frequency and is adjusted so that ideally no more than 10 to 20% of the aliquots contain a bacterial cell transformed with a mutant phage. Mutations are detected as revertants of an amber mutation (am3) in phiX174 am3, cs70. The minimum burst size of non-revertant phiX am3, cs70 from splenic DNA on a permissive bacterial strain was larger than 30 plaque-forming units (pfu). Based on this observation, a burst size of 31 plaque-forming revertants was chosen as the minimum burst size of a fixed mutation. The single burst assay was tested on DNA from spleens of animals that were treated with 150 mg/kg 1-ethyl-1 nitrosurea. Only the fraction of aliquots with single bursts of revertants (> 30) increased in the treated animals compared to the controls. In contrast, there was no difference between treated and control animals for revertant frequencies calculated for burst sizes < or =30 pfu. Among the spontaneous mutations, only 30% were caused by mutations fixed in animals (i.e. burst size >30 pfu). Total average revertant frequency measured in DNA from treated animals was less than twofold more than the average spontaneous frequency (P = 0.048). When frequencies were based on burst sizes >30, there was a 4.6-fold increase among treated animals compared with controls (P = 0.026). The single burst-assay resulted in a more sensitive test for mutagenicity because it eliminated noise from in-vitro mutations.
Assuntos
Bacteriófago phi X 174/genética , Análise Mutacional de DNA/métodos , Animais , Adutos de DNA , Etilnitrosoureia , Vetores Genéticos , Camundongos , Camundongos Transgênicos , Mutagênicos , Mutação , Baço/metabolismo , Transformação Genética , TransgenesRESUMO
In mutation assays using transgenic mice, with recoverable vectors such as PhiX174 am3, cs70, mutations originate from two sources: (1) in vivo mutations, that is, mutations that were fixed in the mouse, or (2) ex vivo mutations, that is, mutations that were fixed during recovery or plating. When a bacteriophage infects a bacterium, it multiplies and bursts the cell, releasing a number of phages referred to as the burst size. Our method for distinguishing between in vivo mutations and ex vivo mutations estimates the average number of bursts, the denominator of in vivo mutant frequencies, by dividing the total plaque-forming units (PFU) by the average number of phages in a burst. Herein, we outline a probability model relating observed plaque counts to the burst size and present the statistical method used to estimate the burst size. The average size of a single burst from nonrevertant phages was estimated in eight studies under the conditions of our mutation assay. The average burst size was stable across studies at 182.5 plaques per burst (standard error, 14.25). The probability that a burst is a specific size was approximated by a negative binomial distribution, which implies a Poisson-Pascal distribution for the observed plaque counts. The observed plaque counts were adequately fit by this approximation. Environ. Mol. Mutagen. 37:356-360, 2001 Published 2001 Wiley-Liss, Inc.
Assuntos
Bacteriófago phi X 174/genética , Análise Mutacional de DNA , Camundongos Transgênicos , Animais , Camundongos , Modelos Genéticos , Modelos Estatísticos , Mutação , Distribuição de PoissonRESUMO
Data from the National Toxicology Program's carcinogenesis study of fumonisin B1 in B6C3F1 mice, conducted at the National Center for Toxicological Research, were used to fit the Moolgavkar-Venzon-Knudson (MVK) two-stage, clonal-expansion model of carcinogenesis. In addition to tumour data from the conventional 2-year bioassay, the study included data on tissue weights, cell proliferation, cell death, and sphingolipid metabolism in primary target organs. The model was used to predict 2-year liver tumour rates in female and male mice based on differences among dose groups in the effect of fumonisin B1 on the growth of normal tissue and on the proliferation of preneoplastic cells as a compensatory response to sphinganine-induced cell death. Fumonisin B1 was assumed to be non-genotoxic, i.e. the model did not include any effect of fumonisin B1 on either of the two mutation rates of the MVK model. The model was able to reproduce reasonably well the observed tumour rates in both female and male mice, predicting substantially increased rates above background only at the highest doses of fumonisin B1 in females.
Assuntos
Ácidos Carboxílicos/toxicidade , Carcinógenos Ambientais/toxicidade , Contaminação de Alimentos , Fumonisinas , Neoplasias Hepáticas Experimentais/induzido quimicamente , Modelos Biológicos , Esfingosina/análogos & derivados , Animais , Peso Corporal , Morte Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Transformação Celular Neoplásica , Relação Dose-Resposta a Droga , Feminino , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Micotoxinas/toxicidade , Tamanho do Órgão/efeitos dos fármacos , Medição de Risco/métodos , Fatores Sexuais , Esfingosina/metabolismoRESUMO
NCTR measured sphinganine concentrations in the livers of mice and in the livers and kidneys of rats in conjunction with a tumour bioassay. In our model of the tumour incidence, target-tissue levels of sphinganine serve as a biomarker for a dose response of fumonisin B1 on cell death. Initially we questioned the utility of sphinganine levels in this role because they were highly variable when compared across time points. In spite of this concern, a conceptual framework and data are presented that support the use of sphinganine as a biomarker for a dose response of fumonisin B1 on cell death. This framework is reasonably consistent with observed sphinganine concentrations in the examined tissues, the literature on fumonisin's effects on sphingolipid synthesis, and our hypothesized mechanism through which fumonisin B1 increases age-specific tumour incidence.
Assuntos
Apoptose/efeitos dos fármacos , Ácidos Carboxílicos/farmacologia , Carcinógenos Ambientais/farmacologia , Inibidores Enzimáticos/metabolismo , Fumonisinas , Fígado/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Animais , Apoptose/fisiologia , Biomarcadores/análise , Ácidos Carboxílicos/sangue , Carcinógenos Ambientais/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Contaminação de Alimentos , Meia-Vida , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/citologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Micotoxinas/sangue , Micotoxinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Endogâmicos F344RESUMO
PURPOSE: To investigate the associations between inflammation tests and radiation dose in A-bomb survivors. SUBJECTS AND METHODS: Subjects were A-bomb survivors who underwent inflammation tests of leukocyte counts, neutrophil counts, erythrocyte sedimentation rate, corrected erythrocyte sedimentation rate, alpha-1 globulin, alpha-2 globulin and sialic acid between 1988 and 1992. Associations with radiation dose (DS86) were analyzed by regression analysis and heterogeneity among inflammatory diseases, anaemia at examination, or history of cancer was also tested. RESULTS: The associations with radiation dose were statistically significant for leukocyte counts (71.0mm(-3) Gy(-1), p=0.015), erythrocyte sedimentation rate (1.58 mm h(-1) Gy(-1) , p = 0.0001), corrected erythrocyte sedimentation rate (1.14mm h(-1) Gy(-1), p=0.0001), alpha-1 globulin (0.0057 g dl(-1) Gy(-1), p=0.0001), alpha-2 globulin (0.0128 g dl(-1) Gy(-1), p=0.0001), and sialic acid (1.2711 mg dl(-1) Gy(-1), p=0.0001) but not for neutrophil counts (29.9 mm(-3) Gy(-1), p=0.17). Heterogeneity was not statistically significant. Among inflammatory diseases, associations were the strongest for chronic thyroiditis and chronic liver diseases. CONCLUSIONS: This study suggests statistically significant association between inflammation in A-bomb survivors and radiation dose of during 1988-1992. The association might contribute, as an epigenetic and/or bystander effect, to development of several radiation-induced disorders.
Assuntos
Inflamação/etiologia , Guerra Nuclear , Idoso , Sedimentação Sanguínea , Relação Dose-Resposta à Radiação , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Análise de RegressãoRESUMO
A thermostable phenol sulfotransferase, SULT1A1, has been implicated in numerous detoxification and bioactivation pathways; however, little is known regarding its endogenous function or its putative role in mediating risk for human environmental disease. A simple endpoint colorimetric assay is described that can be used for rapid phenotyping of SULT1A1 activity in human populations. The assay utilizes a microtiter-plate format and relatively small amounts of platelet cytosol-derived enzyme. The enzyme catalyzes the synthesis of 2-naphthylsulfate from 2-naphthol and 5'-phosphoadenosine 3'-phosphosulfate (PAPS), whereas addition of p-nitrophenyl sulfate to the assay contributes to an effective PAPS-regenerating system. In contrast to other sulfotransferase assay methods, 3'-phosphoadenosine 5'-phosphate (PAP) does not accumulate during the incubation to interfere with enzyme activity, but instead serves as a cofactor to cause the removal of sulfate from p-nitrophenyl sulfate to regenerate PAPS. This reaction concomitantly results in generation of p-nitrophenol that can be quantified colorimetrically at 405 nm (epsilon = 18,200 M(-1)) to give an indirect measure of sulfotransferase activity. Using platelet enzyme preparations from adult human subjects, sulfation rates of two prototypical thermostable phenol sulfotransferase substrates (2-naphthol and p-nitrophenol) and one thermolabile phenol sulfotransferase substrate (dopamine) were determined using standard radiochemical protocols. These data were then compared with results from the colorimetric assay using 2-naphthol as substrate. There was a good correlation between the phenotyping assay and radiochemical assays for both 2-naphthol sulfotransferase and p-nitrophenol sulfotransferase activity (r = 0.85 and 0.69, respectively). However, SULT1A1 activity was approximately 10 to 20 times higher with the colorimetric determination. As anticipated, there was no correlation between SULT1A1 activity and dopamine sulfotransferase activity (r = 0.07) in these human platelet preparations. This inexpensive and rapid method for phenotyping SULT1A1 activity may help investigators assess a role for this enzyme in disease susceptibility.
Assuntos
Plaquetas/enzimologia , Colorimetria/métodos , Sulfotransferases/metabolismo , Adulto , Idoso , Citosol/enzimologia , Humanos , Pessoa de Meia-Idade , Naftóis/metabolismo , Fenótipo , Especificidade por Substrato , Sulfotransferases/genéticaRESUMO
The Poisson distribution is a fundamental probability model for count data, and is a natural model for the observed plaque counts in mutation assays using animals with lambda or PhiX174 transgenes. The Poisson likelihood for observed counts is a function of the mutant fraction, and it is straightforward to derive the associated maximum likelihood estimate of the mutant fraction and its variance. The estimate is easy to calculate, and if not the same, very similar to ad hoc estimates in current use. The model indicates the proper way to combine data from a number of plates, possibly prepared with different sample dilutions. The estimator of the mutant fraction is biased as a consequence of dividing by a random variable, the plaque count used to calculate the total recovered plaque-forming units. Fortunately, the bias becomes negligible as this count becomes large. On the other hand, increasing this count can increase the variance by decreasing the amount of sample assayed for mutant phages. Concurrent heed to the bias and the variance provides some guidance as to the optimum allocation of a sample into portions assayed for mutant phages and total recovered phages. The distribution of the estimate of the mutant fraction is related to the binomial distribution. This relationship implies a binomial distribution for the mutant count conditional on an overall count (either the sum of mutant and counted total plaques or the sum of counted mutant and non-mutant plaques). A special but important case occurs when each plate can be evaluated for mutant plaques and non-mutant plaques. Then, the observed proportion of mutants estimates the mutant fraction. More generally, the relationship to a binomial distribution provides a procedure for calculating a confidence interval.
Assuntos
Camundongos Transgênicos/genética , Testes de Mutagenicidade/estatística & dados numéricos , Mutação , Animais , Bacteriófagos/genética , Distribuição Binomial , Intervalos de Confiança , Funções Verossimilhança , Camundongos , Modelos Biológicos , Distribuição de Poisson , ProbabilidadeRESUMO
Many studies have suggested a relationship between certain alleles of the human leukocyte antigen (HLA) and the prevalence of some diseases or the immunological responsiveness to certain antigens. Furthermore, our studies in the past have demonstrated decreased immune function among atomic-bomb survivors who were exposed to high doses of radiation. However, no studies have addressed the possibility of various degrees of radiation-induced immune suppression being dependent on HLA type. To investigate the possibility of differing frequency distributions of HLA type in the Hiroshima atomic bomb survivors, HLA-DQA1 alleles and HLA-DR antigens were typed for 291 survivors in a high-dose group (>1.5 Gy), 339 survivors in an intermediate-dose group (0.005-1.5 Gy), and 388 in a distally exposed control group (<0.005 Gy). These doses are whole-body exposures, mainly from gamma-rays but with a small neutron component. When examinees were grouped by distinct pairs of HLA-DQA1 allele or HLA-DR antigen, no sex- or dose-related differences were found. However, when subjects were grouped by the presence of a specific allele or antigen, males carrying DQA1*0103 in at least one of their two HLA-DQA1 loci exhibited frequency distributions that decreased as radiation dose increased. These results suggest, although weakly, a possible population bias among male survivors with respect to HLA polymorphism. However, this bias is unlikely to be great enough to have a substantial effect on the cancer risk estimates.
Assuntos
Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Guerra Nuclear , Polimorfismo Genético , Sobrevida/fisiologia , Adolescente , Adulto , Fatores Etários , Alelos , Viés , Criança , Pré-Escolar , Relação Dose-Resposta à Radiação , Feminino , Raios gama , Cadeias alfa de HLA-DQ , Humanos , Lactente , Japão , Masculino , Pessoa de Meia-Idade , NêutronsRESUMO
Cancer mortality for the period from October 1950 through May 1992 was analyzed in atomic bomb survivors exposed in utero. Risk estimates for this group were also compared to those for survivors who were less than 6 years old at the time of exposure. The cohorts studied include 807 in utero survivors and 5,545 persons exposed during childhood with all members of both groups having estimated doses of at least 0.01 Sv. The comparison group includes 10,453 persons with little (<0.01 Sv) or no exposure. Analyses were limited mainly to cancer deaths occurring between the ages of 17 and 46. Only 10 cancer deaths were observed among persons exposed in utero. However, there is a significant dose response with an estimate of excess relative risk per sievert (ERR/Sv) of 2.1 (90% confidence interval of 0.2 to 6.0). This estimate does not differ significantly from that for survivors exposed during the first 5 years of life. The cancer deaths among those exposed in utero involved leukemia (2), female-specific organs (3) and digestive organs (5). Nine deaths occurred in females, where the excess risk for all solid cancers has a 90% confidence interval on the ERR/Sv of 1.6 to 17. Significant risks were found for cancers of the digestive system [90% confidence interval (CI) on the ERR/Sv of 0.7 to 20] and for female-specific cancers (90% CI on the ERR/Sv of 0.7 to 42). These risks do not differ significantly from those seen in females exposed as children. There were no deaths from solid cancer in men exposed in utero. The ERR/Sv has an upper 95% confidence bound of 2.5 which does not differ from that for exposed children, where the upper 95% confidence bound is 1.5. The sexes differ even when female-specific cancers are excluded from the comparison. Although there were only two leukemia deaths among those exposed in utero, the leukemia death rate for this group is higher than that in the comparison group (P = 0.054) with an exposure effect that is about half the magnitude and not significantly different from that seen after childhood exposure (P = 0.103). However, there is no evidence of a dose response among those exposed in utero because no high-dose leukemia deaths were observed, a result that differs considerably from that for those exposed as children. There is a need for caution in the interpretation of these data. First, the number of cancer deaths is small; second, there is unexplained significant difference in the mortality from solid cancer between the sexes; and third, the excess of leukemia in those exposed in utero is not reflected in an increasing dose response.
Assuntos
Neoplasias Induzidas por Radiação/mortalidade , Guerra Nuclear , Adulto , Criança , Feminino , Feto/efeitos da radiação , Seguimentos , Raios gama , Humanos , Japão , Masculino , Nêutrons , Gravidez/efeitos da radiaçãoRESUMO
Most estimates of the number of women with breast implants appear to be extrapolations of industry or clinical data. While both provide valuable information, the former about the total number of devices ever produced or sold and the latter about the cumulative number of surgeries performed, neither can be used to directly estimate the prevalence of women with silicone gel or saline implants. In 1989, Market Facts, Inc., conducted a mail survey of 40,000 households chosen as representative of the population of the United States and received responses from 70.7%. Overall, the prevalence was 8.08 per 1,000 women with about 60% of the devices reportedly implanted for cosmetic reasons. The procedure was more common among Whites of the higher socio-economic classes. Based upon the results of this survey, the total number of US women in 1989 with breast implants was estimated to be 815,700 (95% confidence interval: 715,757-924,729).
Assuntos
Implantes de Mama/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Intervalos de Confiança , Etnicidade , Feminino , Humanos , Pessoa de Meia-Idade , Prevalência , Estados Unidos/epidemiologiaRESUMO
In a review of the chest radiographs of 1152 consecutively examined subjects, 10 cases (0.87%) of extensive tracheobronchial calcification were identified. In addition, 51 subjects having this coded diagnosis were identified among 11,758 members of a fixed population sample. Sixty of these 61 subjects were women. Tracheobronchial calcification usually appeared after the age of 60. The subjects' clinical and other radiologic diagnoses were reviewed and tracheobronchial calcification appeared to have no clinical significance. Histologic findings in autopsied cases showed the calcifications and ossifications to be in the cartilaginous rings themselves. However, the reason for the overwhelming prevalence of this entity in women remains to be resolved.
Assuntos
Broncopatias/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Doenças da Traqueia/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Brônquios/patologia , Broncopatias/patologia , Calcinose/patologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Traqueia/patologia , Doenças da Traqueia/patologiaRESUMO
The responsiveness of peripheral blood lymphocytes to allogenic antigens in mixed lymphocyte culture (MLC) was measured in 139 atomic-bomb survivors. The study revealed a significant decrease in MLC response with increasing dose of previous radiation exposure. This decline was marked in the survivors who were older than 15 at the time of the bomb (ATB). The results suggest a possible relationship between the recovery of T-cell-related function and the thymic function which processes mature T cells for the immune system. Thus it may be that in the advanced age ATB group, the thymus function had started to involute, allowing less recovery of T-cell function compared to young survivors who had adequate processing T-cell activity.
Assuntos
Envelhecimento/imunologia , Imunidade Celular/efeitos da radiação , Guerra Nuclear , Idoso , Relação Dose-Resposta à Radiação , Humanos , Japão , Teste de Cultura Mista de Linfócitos , Pessoa de Meia-IdadeRESUMO
Male C57BL/6N mice were administered a single ip injection of 30 mg of N-methyl-N-nitrosourea (MNU)/kg of body weight. Additional groups were treated similarly every 3 hours for the next 24 hours. Adenocarcinomas of the small intestine were the major treatment-related tumors, with the total incidence being 38% at 250 days after injection. There was a significant circadian variation for tumor induction; the maximum number of intestinal tumors (approximately equal to 55%) tended to occur when the MNU was administered during the middle of the light period (6:00 to 18:00), while the tumor incidence was at a minimum (approximately equal to 10%) when the MNU was given in the middle of the dark phase (18:00 to 6:00). These data are discussed in relation to DNA synthesis and repair and MNU-induced cellular toxicity.
Assuntos
Ritmo Circadiano , Neoplasias Intestinais/induzido quimicamente , Metilnitrosoureia/toxicidade , Adenocarcinoma/induzido quimicamente , Animais , DNA/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Intestino Delgado , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Previous studies have suggested that reserpine treatment may result in altered heart development. In order to more fully investigate this possibility, reserpine was administered s.c. at 0, 0.375, or 0.75 mg/kg/day to pregnant rats on gestation days 12-15. Maternal weight gain, as well as pup weight on postnatal day (PND) 1, was significantly reduced in a dose-dependent manner. Litter size was unaffected, but reserpine-treated dams had more dead pups than did control dams. On PND 1, litters were randomly standardized at ten pups each for analysis on PNDs 5, 8, 15, and 22. Pup body weight and heart weight were reduced in a dose-related manner at all ages measured. The decreased heart weights were probably due to decreases in cell number. Beta-adrenergic receptor concentration was significantly reduced only on PND 5, at the low reserpine dose, and was not considered to be a treatment effect. Prenatal reserpine exposure had no effect on levels of basal cardiac ornithine decarboxylase (ODC), an enzyme associated with growth and development. Cardiac ODC stimulation by insulin and isoproterenol also showed no effects of maternal reserpine treatment. The results suggest that maternal reserpine treatment may lead to adverse effects in the developing offspring.