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Biomedical subjects

D C Thomas

Publications and source records attributed to D C Thomas.

At least 127 records · Page 7Linked to original sources
PubMed1988

Effect of interferons and poly(I):poly(C) on the pathogenesis of the diabetogenic variant of encephalomyocarditis virus in different mouse strains.

Interferon (IFN) can either prevent or exacerbate the pathogenic effects of the diabetogenic variant of encephalomyocarditis (EMC-D) virus. The effect seen is dependent upon the mouse strain and the time of IFN administration. For example, IFN-alpha beta protects SWR/J but not ICR Swiss male mice against the diabetogenic effects of the virus. Administration of either IFN-alpha beta or the IFN-inducer poly(I):poly(C) 4 days post infection, results in an exacerbation of the infection in ICR Swiss and C57BL/6 male mice. Studies have been initiated to investigate the role of the IFN system in the pathogenesis of this virus infection. In this study IFNs or poly(I):poly(C) were administered to several mouse strains at 24 h before or 4 days after infection with EMC-D virus. The results of such treatment ranged from complete protection of the animals from the diabetogenic effects of the virus to exacerbation of the infection as reflected by the virus content in selected organs. The effect was dependent upon the mouse strain, the type of IFN, and the time of its administration in relation to virus infection.

Animals↗
PubMed1988

Methylmercury and the health of autochthons in northwest Quebec.

We conducted a cross-sectional epidemiologic and clinical study to evaluate the nature, magnitude, and frequency of unfavourable health states among residents of northwest Quebec. Of particular interest were the possible occurrence of Minamata disease and any other neurological abnormalities. We also sought to determine whether industrial or naturally-occurring mercury in the region's environment were causally associated with any disorders that might be detected. A total of 321 subjects were studied in four groups with contrasting exposure to point-source mercury from a chlor-alkali plant in the area. Methylmercury in hair served as the marker of subject's ingestion of any organic mercury (natural or industrial). Ten pre-chosen target variables, seven clinical and three neurophysiological, were assessed in all subjects. Relationships between mercury in hair and each target variable were calculated. We determined whether gradients in target variables corresponded to gradients in potential exposure of the subjects to the aquatic emissions of the chlor-alkali plant. Minamata disease was not found. Diabetes and alcohol-related health problems assessed as important clinically plausible confounders, were common. Differences in frequency or magnitude of clinical, toxicological, and physiological findings among the contrast groups were small and not of clinical or statistical significance. There were definite relationships between mercury in hair and four target variables despite the low values of mercury measured and the mild nature of the health problems observed. This would suggest that verifiable biological threshold levels for clinical effects, if such exist, may be substantially lower among Canadians than those currently adopted as policy for adults elsewhere. A gradient was found only for two of the ten target variables. Clinically meaningful alternate hypotheses for observed health effects emerge in the data and agree with observations in the field made by consulting clinical experts.

Animals↗
PubMed1987

Disease, lifestyle, and consanguinity in 58 American Gypsies.

Medical data on 58 Gypsies in the area of Boston, Massachusetts, were analysed together with a pedigree linking 39 of them in a large extended kindred. Hypertension was found in 73%, diabetes in 46%, hypertriglyceridaemia in 80%, hypercholesterolaemia in 67%, occlusive vascular disease in 39%, and chronic renal insufficiency in 20%. 86% smoked cigarettes and 84% were obese. Thirteen of twenty-one marriages were consanguineous, yielding an inbreeding coefficient of 0.017. The analysis suggests that both heredity and environment influence the striking pattern of vascular disease in American Gypsies.

Adolescent↗
PubMed1987

Fitting models of carcinogenesis to a case-control study of breast cancer.

Data from a case-control study of breast cancer in 441 cases and matched controls aged less than or equal to 38 in Los Angeles is fitted to two models of carcinogenesis: the two-stage model of Moolgavkar and Knudson; and a multistage adaptation of the log/log model proposed by Pike et al. In the two-stage model, risk factors (here age at menarche, age at first pregnancy, abortion, regularity of cycling, benign breast disease, and use of oral contraceptives (OCs] are postulated to act either by increasing the rate of mutation of normal to intermediate or of intermediate to malignant stage cells, or by increasing the proliferation rates of such cells. In the multistage model, it is postulated that all transition rates are equally determined by the rate of cell turnover, which is in turn influenced by risk factors. In both models, positive family history is modelled in two ways: (1) all cells may have started in an intermediate stage at birth, with probability depending on the number and degree of affected family members; or (2) as an event rate modifier in the same way as other covariates. With only menarche or menarche and family history included, the multistage and two-stage models both produced likelihoods very similar to those from a simple logistic model, though both fit better than the logistic model as more covariates were added to the model. The two stage models offer greater flexibility in modelling the time at which each factor is most effective. We found irregular menstrual cycling to reduce the rate of proliferation of normal cells or their mutation rate to intermediate cells by 50% (p less than 0.025) and use of OCs to increase these rates by 3.25 fold (p less than 0.01). Having completed a pregnancy of more than 26 weeks gestation appeared to reduce the rate of intermediate cell proliferation by 5% (p less than 0.05) relative to a baseline rate of 14% per year. Benign breast disease was associated with a 1.60 fold increased rate of the second mutation (p less than 0.025). In all models, family history was by far the strongest risk factor (RR = 4.44 from the logistic model, p less than 0.0001). Covariates showed similar effects in the multistage model, though their magnitudes were slightly different.

Adult↗
PubMed1987

Use of computer simulation to explore analytical issues in nested case-control studies of cancer involving extended exposures: methods and preliminary findings.

A Monte Carlo simulation program has been designed to generate case-control study data from hypothetical cohorts of individuals exposed to one or more carcinogens at intensities which vary over time. Exposure distributions are specified by such parameters as the probability of any exposure, the distributions of age at first and last exposure, the distribution of intensity as a function of time, and the correlations between exposures. Within subcohorts generated in this way, age-specific cancer rates are computed based on the multistage model of carcinogenesis (other models will be considered in the future). Age and possibly exposure-dependent censoring rates are also computed. Cancer cases are randomly generated from the resulting age and cause of death distribution and age-matched controls are drawn by sampling from the survival distribution. The "true" exposure histories, used to generate the cases and controls, are then corrupted by various random and systematic sources of error. The resulting case-control data are fitted to simple exposure indices as well as more sophisticated models of carcinogenesis. In preliminary simulations of a single carcinogen, it appeared that exposure indices derived from the multistate model could correctly estimate the stage at which the carcinogen acted when exposure is limited to a constant intensity over time, even when that intensity was measured with considerable error. These indices also fitted substantially better than simple duration, average intensity, or cumulative exposure. Further investigations will assess such issues as the additional information obtained by appropriately exploiting a time-dependent history, the effect of time-dependent exposure measurement errors, and the robustness of inferences when the assumed model is incorrect.

Computer Simulation↗
PubMed1986

Activities and incision patterns of ABC excinuclease on modified DNA containing single-base mismatches and extrahelical bases.

ABC excision nuclease of Escherichia coli is a DNA repair enzyme that recognizes major helical distortions caused by bulky base adducts and incises on both sides of the adduct, thus removing the modified nucleotides in the form of a 12-13-base long oligomer. We tested the enzyme with substrates that contained unusual helical structures caused by single-base mismatches or one, three, or four extrahelical bases (loops). We find that the enzyme does not cut DNAs containing helical perturbations caused by these structures. However, when the mismatched or extrahelical bases are modified with 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide, a reagent specific for unpaired G and T residues, the enzyme incises at the modified nucleotides in the regular manner. In addition, we find that when mismatches and loops are located near pyrimidine dimers and (6-4) photoproducts they do not inhibit incision at the photoproducts by the excinuclease but sometimes affect the incision pattern. Our results indicate that ABC excinuclease may be a useful enzymatic reagent to probe the structural changes caused by mismatches and deletions in DNA and provide additional information on the requirements for incision by this repair enzyme.

Base Composition↗
PubMed1986

Sequences of Escherichia coli uvrA gene and protein reveal two potential ATP binding sites.

We have determined the nucleotide sequence of the uvrA gene of Escherichia coli. The coding region of the gene is 2820 base pairs which specifies a protein of 940 amino acids and Mr = 103,874. The polypeptide sequence predicted from the DNA sequence was confirmed by analyzing the UvrA protein: the sequence of the first 7 NH2-terminal amino acids as well as the amino acid composition of the pure protein agreed with those predicted from the nucleotide sequence. By comparing the sequence of UvrA protein to the amino acid sequences of other ATPases, we found that two regions in the UvrA protein, separated from one another by about 600 amino acids, have the highly conserved G-X4-GKT(S)-X6-I(V) sequence found at the active sites of many, but not all, ATPases. Our findings suggest that UvrA protein may have two ATP binding sites.

Adenosine Triphosphatases↗
PubMed1986

Sequences of the E. coli uvrB gene and protein.

The UvrB protein is one of the three subunits of the E. coli ABC excinuclease. We have reported the sequences of the other two subunits, the UvrA and UvrC proteins. In this paper the sequence of the UvrB protein is presented. The protein sequence was determined from the DNA sequence of the uvrB gene and was confirmed by sequencing the NH2-terminus of the UvrB protein and analyzing its overall amino acid composition. The coding region of uvrB is 2019 basepairs, specifying a protein of 672 amino acids and Mr of 76,118. The sequence of the UvrB protein shows a moderate level of homology to that of the UvrC protein and to the ATP binding site of the UvrA protein. During purification of UvrB protein a proteolytic product, UvrB, is produced in high quantities. We find that UvrB results from removal of about 40 amino acids from the COOH-terminus of the UvrB protein. The uvrB gene has complex regulatory features. On the 5' side, the coding region is preceded by 3 promoters, a DnaA box and an SOS box. On the 3' side the gene is followed by an REP (Repetitive Extragenic Palindrome) sequence which has been implicated in gene regulation by an unknown mechanism.

Amino Acid Sequence↗
PubMed1986

The rare-disease assumption revisited. A critique of "estimators of relative risk for case-control studies".

The extension of case-control methods to the study of common outcomes has led to the development of several design and analysis techniques which do not employ the rare-disease assumption. Unfortunately, the principles underlying valid application of these techniques are more subtle than those first considered by Cornfield in the rare-disease setting, and appear to be easily misunderstood. We especially wish to caution that: The unrestricted inclusion of prevalent cases in the control group (as described by Hogue et al. for estimation of the risk ratio) will not make the odds ratio an unbiased estimate of the risk ratio (or anything else). In their response to our article, following, Hogue et al. describe restrictions on prevalence and duration necessary for the odds ratio from a case-exposure design to unbiasedly estimate the risk ratio in a stable population; these conditions were not mentioned in their original article, and in their new paper Hogue et al. do not provide mathematical proof that the conditions are sufficient to guarantee unbiasedness. Exclusion ("decontamination") of incident cases from the control group (as recommended by Hogue et al. for testing and test-based interval estimation) will result in improperly narrow risk-ratio confidence intervals whether or not the population is stable, and, in unstable populations, will generally lead to an invalid test. Methods that replace the rare-disease assumption with the stable-population assumption (such as case-exposure designs applied to open populations) will not yield unbiased results when the source population is a fixed cohort. (Of course, this will not be an issue for methods that are not based on either assumption, such as the case-base design applied to fixed cohorts, and the matched density design.) As each case-control design has certain practical implications for selection and interviewing, in choosing a design one should carefully consider practical issues (such as vulnerability to recall bias and ease of control selection) in addition to the statistical issues discussed here. In general, however, one should be wary of methods of studying incidence that involve the use of prevalent cases (such as the approach of Hogue et al.): prevalence is influenced by factors related to treatment, recovery, and fatality, and thus any etiologic study employing prevalent cases may be biased by such factors.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1986

Secular trends in histologic types of lung cancer.

The histology pattern of lung cancer in Los Angeles County was reviewed for a 10-year period, 1972-81. In men, the total lung cancer incidence has been fairly constant, but there has been a shift in the histology pattern with an increase in adenocarcinoma and a decrease in "other" cell type (i.e., carcinoma not otherwise specified, large-cell and undifferentiated tumors). This changing histology pattern may be partly due to changes in diagnostic standards and practices. With the assumption that these changes are comparable in men and women, the "true" annual rate of change was estimated for each lung cancer cell type in women. All lung cancer types have increased in women; of the cell types squamous cell carcinoma, small-cell carcinoma, and adenocarcinoma, small-cell carcinoma showed the largest rate of annual increase and adenocarcinoma, the smallest.

Adenocarcinoma↗
PubMed1985

Amplification and purification of UvrA, UvrB, and UvrC proteins of Escherichia coli.

The UvrA, UvrB, and UvrC proteins of Escherichia coli are subunits of a DNA repair enzyme, ABC exci nuclease. In order to amplify these proteins, we have joined the artificial canonical promoter tac (Amann E., Brosius, J., and Ptashne, M. (1983) Gene (Amst.) 25, 167-178) to the uvr genes to obtain plasmids that express these genes under the control of the lac repressor. When cells carrying the tac-uvr plasmids are induced by the gratuitous lac inducer isopropyl-beta-D-galactoside the Uvr proteins are overproduced reaching a level of 10-20% of total cellular proteins after 6-8 h of induction. We have developed methods to purify all three Uvr proteins, UvrA, UvrB, and UvrC, in milligram quantities and to near homogeneity from these overproducing cells. The purified UvrA protein is an ATPase but UvrB and UvrC proteins are not. However, UvrB protein stimulates the ATPase activity of UvrA protein by a factor of 1.5 in the presence of double-stranded DNA and by a factor of about 2.6 in the presence of UV-irradiated DNA but not in the absence of DNA.

Adenosine Triphosphatases↗
PubMed1985

Sample size determination in case-control studies: the influence of the distribution of exposure.

In the design of case-control studies, the determination of the required number of cases and controls is based on consideration of the strength of the relationship between the disease and exposure to the putative cause, the variability in exposure within the population under study, and the desired size and power of the statistical test. This paper derives sample size equations for studies with a continuous exposure which allow the investigator to specify the strength of the relationship between disease and exposure in terms of relative risk, etiologic fraction or the slope of an exposure response relationship. With these formulations it becomes apparent that the size of the sample increases with decreasing variability in exposure in the population under study, a finding not apparent in the use of conventional methods of sample size determination for continuous data. The ability of a case-control study to detect a significant association between disease and exposure therefore depends critically on the distribution of exposure which exists in the community to be studied. Implications of these findings for studies of diet and cancer are discussed.

Canada↗
PubMed1985

The efficiency of matching in case-control studies of risk-factor interactions.

We have examined the relative efficiency of matching vs not matching on a binary exposure variable in a case-control study of its interaction with another binary exposure variable. Interaction is treated as a parameter measuring departure from multiplicativity. Efficiency is considered both in the presence and absence of other matching variables, the former case requiring use of matched-pair estimators. In most circumstances examined, matching on one variable led to a less efficient estimator of the interaction parameter. If both variables were related to disease, the only circumstance in which matching always improved efficiency was when the high-risk level of the matching variable was uncommon and not positively associated with the high-risk level of the other variable. Matching always appeared to harm efficiency when the high risk level of the matching variable was common. Other disadvantages of matching are that it precludes estimation of the main effect of the matching variable and fitting of non-multiplicative models, and increases the difficulty of control selection.

Epidemiologic Methods↗