Biomedical subjects
Publications and source records attributed to M H Smith.
The epidemiology, pathogenesis, and clinical picture of primary tuberculosis are presented as they are seen today in the United States in children and adolescents. Diagnosis, treatment, and prevention of the disease are discussed in detail.
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Genetic variability at 36 loci was studied in white-tailed deer (Odocoileus virginianus) populations, on the Savannah River Plant (SRP) in South Carolina. Mean multilocus heterozygosity (H), percentage of polymorphic loci (P) and average number of alleles per locus (A) for white-tailed deer were calculated and compared with values for white-tailed deer from several locations (SRP deer: H = 9.9 per cent, P0.05 = 30.6 per cent, A = 1.89; white-tailed deer overall: H = 10.4 per cent, P0.05 = 32.3 per cent, A = 1.94). Frequency distributions for single locus heterozygosity values (h) and the number of alleles per locus for white-tailed deer were found to be significantly different from those of mammals in general. Analysis of single-locus data based on quaternary structure and functional groups of proteins failed to demonstrate expected differences as predicted from the literature. White-tailed deer have a high level of heterozygosity, but they do not exhibit many of the life history and environmental characteristics associated with high heterozygosity in other animals.
Genetic diversity in natural populations of the bacterium Pseudomonas cepacia was surveyed in 10 enzymes from 70 clones isolated along a landscape gradient. Estimates of genetic diversity, ranging from 0.54 to 0.70, were higher than any previously reported values of which we are aware and were positively correlated with habitat variability. Patterns of bacterial genetic diversity were correlated with habitat variability. Findings indicate that the source of strains used in genetic engineering will greatly affect the outcome of planned releases in variable environments. Selection of generalist strains may confer a large advantage to engineered populations, while selection of laboratory strains may result in quick elimination of the engineered strains.
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The emergence of influenza A viruses which had acquired resistance to rimantadine during a clinical trial (C. B. Hall, R. Dolin, C. L. Gala, D. M. Markovitz, Y. Q. Zhang, P. H. Madore, F. A. Disney, W. B. Talpey, J. L. Green, A. B. Francis, and M. E. Pichichero, Pediatrics 80:275-282, 1987) provided the opportunity to determine the genetic basis of this phenomenon. Analysis of reassortant viruses generated with a resistant clinical isolate (H3N2) and the susceptible influenza A/Singapore/57 (H2N2) virus indicated that RNA segment 7 coding for matrix and M2 proteins conferred the resistant phenotype. Resistant viruses isolated from seven patients each contained a single change in the nucleotide sequence coding for the M2 protein which resulted in substitutions in amino acid 30 (two viruses) or 31 (five viruses) in the transmembrane domain of the molecule. These changes occurred in locations identified in influenza viruses selected for resistance to amantadine in tissue culture and indicate a common mechanism of action of the two compounds in cell culture and during chemotherapeutic use.
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A three-parameter model for directly estimating imprecision profiles from replicated immunoassay results is compared with a six-parameter indirect profile model obtained by the usual method of combining error in the raw response measurements with the slope of the standard curve. Direct estimation is likely to be less reliable when based on the limited data collected from a single assay, and may underestimate variability at high concentrations when many results are clustered at the upper end of the concentration range. However, at concentrations near the assay detection limit (often a region of particular interest), direct estimation is superior to the indirect method if a logistic or related function is used as the standard curve model. Direct estimation of imprecision profiles has useful application whenever the internal details of an assay system are not readily available, for example, in analysis of data collected in external surveys.
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We investigated an unusually large and severe outbreak of hepatitis B, primarily involving parenteral drug abusers and their sexual contacts, in Worcester, Massachusetts, over a 21-month period from 1983 to 1985. Of 135 patients with drug-related acute hepatitis B, 81 percent were parenteral drug abusers and 19 percent had sexual contact with drug abusers; 13 fulminant cases resulted in 11 deaths. Among the patients with hepatitis B, evidence of delta virus infection was found in 54 percent of drug abusers, 33 percent of their sexual contacts, and 9 percent of other patients with acute hepatitis B (P less than 0.001). Most of the delta infections (86 percent) were coinfections with hepatitis B virus; the balance were superinfections. Delta infection was strongly associated with fulminant hepatitis: 91 percent of patients with a fulminant outcome had delta infection, as compared with 45 percent of less severely ill drug abusers and their contacts (P = 0.0037). Alcohol, other drugs, and other hepatitis viruses could not be implicated as hepatotoxic cofactors for fulminant disease. This outbreak appeared to result from the concurrent spread of hepatitis B and delta viruses among new drug users. Control measures included the distribution to physicians of guidelines on prophylaxis in contacts of patients with hepatitis B, health education for drug abusers, and a hepatitis B vaccination program. Despite these efforts, the outbreak continued unabated until the number of new cases began to decline slowly in late 1986.
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A computer program is described for estimating a simple one or two parameter variance function using approximate conditional likelihood. The inverse of the fitted function provides a smooth weighting function for use in subsequent manipulation of the data. The program is designed for immunoassays, where both the raw experimental observations, and the final results from data reduction, are well known to exhibit nonuniformity of variance, but it may also have application in other areas where the observations follow approximately normal distributions and a weighting function is required. Five variance function forms are optionally available as subroutines, and if necessary, one or more of these can be incorporated into existing software with trivial modification. The test of fit of the assumed function provides an objective criterion for detecting outliers, and the program includes automatic outlier exclusion as an option.
A computer was used to produce and store a large body of simulated thyroxine and thyrotropin radioimmunoassay results over wide concentration ranges. Sets of 24 results, designed to represent results returned to an external quality assessment survey, were randomly drawn from the stored results in order to compare limited data survey estimates of imprecision with the 'true' values obtained from the population data. Results show that estimation of an imprecision profile has advantages over the usual index of imprecision, but that neither form of estimate is particularly reliable when the available data is limited. Results suggest that survey organisers should place considerably less emphasis on results from any one survey and greater emphasis on analysing cumulative data and method comparison data.
Peptides corresponding to each of the three intracytoplasmic exons (i.e. exons 6, 7 and 8) of the murine class I H-2Kb gene were synthesized, coupled to bovine serum albumin and used as immunogens in rabbits. In each case the antisera were found to react with the immunizing peptide coupled to a heterologous carrier, and recognized class I heavy chains electrophoretically transferred from SDS-polyacrylamide gels to nitrocellulose. Immunoprecipitation of class I antigens from Nonidet P-40 (NP-40) solubilized EL-4 (H-2b) tumour cells by each of the antisera reflected their ability to recognize the corresponding determinants in non-denatured class I molecules. The same sera were also able to immunoprecipitate class I molecules from NP-40 solubilized RDM-4 (H-2k) and P815 (H-2d) tumour cells, indicating the cross-reactive nature of these antisera for different class I alleles. In addition to reacting with the class I heavy chain in its conventional form as a dimer with beta 2-microglobulin, the antiserum specific for the exon 8 peptide was able to react with "free" (i.e. non-beta 2-microglobulin-associated) class I heavy chains. Thus, a unique set of immunological reagents has been prepared which offer a new approach to studying the structural and functional features of the cytoplasmic domain of class I H-2 antigens.
Amantadine (1-aminoadamantane hydrochloride) is effective in the prophylaxis and treatment of influenza A infection. In tissue culture this selective, strain-specific antiviral inhibits either the initiation of infection or virus assembly. The basis of these actions is similar and both the haemagglutinin and M2 proteins are implicated suggesting that amantadine interferes with their functions or the interactions between these two virus proteins. Mutations which confer resistance to amantadine are restricted to four amino acids within a hydrophobic sequence of M2 indicating that the primary target of drug action is the membrane-associated portion of this molecule.
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Amantadine (1-aminoadamantane hydrochloride) is effective in the prophylaxis and treatment of influenza A infections. In tissue culture this selective, strain-specific antiviral activity occurs at relatively low concentrations (5 microM or less), which inhibit either the initiation of infection or virus assembly. The data reported here demonstrate that the basis of these actions is similar and resides in the virus-coded M2 membrane protein, the product of a spliced transcript of RNA segment 7. Mutations which confer resistance to amantadine are restricted to four amino acids within a hydrophobic sequence, indicating that the drug is targetted against the putative membrane-associated portion of the molecule. The influence of the virus haemagglutinin on the amantadine sensitivity of virus strains implies that the drug may interfere with interactions between these two virus proteins.