Evaluating biological plausibility in supporting evidence for action through systematic reviews in public health.

OBJECTIVES: The objective of this research was to develop and test methods for accessing and evaluating information on the biological plausibility of observed associations between exposures or interventions and outcomes to generate scientific evidence for action consistent with practice in systematic reviews. STUDY DESIGN: To undertake this research, we used the example of the observed associations between antimicrobial use in food animals and increased risks of human exposures to antimicrobial-resistant pathogens of zoonotic origin. METHODS: We conducted a scoping search using terms related to biological plausibility or mechanism to identify key references. As recommended by these references, we also used expert consultation with researchers and a public health informationist. We used their recommendations, which included expert consultation, to identify mechanisms relevant to biological plausibility of the association we selected to test. We used the reviews conducted by the World Health Organization (WHO) Guidelines Development Group in support of reducing antimicrobial use in food animal production to populate our model for assessing biological plausibility. RESULTS: We were able to develop a transparent model for biological plausibility based on the adverse outcome pathway used in toxicology and ecology. We were also able to populate this model using the WHO reviews. CONCLUSIONS: This analysis of biological plausibility used transparent and validated methods to assess the evidence used in systematic reviews based on the observational studies accessed through searches of the scientific literature. Given the importance of this topic in systematic reviews and evidence-based decision-making, further research is needed to define and test the methodological approaches to access and properly evaluate information from the scientific literature.

Mutagenicity of aryl propylene and butylene oxides with salmonella.

10 aryl propylene oxides and 6 aryl butylene oxides were synthesized. Dose-mutagenicity relationships were studied for these compounds and for 1,2-epoxybutane, using both the preincubation and plate incorporation Ames tests with Salmonella typhimurium strains TA100 and TA1535. Structure-mutagenicity relationships were further examined by concurrent testing at single doses with the plate incorporation assay in strain TA100. In both series of compounds, mutagenicity showed very correlation to chemical reactivity, molar volume and partition values. However, all compounds were mutagenic in at least one system with the propylene oxides being more mutagenic than the corresponding butylene oxide derivatives. The naphthyl derivatives in each series were the most mutagenic.

Mutagenicity of aromatic glycidyl ethers with Salmonella.

6 aromatic glycidyl ethers containing naphthyl, biphenyl or benzylphenyl substituents were synthesized. These epoxides together with the commercially available compounds 2-biphenylyl glycidyl ether were examined for dose-mutagenicity relationships using the plate incorporation Ames test with Salmonella typhimurium strains TA100 and TA1535. Structure-mutagenicity relationships were further examined for these compounds and 3 phenyl glycidyl ethers by concurrent testing at a single dose with strain TA100. Meaningful correlations could not be established for the mutagenicity of these epoxides to their molecular volumes, partition values, nor to their reactivities with the model nucleophile, 4-(4-nitrobenzyl) pyridine. However, it was noted that increased conjugated aromatic unsaturation with its resulting planarity led to increased mutagenicity and that this effect decreased when it was further removed from the epoxide moiety.

Mutagenicity of para-substituted alpha-methylstyrene oxide derivatives with Salmonella.

A series of 5 para-substituted alpha-methylstyrene oxide derivatives have been synthesized and together with alpha-methylstyrene oxide as well as styrene oxide have been studied as to their mutagenicity with the TA100 and TA1535 strains of Salmonella typhimurium. A multiple regression analysis model has been developed which describes the mutagenicity of the alpha-methylstyrene oxides in TA100. An increase in van der Waals volume was the most important variable in the model with greater improvement occurring with inclusion of the Hammett values for the para substituents on the compounds. The alpha-methylstyrene oxides were less active alkylating agents with 4-(p-nitrobenzyl)pyridine than styrene oxide and with pyridine all reactivity was at the beta-epoxide carbon. However all the alpha-methylstyrene oxide derivatives, except for the bromo compound where toxicity was evident, showed mutagenicity values either greater or comparable to that of styrene oxide. These studies would indicate that reactivity at the beta-carbon should also be a factor in describing the mutagenicity of the parent styrene oxide series.

DNA representation of variegating heterochromatic P-element inserts in diploid and polytene tissues of Drosophila melanogaster.

Position-effect variegation (PEV) is the mosaic expression of a euchromatic gene brought into juxtaposition with heterochromatin. Fourteen different transformed Drosophila melanogaster lines with variegating P-element inserts were used to examine the DNA levels of these transgenes. Insert sites include pericentric, telomeric and fourth chromosome regions. Southern blot analyses showed that the heterochromatic hsp26 transgenes are underrepresented 1.3- to 33-fold in polytene tissue relative to the endogenous euchromatic hsp26 gene. In contrast, the heterochromatic hsp26 transgenes are present in approximately the same copy number as the endogenous euchromatic hsp26 gene in diploid tissue. It appears unlikely that DNA loss could account for the lack of gene expression in diploid tissues seen with these examples of PEV.

Reactivity of mutagenic propylene oxides with deoxynucleosides and DNA.

In an extension of previous studies with deoxycytidine and thymidine reactivities, propylene oxide, glycidol, epichlorohydrin, and trichloropropylene oxide were reacted with deoxyguanosine as well as deoxyadenosine and, except for the trichloro compound, with DNA. Reactivity with the purine deoxynucleosides as well as the four deoxynucleosides in DNA were quantitated by HPLC methods. Correlations were found for the reactivity with individual deoxynucleosides in solution to Taft sigma electron-withdrawing values of the substituents on the epoxides and for reaction with model nucleophiles. In general, these correlations were not as pronounced for the reactivities of the propylene oxides with the nucleosides in DNA. Correlations for reactivity of the propylene oxides with the individual deoxynucleosides in solution and in DNA, except for dThd, were indicated for mutagenicity in TA100 in the liquid-preincubation Ames test. However, this was not the case for mutagenicities determined with the plate incorporation procedure nor with TA1535, where the relative mutagenicity of trichloropropylene oxide was the outstanding difference. Trichloropropylene oxide appeared to depend upon the error-prone system in TA100 for full expression of its mutagenicity.

Sarampion. II: inmunidad inducida por vacunacion. / Measles. II: inmunity induced by vaccination

Los autores procedieron a la vacunacion contra sarampion de 166 lactantes de 8 a 11 meses de edad y comprobaron una sero-conversion muy satisfactoria, medida con la prueba de la inhibicion de la hemoaglutinacion en un 91% de los casos. Al investigar 1 ano despues, en 111 de estos ninos, la presencia de anticuerpos especificos se comprobo que en un tercio de ellos las tasas de anticuerpos habian disminuido en forma manifiesta. En virtud de estos resultados los autores consideran conveniente sugerir el cambio del sistema de vacunacion contra sarampion en Chile

Estudio viral y parasitario en personal de un consultorio periferico. / Viral and parasitological study among personnel of a peripheric policlinic

Los autores-motivados por varios casos de embarazos patologicos afectaron a algunas funcionarias de uno de los Consultorios Perifericos investigaron las causas eventuales de estas anomalias a traves del analisis de las tasas de anticuerpos contra rubeola, citomegalovirus, virus herpes simple, toxoplasmosis y chagas, de todos los funcionarios (82 personas). Las tasas registradas en los distintos rubros antes senalados permiten concluir, que los resultados se encuadran dentro del promedio normal de la poblacion chilena y que en los cuatro casos de anomalias obstetricas les causas probables fueron rubeola (2), toxoplasmosis (1) y cuerpo extrano (1)