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Biomedical subjects

P Toltzis

Publications and source records attributed to P Toltzis.

7 recordsLinked to original sources

Zidovudine-associated embryonic toxicity in mice.

A novel toxicity associated with zidovudine (AZT), the standard antiviral therapy for infection with human immunodeficiency virus, is described. When AZT was administered to mice to evaluate its safety during gestation, the animals failed to complete pregnancy successfully. Mice receiving AZT during gestation yielded fewer fetuses (P = .003) and greater numbers of resorptions (P = .003) per pregnant mouse compared with untreated animals. Drug effects on adult mice were assessed to determine if toxicity could account for the pregnancy failures. However, adult animals receiving AZT demonstrated no adverse effects with regard to growth, food consumption, activity, or ovarian histology. A direct toxic effect of AZT on the mouse embryo was tested by cultivating single-cell fertilized oocytes in vitro in the presence of increasing concentrations of drug. Exposure to AZT was highly correlated with failure to develop to the blastocyst stage (P less than .001). These data indicate that AZT has a direct toxic effect on the developing mouse embryo. Further analysis of the nature of this toxicity may be important in designing less toxic antiretroviral agents and in planning future uses of AZT.

Animals

Viral encephalitis.

Nonherpetic encephalitis outside the newborn period is usually a self-limited disease. The majority of patients will recover without significant sequelae, and require only supportive therapy during the acute illness. Though the underlying viral etiology frequently will escape detection, identification of the infecting agent has considerable prognostic value which can complement clinical measures of severity of disease. The most important initial task of the clinician faced with a case of presumptive viral encephalitis is to eliminate the possibility of a treatable illness. Once this has been done, the diagnosis of viral encephalitis can be supported by documenting the characteristic slow-wave background activity on EEG, and a mild lymphocellular pleocytosis in the CSF. Because viral encephalitis can be caused by such a large number of organisms, the search for an etiology can be daunting. Realizing that all the agents described above can, at times, cause encephalitis without any clue to their identity, one nevertheless may use several pieces of historical information to narrow the possibilities. Travel history, animal exposures, immunization history, and seasonality all may help to steer the search in a particular direction and, indeed, may point to a nonvirologic cause as well. In addition, detection of extraneurological signs and symptoms may strongly indicate a specific virologic diagnosis. Finally, knowledge of concurrent community epidemic patterns, and of surveillance data routinely collected by local and state health departments, can help to increase or decrease the likelihood of a given pathogen. The causative viral agent usually can be identified by serological testing and viral culture. Occasionally, single serological determinations are diagnostic: in rabies (when the patient has not received immune prophylaxis), eastern equine encephalitis, and HIV, since seropositivity is strongly associated with symptomatic illness; and in Epstein-Barr virus, if a panel of antibody determinations which can time the infection is available. In addition, high CSF: serum titers for antibody against any neurotropic agent is usually diagnostic, though the absence of a high central nervous system antibody titer does not eliminate any potential viral pathogen. With these few exceptions, a single serological determination for a given pathogen is almost always impossible to interpret; paired sera (one obtained upon diagnosis, and one obtained 10 to 14 days later, either just prior to hospital discharge or at a follow-up visit) are far more helpful. Many viruses that directly infect the central nervous system are difficult to recover from the CSF; therefore, viral isolation from the nasopharynx and stool also should be sought.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenoviridae Infections

Current issues in neonatal herpes simplex virus infection.

Significant progress has been made in the recognition and treatment of herpes simplex disease in the newborn. This review discusses four current issues surrounding this severe and important infection. First, the reasons underlying the failure of antenatal screening programs to identify high-risk pregnancies for herpes simplex are analyzed. Second, typical and atypical clinical manifestations of neonatal herpetic infection are reviewed. Third, determinants of disease, particularly the immune status of the mother and child, and their therapeutic implications are discussed. Finally, controversies surrounding antiviral therapy are examined.

Acyclovir

Current issues in central venous catheter infection.

The majority of central venous line-associated infections are caused by organisms on the skin near the exit site gaining access to the intravascular segment of the catheter. A variety of strategies have been used in an effort to reduce catheter contamination, but one innovation--the semipermeable transparent dressing--may actually increase infection risk. On the other hand, new catheter materials and designs probably reduce the risk. There are only a limited number of well-designed studies of the increasingly popular totally implantable catheter system and the multilumen line, but it appears that the former is associated with a low rate of infection, while the latter may be more hazardous than the single-lumen line.

Bacterial Infections

Effect of phosphorylated ribavirin on vesicular stomatitis virus transcription.

The effect of phosphorylated ribavirin on a vesicular stomatitis virus (VSV) in vitro transcription reaction was examined. Viral mRNA synthesized in the presence of the 5' mono-, di-, and triphosphorylated forms of the drug translated with equal efficiencies under the test conditions. However, all three phosphorylated species inhibited VSV transcription. The mono- and diphosphorylated forms of the drug possessed approximately two to three times the inhibitory activity as the triphosphorylated form. Transcripts synthesized in the presence of drug were full length and were absent of incorporated drug. Inhibition by ribavirin 5'-diphosphate could be reversed by the addition of UTP, CTP, and GTP, while the addition of GDP to the reaction did not reverse inhibition. Ribavirin diphosphate was added to a La Crosse virus in vitro transcription assay to determine whether an inhibitory effect could be established in a viral system that was more sensitive to ribavirin than was VSV; it led to profound inhibition of RNA synthesis at concentrations as low as 0.1 microgram/ml. These data suggest that ribavirin has an effect on the initial steps of transcription by some RNA-dependent RNA polymerases and that this effect may be mediated by several phosphorylated forms.

Nucleotides

Effect of ribavirin on macromolecular synthesis in vesicular stomatitis virus-infected cells.

Ribavirin at 200 micrograms/ml inhibited vesicular stomatitis virus (VSV) growth in Chinese hamster ovary (CHO) cells by 2.5 logs. To determine the mechanism of this inhibition, viral macromolecular synthesis was examined. VSV primary transcription remained unaffected, but overall VSV RNA synthesis decreased by 40 to 60%. When ribavirin was added 1.5 h after infection, inhibition of progeny production was partially lost, indicating that the antiviral effect was on an early stage after primary transcription. Inhibition of RNA polymerization by premature chain termination was not evident. Viral translation, on the other hand, was reduced by 95% with an inhibition of every protein species. Furthermore, viral RNA synthesized in the presence of ribavirin did not translate well in an in vitro translation system. In contrast, uninfected CHO cells treated with ribavirin showed a greater sensitivity in RNA synthesis than in protein synthesis. This suggests that the cellular translational machinery was not directly affected. Short-term treatment of cells resulted in negligible toxicity, but after 24 h there was marked alteration of cellular integrity. These results, taken together with data on other viruses, suggest that in the presence of ribavirin, dysfunctional VSV mRNA was synthesized, resulting in its failure to be translated. The selective antiviral effects of ribavirin and its relative lack of toxicity for host cells may be predicted on the basis of mRNA turnover and the requirements for de novo functional mRNA.

Animals