Modulation of trenimon-induced cytotoxicity by DT-diaphorase in isolated rat hepatocytes under aerobic versus hypoxic conditions.

Trenimon belongs to a class of aziridinylbenzoquinone anticancer drugs that cross the blood-brain barrier. In this study we have investigated the molecular mechanisms for trenimon-induced toxicity in aerobic versus hypoxic conditions with the use of freshly isolated rat hepatocytes. The following evidence suggests the mechanisms for trenimon detoxification involves reduction by DT-diaphorase, while the cytotoxic mechanism involves macromolecular alkylation under hypoxic conditions as well as oxidative stress under aerobic conditions. (a) Hepatocyte cytotoxicity induced by trenimon (250 microM) under aerobic conditions ensued following an initial induction of cyanide-resistant respiration and partial oxidation of glutathione to oxidized glutathione. Trenimon reduction to the hydroquinone by the hepatocytes was rapid. Inhibition of hepatocyte DT-diaphorase by dicumarol increased trenimon-induced cytotoxicity by approximately 10-fold, and markedly inhibited hydroquinone formation. Furthermore, both cyanide-resistant respiration and oxidized glutathione formation were markedly increased, resulting in depletion of oxygen in the media. Trenimon reduction to the hydroquinone then occurred. This suggests that DT-diaphorase in normal hepatocytes prevents the formation of the semiquinone that causes cytotoxic protein alkylation and oxidative stress. (b) Hepatocyte cytotoxicity induced by trenimon (350 microM) under hypoxic conditions ensued following glutathione depletion without oxidized glutathione formation. Inactivation of hepatocyte DT-diaphorase by dicumarol under hypoxic conditions increased trenimon-induced cytotoxicity by approximately 3.5-fold and increased semiquinone radical levels 2-fold without affecting its reduction rate. This suggests that the cytotoxic mechanism involves protein alkylation by semiquinone radicals formed by reductases catalyzing a one-electron reduction of trenimon.     

How does prosthesis head size affect vibration transmission in ossiculoplasty?

OBJECTIVES: The transmission of vibrations from the tympanic membrane to the stapes footplate by an ossicular reconstruction prosthesis is affected by the size of the prosthesis head. We sought to determine if augmenting or reducing the head size of prosthesis had a systematic effect on transmission of vibrations to the stapes. STUDY DESIGN: We conducted a fresh cadaveric temporal bone middle ear study. METHODS: The incus was replaced with a prosthesis using a tympanic membrane to stapes head (TASH)-type hydroxyapatite prosthesis in nine fresh cadaveric temporal bones. Three prosthesis head sizes were created: unaltered, reduced, and augmented. Stapes vibrations were measured with a laser Doppler vibrometer in response to acoustic frequency chirps at 90 dB SPL. RESULTS: All three head size prostheses resulted in smaller stapes vibrations than the intact ear. There was no difference in the vibration transmission between the three different head sizes. All prostheses showed a vibration loss of 10 to 15 dB compared to the intact ear. CONCLUSIONS AND SIGNIFICANCE: Within the range of sizes tested, prosthesis head size had little impact on vibration transmission to the stapes footplate.     

Japanese encephalitis after a two-week holiday in Bali

Japanese encephalitis is described in a 10-year-old girl after a short holiday in Bali. Four days after returning to Australia the patient presented with a high fever, stupor and rapidly-developing focal neurological signs. Recovery occurred gradually over a period of three months and she has returned to school. Japanese encephalitis viral infection was confirmed by a marked rise in specific haemagglutination-inhibition antibodies and the presence of immunoglobulin M antibodies to the flavivirus group. It is important to be aware of the possibility of arboviral infection in patients with encephalitis. In view of the recent outbreaks of Japanese encephalitis in Asia, travellers to the region should be warned to protect themselves from mosquito-bites.     

Hepatotoxicity in HIV-infected children and adolescents on antiretroviral therapy.

CONTEXT AND OBJECTIVE: Adverse drug reactions are a significant problem in patients on antiretroviral therapy (ART). We determined liver enzyme elevation frequencies in HIV-infected children and adolescents receiving ART, and their association with risk factors. DESIGN AND SETTING: Cross-sectional study, at the Pediatrics Immunodeficiency Division, University Hospital, Universidade Estadual de Campinas. METHODS: Medical records of 152 children and adolescents (54.6% male; median age 7.48 years) were analyzed, with a mean of 2.6 liver enzyme determinations per patient. Clinically, patients were classified in categories N (6), A (29), B (78) and C (39). Serum levels of aspartate aminotransferase and alanine aminotransferase were evaluated. Hepatotoxicity was scored as grade 1 (1.1-4.9 times upper limit of normality, ULN), grade 2 (5.0-9.9 times ULN), grade 3 (10.0-15.0 times ULN) and grade 4 (> 15.0 times ULN). To assess hepatotoxicity risk factors, odds ratios (OR) and adjusted odds ratios (aOR) for age, gender, TCD4+ cell count, viral load and medication usage were calculated. RESULTS: We observed grade 1 hepatotoxicity in 19.7 % (30/152) patients. No cases of grade 2, 3 or 4 were detected. There was a significant association between hepatotoxicity and use of sulfonamides (OR, 3.61; 95% confidence interval (CI), 1.50-8.70; aOR, 3.58; 95% CI, 1.44-8.85) and antituberculous agents (OR, 9.23; 95% CI, 1.60-53.08; aOR, 9.05; 95% CI, 1.48-55.25). No toxicity was associated with ART. CONCLUSIONS: One fifth of patients experienced mild hepatotoxicity, attributed to antituberculous agents and sulfonamides. Our results suggest that ART was well tolerated.     

Serological diagnosis of infection by Shigella dysenteriae-1 in patients with bacillary dysentery

A total of 192 samples of serum from 113 Sri Lankan patients with clinical dysentery was examined for antibodies of the IgM class to the lipopolysaccharides (LPSs) of Shigella dysenteriae-1 and Escherichia coli O157:H7. By means of ELISA and immunoblotting, 59 patients were found to have serum antibodies to the LPS of S. dysenteriae-1 only. Four samples from one patient were found to contain serum antibodies to the LPSs of both S. dysenteriae-1 and E. coli 0157: H7. Antibodies to the LPS of S. dysenteriae-1 were also detected in 16 samples from 25 children, from Sri Lanka, with no previous history of dysentery; one of these children also had antibodies to the LPS of E. coli 0157: H7. Analysis of 16 samples from apparently healthy children in the U.K. showed that only one serum contained antibodies to the LPS of S. dysenteriae-1. This patient had a history of recent travel to Pakistan. The isolation of S. dysenteriae-1 remains the preferred test for the diagnosis of bacillary dysentery. The use of serology as a means of providing evidence of infection with S. dysenteriae-1, however may prove to be a useful adjunct to cultural techniques but needs to be validated in an area where this organism is endemic.