Metabolism and Toxicity of Thioacetamide and Thioacetamide SOxide in Rat Hepatocytes

“This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/tx3002719The hepatotoxicity of thioacetamide (TA) has been known since 1948. In rats, single doses cause centrilobular necrosis accompanied by increases in plasma transaminases and bilirubin. To elicit these effects TA requires oxidative bioactivation leading first to its S-oxide (TASO) and then to its chemically reactive S,S-dioxide (TASO2) which ultimately modifies amine-lipids and proteins. To generate a suite of liver proteins adducted by TA metabolites for proteomic analysis, and to reduce the need for both animals and labeled compounds, we treated isolated hepatocytes directly with TA. Surprisingly, TA was not toxic at concentrations up to 50 mM for 40 hr. On the other hand, TASO was highly toxic to isolated hepatocytes as indicated by LDH release, cellular morphology and vital staining with Hoechst 33342/propidium iodide. TASO toxicity was partially blocked by the CYP2E1 inhibitors diallyl sulfide and 4-methylpyrazole, and was strongly inhibited by TA. Significantly, we found that hepatocytes produce TA from TASO relatively efficiently by back-reduction. The covalent binding of [14C]-TASO is inhibited by unlabeled TA which acts as a “cold-trap” for [14C]-TA and prevents its re-oxidation to [14C]-TASO. This in turn increases the net consumption of [14C]-TASO despite the fact that its oxidation to TASO2 is inhibited. The potent inhibition of TASO oxidation by TA, coupled with the back-reduction of TASO and its futile redox cycling with TA may help explain phenomena previously interpreted as “saturation toxicokinetics” in the in vivo metabolism and toxicity of TA and TASO. The improved understanding of the metabolism and covalent binding of TA and TASO facilitates the use of hepatocytes to prepare protein adducts for target protein identification

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events

A histologic evaluation of the human dental pulp following treatment by the Caridex caries removal system

PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact [email protected] photographs included.Caridex is a trademark.Thesis (M.Sc.D.)--Boston University, Henry M. Goldman School of Graduate Dentistry, 1987 (Endodontics)Bibliography : leaves 127-136.A histological study to evaluate human pulpal responses following caries removal treatment by the Caridex caries removal system was conducted utilizing fifteen human teeth. The teeth employed in this investigation were previously scheduled to be extracted and possessed a carious lesion involving only enamel and dentin. Vitality of the dental pulp was confirmed through a series of diagnostic tests. Following caries removal by the Caridex system, a temporary zinc oxide-eugenol (ZOE) restoration was placed in the cavity preparation. The teeth were extracted either seven days post-operatively or thirty days post-operatively,　and then histologically prepared and examined. Histological evaluation of the specimens in the seven day post-operative group revealed three specimens which demonstrated a possible hyperemic response; two specimens displayed a generalized inflammatory response indicative of a carious pulp exposure,　although no exposures were observed; one specimen revealed a localized inflammatory response; and two specimens displayed normal pulp tissue. Examination of specimens in the thirty day post-operative group found three specimens which demonstrated a possible hyperemic response, and four specimens which displayed normal pulp tissue. No generalized or localized inflammatory response was noted. Analysis of the histologic sections also revealed that six of the fifteen specimens showed evidence of dental caries remaining on the surface of the cavity preparation and extending into dentinal tubules. Additionally, caries removal by the Caridex system was noted to be a slow and lengthy process. Actual caries removal time ranged from nine minutes to　22　minutes, with an average caries removal treatment phase of 15.5　minutes. Based on the evaluation of the teeth utilized in this study, the following conclusions may be drawn: 1. No significant inflammatory response was observed in carious teeth following treatment by the Caridex caries removal system in either the seven day or thirty day post-operative groups which could be attributable to the Caridex system. 2. Dental caries were found to remain on the cavity preparation surface following diligent caries removal treatment utilizing the Caridex system in　40%　of the teeth studied. 3. Exceptionally long caries removal treatment times were necessary in order to obtain clinically caries-free cavity preparations.　However, histologically, caries were demonstrated to still be evident in six of the fifteen specimens studied. 4. The Caridex caries removal system seems to be a good marketing tool for dentists however, with incomplete caries removal, protracted treatment times, the relatively high cost of the system, and the need for rotary instruments after caries removal in order to refine the cavity preparation and place retention, the Caridex system does not appear to be a practical addition to the dental armamentarium of caries removal techniques as it currently exists