The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the female reproductive tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. There is also a section on normal cyclical changes observed in the ovary, uterus, cervix and vagina to compare normal physiological changes with pathological lesions. A widely accepted and utilized international harmonization of nomenclature for female reproductive tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

Ochratoxin A (OTA) is a mycotoxin often found in cereals as a contaminant, and it is known to cause severe nephrotoxicity in animals and humans. There have been several investigations studying the mode of action of this toxicant, suggesting inhibition of protein synthesis, formation of DNA adducts, and provocation of DNA single-strand breaks as a result of oxidative stress, but little is known about the transcriptional alterations underlying OTA-derived nephrotoxicity so far. We carried out DNA microarray analyses to assess OTA-specific expression profiles in vivo and in vitro. Cultures of primary rat proximal tubular cells and male Wistar rats were treated with a low dose (5 microM and 1 mg/kg, respectively) or a high dose (12.5 microM and 10 mg/kg, respectively) of OTA for 24 or 72 h. Microarray experiments were carried out after dual fluorescent labeling of sample cDNA, and data analysis was performed utilizing different statistical methods. Validity of selected microarray data was confirmed by quantitative real-time PCR. We were able to demonstrate that microarray data derived from our proximal tubule cell (PTC) culture model were highly comparable to the in vivo situation. Marked treatment-specific transcriptional changes were detected for genes involved in DNA damage response and apoptosis (upregulation of GADD 153, GADD 45, annexin V), response to oxidative stress (differential expression of hypoxia-inducible factor 1 and catalase), and inflammatory reactions (upregulation of alpha 2 macroglobulin, ceruloplasmin, and cathepsin S). We conclude that our results provide a molecular basis for interpretation of OTA-induced nephrotoxicity.

No abstract

No abstract