ERK-MAPK signaling opposes Rho-kinase to promote endothelial cell survival and sprouting during angiogenesis

Inhibition of ERK-MAPK signaling by expression of dominant-negative MEK1 in the tumor vasculature suppresses angiogenesis and tumor growth. In an organotypic tissue culture angiogenesis assay, ERK-MAPK inhibition during the migratory phase results in loss of bipolarity, detachment, and cell death of isolated endothelial cells and retraction of sprouting tubules. These effects are the consequence of upregulated Rho-kinase signaling. Transient inhibition of Rho-kinase rescues the effects of ERK-MAPK inhibition in vitro and in vivo, promotes sprouting, and increases vessel length in tumors. We propose a regulatory role of Rho-kinase by ERK-MAPK during angiogenesis that acts through the control of actomyosin contractility. Our data delineate a mechanism by which ERK-MAPK promotes endothelial cell survival and sprouting by downregulating Rho-kinase signaling.     

The acquisition and application of absorption, distribution, metabolism, and excretion (ADME) data in agricultural chemical safety assessments

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Incorporation of pharmacokinetic studies describing absorption, distribution, metabolism, and excretion is an essential tool for improving the design and interpretation of toxicity studies and their application for safety assessment. A tiered approach is described in which basic pharmacokinetic studies, similar to those for pharmaceuticals, are conducted for regulatory submission. Subsequent tiers provide additional information in an iterative manner, depending on pharmacokinetic properties, toxicity study results, and the intended uses of the compound.     

Progression of visual field loss in open angle glaucoma in the Melbourne Visual Impairment Project

PURPOSE: To quantify the progression of visual field loss in participants with open angle glaucoma. METHODS: Cluster random samples of 3271 participants participated in this study. Each participant underwent a standardized ophthalmic examination, which included intraocular pressure measurement, Humphrey 24-2 Fastpac visual field testing and stereophotography of the optic disc. At baseline 118 participants were identified as possible, probable or definite open angle glaucoma and 74 (62.7%) of these were seen again at the follow-up examination. Progression of visual field loss was defined using three methods: the Advanced Glaucoma Intervention Study criteria, the modified Anderson criteria and the Blumenthal method. RESULTS: In total, 49% of subjects showed progressive visual field loss with at least one method. The Blumenthal criteria yielded the highest rate of progression (37%), followed by the modified Anderson method (33%) and the Advanced Glaucoma Intervention Study method (16%). The progressive visual field loss was associated with baseline glaucoma status (P = 0.02); 65% of the definite glaucoma progressed, compared with 57% of the probable glaucoma and 25% of the possible glaucoma. Participants who had been previously diagnosed with glaucoma had a higher rate of progression (54%) when compared with those who had not been diagnosed previously (47%). In total, 50% (four of eight) of those receiving glaucoma medication at baseline had progressive visual field loss; all were in the definite glaucoma category. CONCLUSION: Despite use of glaucoma medications the majority of glaucoma patients managed by their regular ophthalmologist experienced progressive visual field loss over a 5-year period.     

Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases

New therapies directed at ameliorating or altering autoimmune diseases represent an area of significant medical need. Included amongst autoimmune diseases are problems related to transplantation rejection, as well as a number of neurological diseases such as Multiple Sclerosis (MS). A new group of molecular targets that may lead to novel therapies are lysophospholipid (LP) receptors. A large range of biological activities has been attributed to the actions of these simple phospholipids that include well-studied members lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). Documented cellular effects of these lipid molecules encompass growth-factor-like influences on cells, including but not limited to survival, migration, adhesion differentiation, as well as pathophysiological actions associated with cancer. In turn, these cellular effects have roles in developing and adult organ systems such as the nervous system, cardiovascular system, reproductive system and, of relevance here, the immune system. The mechanisms for these actions can be attributed to a growing family of cognate, 7-transmembrane G protein-coupled receptors (GPCRs), with documented validation through studies utilizing pharmacology, molecular genetics and an enlarging repertoire of chemical tools having agonist or antagonist properties. The growing literature on immunological effects of LP receptors, particularly those mediating the effects of S1P, has suggested possible therapeutic roles for this class of receptors. In particular, entry into humans of a non-selective S1P receptor agonist, FTY720, for kidney transplantation and possibly other indications (e.g., Multiple Sclerosis), has raised prospects for efficacious treatment of human diseases based on LP receptor targets. Here we provide a brief introduction to receptor-mediated lysophospholipid signaling and discuss its basic and potential therapeutic roles in autoimmune-related diseases.     

Metabolism of [14C]Cefaclor, a Cephalosporin Antibiotic, in Three Species of Laboratory Animals

The metabolic fate of the orally effective cephalosporin antibiotic cefaclor (Lilly 99638) has been studied in rats, mice, and dogs. Cefaclor is efficiently absorbed from the gastrointestinal tract as the intact antibiotic. In rats and mice, cefaclor, for the most part, escapes metabolism in the body and is eliminated unchanged as unaltered antibiotic, primarily by renal excretion. In dogs, however, cefaclor is more labile to metabolism and only a portion of the administered antibiotic is eliminated unchanged via the kidney.     

Genitourinary infection with Ureaplasma urealyticum in women attending a sexually transmitted diseases clinic

Ureaplasma urealyticum was detected in the cervix of 49·9% and in the urine of 47·7% of women attending a department of genitourinary medicine. Isolation of U urealyticum was not related to diagnosis, nor was there any association between the presence of the organism and any symptoms or signs of genital tract disease. Fewer organisms were detected in the cervix of women who had a concurrent infection with Chlamydia trachomatis than in women who had not. A pathological role for U urealyticum has not been established.