AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes.

Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo-controlled phase IIa study evaluated the dose-effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33-35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 200 mg twice daily, AMG 151 at 100, 200 or 400 mg once daily or matching placebo for 28 days. A significant linear dose-effect trend was observed with the twice-daily regimen (p = 0.004) for change in FPG to day 28. No trend was observed with the once-daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin.

Anemia treatment with Q2W darbepoetin alfa in patients with chronic kidney disease naïve to erythropoiesis-stimulating agents.

OBJECTIVE: To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy. RESEARCH DESIGN AND METHODS: This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb) < 11.0 g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75 microg/kg and titrated to achieve and maintain Hb levels at 11.0-13.0 g/dL. Treatment was administered from week 1 to week 19. MAIN OUTCOME MEASURES: The primary endpoint was the proportion of subjects who achieved Hb > or = 11 g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed. RESULTS: Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hb > or = 11 g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hb > or = 11 g/dL were 60 and 80 microg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects. CONCLUSIONS: This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00112008.

Calcium signaling induced by adhesion mediates protein tyrosine phosphorylation and is independent of pHi.

Our goal was to evaluate early signaling events that occur as epithelial cells make initial contact with a substrate and to correlate them with phosphorylation. The corneal epithelium was chosen to study signaling events that occur with adhesion because it represents a simple system in which the tissue adheres to a basal lamina, is avascular, and is bathed by a tear film in which changes in the local environment are hypothesized to alter signaling. To perform these experiments we developed a novel adhesion assay to capture the changes in intracellular Ca(2+) and pH that occur as a cell makes its initial contact with a substrate. The first transient cytosolic Ca(2+) peak was detected only as the cell made contact with the substrate and was demonstrated using fluorimetric assays combined with live cell imaging. We demonstrated that this transient Ca(2+) peak always preceded a cytoplasmic alkalization. When the intracellular environment was modified, the initial response was altered. Pretreatment with 1,2-bis(o-aminophenoxy)ethane-N,N, N'N'-tetraacetic acid (BAPTA), an intracellular chelator, inhibited Ca(2+) mobilization, whereas benzamil altered the duration of the oscillations. Thapsigargin caused an initial Ca(2+) release followed by a long attenuated response. An inositol triphosphate analog induced a large initial response, whereas heparin inhibited Ca(2+) oscillations. Inhibitors of tyrosine phosphorylation did not alter the initial mobilization of cytosolic Ca(2) but clearance of cytosolic Ca(2+) was inhibited. Exposing corneal epithelial cells to BAPTA, benzamil, or thapsigargin also attenuated the phosphorylation of the focal adhesion protein paxillin. However, although heparin inhibited Ca(2+) oscillations, it did not alter phosphorylation of paxillin. These studies demonstrate that the initial contact that a cell makes with a substrate modulates the intracellular environment, and that changes in Ca(2+) mobilization can alter later signaling events such as the phosphorylation of specific adhesion proteins. These findings may have implications for wound repair and development.

Internet and obstetrics and gynecology.

BACKGROUND: The Internet is an unrestricted, easily accessed source of information that has been greatly touted by the mass media. It represents a major advance in information acquisition and dissemination. It is estimated that between 3040 million North Americans alone have access to the Internet. This multimedia reservoir of information has developed into a significant resource for information gathering, especially for those who depend on comprehensive and contemporary information, including scientists and physicians. METHODS AND RESULTS: The purpose of this article is to describe some of the basic and practical services available on the Internet including e-mail, literature searches, interest groups, databases and on-line journals. Our focus is to describe these Internet resources with the physician in mind, and with particular emphasis on Internet applications for the obstetrician/gynecologist. CONCLUSION: The role of the Internet in medicine has not been defined, but continues to evolve. In the field of obstetrics and gynecology, the Internet has already become incorporated in various ways and it is safe to say that we are currently going through a revolution as fundamental to the human civilization as the eighteenth century industrial revolution--the information revolution.

Expression of integrin receptors on plasma membranes of primary corneal epithelial cells is matrix specific.

Modulation of cell behavior may occur through cell adhesion receptors that bind domains of extracellular matrix molecules and mediate cell-substrate signal transduction. It was hypothesized that while primary corneal epithelial cells seeded onto laminin and fibronectin express and synthesize integrin receptors, they are not detected on the plasma membrane until the appropriate ligand is present. The integrin subunits (alpha-6, beta-4 and beta-1) present on the plasma membrane after adherence to laminin and fibronectin were compared with changes that occurred in mRNA expression and protein synthesis. Prior to seeding, the percentage of cells expressing integrin receptors and matrix proteins on their plasma membrane was determined. Negligible laminin and fibronectin (0-7%) were present on the plasma membrane while the population of epithelial cells expressing beta-4 and beta-1 on the plasma membrane was low (21-23%). After 3 hr of adherence the cell population expressing integrin subunits was substrate dependent. The percentage of cells adherent to LM expressing beta-4 was four-fold greater than cells adherent to FN. After 24 hr the percentage of cells cultured on fibronectin expressing beta-4 increased significantly indicating ligand deposition. The expression and protein synthesis of alpha-6 and beta-4 was evaluated and an increase in the synthesis of alpha-6 and beta-4 was not detected until 18 hr on LM and 21 hr on FN. The present results demonstrate that expression and transport of integrin receptors to the plasma membrane of primary corneal epithelial cells after adhesion is regulated by the presence of specific ligands.