beta-Catenin regulates vascular endothelial growth factor expression in colon cancer

To evaluate whether beta-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for beta-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor (VEGF, or VEGF-A) contains seven consensus binding sites for beta-catenin/TCF. Analysis of laser capture microdissected human colon cancer tissue indicated a direct correlation between up-regulation of VEGF-A expression and adenomatous polyposis coli (APC) mutational status (activation of beta-catenin signaling) in primary tumors. In metastases, this correlation was not observed. Analysis by immunohistochemistry of intestinal polyps in mice heterozygous for the multiple intestinal neoplasia gene (Min/+) at 5 months revealed an increase and redistribution of VEGF-A in proximity to those cells expressing nuclear beta-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated beta-catenin up-regulated levels of VEGF-A mRNA and protein by 250-300%. When colon cancer cells with elevated beta-catenin levels were treated with beta-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between beta-catenin signaling and the regulation of VEGF-A expression in colon cancer.     

House dust and inorganic urinary arsenic in two Arizona mining towns

Residents of copper mining and smelting towns may have increased risk of arsenic exposure from elevated arsenic contained in environmental media. To determine the relation of arsenic in house dust to inorganic urinary arsenic concentrations, a door-to-door survey was conducted in Hayden and Winkelman, Arizona. A total of 122 households (404 individuals) participated; 85 provided dust samples. Urine was collected at first morning void and analyzed for total and speciated arsenic. Speciation of arsenic was performed in samples with total arsenic above 10 micro g/l (N=106). The generalized estimating equation was used to determine the relation between urinary and house dust arsenic concentrations, allowing adjustment for the correlation of measurements obtained from the same home. Seafood consumption during the past 3 days and smoking contributed significantly to inorganic urinary arsenic, after adjusting for age and gender. Arsenic in house dust was not significantly associated with inorganic urinary arsenic measurements in this population.     

International Union of Pharmacology. XLI. Compendium of voltage-gated ion channels: potassium channels

This summary article presents an overview of the molecular relationships among the voltage-gated potassium channels and a standard nomenclature for them, which is derived from the IUPHAR Compendium of Voltage-Gated Ion Channels. The complete Compendium, including data tables for each member of the potassium channel family can be found at http://www.iuphar-db.org/iuphar-ic/.     

Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs

Many oral phosphate prodrugs have failed to improve the rate or extent of absorption compared to their insoluble parent drugs. Rapid parent drug generation via intestinal alkaline phosphatase can result in supersaturated solutions, leading to parent drug precipitation. The purpose was to (1) investigate whether parent drugs can precipitate from prodrug solutions in presence of alkaline phosphatase; (2) determine whether induction times are influenced by (a) dephosphorylation rate, (b) parent drug supersaturation level, and (c) parent drug solubility. Induction times were determined from increases in optical densities after enzyme addition to prodrug solutions of TAT-59, fosphenytoin and estramustine phosphate. Apparent supersaturation ratios (sigma) were calculated from parent drug solubility at intestinal pH. Precipitation could be generated for all three prodrugs. Induction times decreased with increased enzyme activity and supersaturation level and were within gastrointestinal residence times for TAT-59 concentration>/=21microM (sigma>/=210). Induction times for fosphenytoin were less than the GI residence time (199min) for concentrations of approximately 352 microM (sigma=4.0). At approximately 475 microM (sigma=5.3) the induction times were less than 90min. For estramustine-phosphate, no precipitation was observed within GI residence times. Enzyme-mediated precipitation will depend on apparent supersaturation ratios, parent drug dose, solubility and solubilization by the prodrug.     

Delayed diagnosis in pediatric blunt trauma

OBJECTIVE: Identification of injuries of a traumatized patient is a mandate for the emergency department (ED) and the trauma team. Delayed diagnosis of injury in trauma patients leads to increased morbidity, mortality, dissatisfaction, and risk of litigation. Comparing children admitted for blunt trauma, with and without delay, this study examines risk factors for delayed diagnosis. METHODS: Delays in diagnosis from 1991 to 1996 were identified during prospective collection of trauma registry data. Controls were randomly selected from the trauma registry. Charts from both groups were retrospectively reviewed. RESULTS: Fifty-eight patients had 65 delays in diagnosis. Significant independent delay variables included: female, motor vehicle crash (MVC)-related mechanism, altered consciousness, higher injury severity score, and multiple injuries (P < 0.05). Trauma team activation, documentation of tertiary survey, and length of hospitalization were greater in patients with delay injuries (P < 0.05). Logistic regression identified MVC-related mechanism, female, facial, and extremity injuries as a combination of predictors. CONCLUSIONS: Delays occurred in 1% of patients. Trauma team care itself did not protect all patients from delay. Injury severity at presentation alone is not an adequate predictor of delayed diagnosis in the pediatric patient. A combination of variables was identified as negative predictors of delay. Further study is needed to validate these criteria, and determine if earlier diagnosis would effect quality.     

Outcomes of bail-out stenting for suboptimal balloon angioplasty during primary intervention in acute myocardial infarction (The CADILLAC trial)

The results of bail-out stenting after unsuccessful primary balloon angioplasty compared with routine stenting or successful balloon angioplasty in acute myocardial infarction are unknown. In the CADILLAC trial, 168 of 1,044 patients (16.1%) randomized to balloon angioplasty crossed over to stenting after unsuccessful dilatation. Event-free survival was similar after bail-out and routine stenting, and was greater than after successful balloon angioplasty.