Use of admission Glasgow Coma Score, pupil size, and pupil reactivity to determine outcome for trauma patients

BACKGROUND: Determination of nonsurvival in trauma patients is difficult because valid prognostic indicators are lacking. It was hypothesized that patients presenting with a Glasgow Coma Score (GCS) of 3 as well as fixed and dilated (FD) pupils do not have a reasonable chance of survival. METHODS: From 1999 through 2001, adult trauma patients (age, >14 years) admitted with a GCS of 3 were reviewed. Patients receiving paralytic agents before initial assessment were excluded from analysis. Fixed and dilated pupils were defined as being 4 mm or more in diameter bilaterally and nonreactive to light. In this study, the FD patients were evaluated for survival, resuscitative measures, surgical procedures, length of hospital stay, and organ donation. The non-FD patients were evaluated for survival and length of hospital stay. RESULTS: Of the 137 patients evaluated with a GCS of 3, 104 had FD pupils and 33 did not. In the FD group, there were no survivors. On arrival, 28 (37.3%) of the patients were declared dead, and no further interventions were undertaken. Of the 76 patients (62.7%) who underwent further resuscitation, which included 53 surgical procedures, 30 died in the resuscitation bay, 39 within 24 hours, 4 within 48 hours, 2 within 72 hours, and 1 on day 6. There were 18 (23.7%) organ donors. Of the 33 patients without FD pupils, 11 (33%) survived to discharge (mean hospital stay, 21.4 days). Of the 22 nonsurvivors (67%), 10 died in the resuscitation bay, 8 within 24 hours, 1 within 48 hours, 1 on day 4, and 2 on day 6. CONCLUSIONS: Patients presenting with a GCS of 3 and FD pupils have no reasonable chance for survival. A significant percentage of these patients can be salvaged for organ donation. This information should be used in deciding to pursue aggressive resuscitation efforts and in discussing prognosis with family. Patients with a GCS of 3 who are not FD should be aggressively resuscitated because many of these patients survive to discharge.     

Modulation of endotoxin-induced endothelial activity by microtubule depolymerization

BACKGROUND: Endotoxin not only activates the Toll-mediated signaling pathway within endothelial cells that leads to neutrophil migration but also causes the polymerization of microtubules. The potential role of this polymerization event, however, is unknown. METHODS: Human umbilical vein endothelial cells stimulated with endotoxin were pretreated with or without the microtubule depolymerizing agent colchicine. Toll-mediated signaling events and protein production were in turn investigated by Western blot, gel shift, and enzyme-linked immunosorbent assay. Finally, neutrophil adhesion was assayed fluorometrically under the various conditions. RESULTS: Endotoxin led to activation of the various Toll-mediated pathways, production of intercellular adhesion molecule-1 and interleukin-8, and subsequent neutrophil adhesion. Pretreatment with colchicine led to selective inhibition of anti-dual phosphorylated extracellular signal-regulated kinase-1/2, anti-dual phosphorylated c-jun N-terminal kinase, and adaptor protein-1; selective enhancement of p38; and no effect on nuclear factor-kappaB. This selective modulation of intracellular signaling resulted in attenuated intercellular adhesion molecule-1, interleukin-8 and prostaglandin E2 production, but enhanced cyclooxygenase-2 expression. As a result, microtubule disruption led to a significant reduction in neutrophil adhesion. CONCLUSION: Microtubule formation is essential to optimal endotoxin-induced intracellular signaling through anti-dual phosphorylated extracellular signal-regulated kinase-1/2, anti-dual phosphorylated c-jun N-terminal kinase, and adaptor protein-1. Failure of these signaling events is associated with a marked reduction in the formation of a proadhesive phenotype that may prove to be beneficial in modulating neutrophil recruitment during sepsis.     

Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter

The (R,R) and (S,S) enantiomers of 2-[(2-methoxyphenoxy)phenylmethyl]morpholine (MeNER) have been radiolabelled with carbon-11 in good yield and at high specific activity. These radiotracers are close analogues of reboxetine, a potent and selective ligand for the norepinephrine transporter (NET). They were examined as potential ligands for imaging NET in vivo by positron emission tomography (PET). The in vivo brain distribution of both [(11)C]-labeled enantiomers were evaluated in rats. Following tail-vein injection of the (R,R)-enantiomer regional brain uptake and washout of radioactivity was homogeneous at all time points examined (5-60 min). In contrast, administration of the (S,S)-enantiomer produced a heterogeneous distribution of radioactivity in brain with highest uptake in the hypothalamus, a NET rich region, and lowest uptake in the striatum, a brain region devoid of NET. Hypothalamus to striatum ratios of 2.5 to one were achieved at 60 min post injection of (S,S)-[(11)C]-MeNER. Pre-injection of the norepinephrine reuptake inhibitors, reboxetine or desipramine, reduced hypothalamus to striatum ratios to near unity while reuptake inhibitors of dopamine and serotonin had no significant effect on binding. In vitro autoradiography studies (rat brain slices) with (S,S)-[(11)C]-MeNER produced a regional distribution pattern that was consistent with the reported distribution of NET. (S,S)-[(11)C]-MeNER has the potential to be the first successful PET ligand to image NET.     

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.