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Cyclooxygenase-2 is a valid target for cancer prevention and treatment. This has been shown in preclinical and clinical cancer prevention studies by using a cyclooxygenase-2 inhibitor, celecoxib. When used in a randomized cancer prevention clinical trial on patients with the inherited autosomal dominant condition, familial adenomatous polyposis, celecoxib proved efficacious. However, a remarkable heterogeneity in patients' responses to the chemopreventive effects of celecoxib was observed. Proteomic profiling of sera from these patients identified several markers, the expression of which was specifically modulated after treatment with celecoxib. A decision tree algorithm identified classifiers for response to celecoxib with relatively high sensitivity but moderate to low specificity. In particular, a spectral feature at m/z 16,961.4 was identified as a strong discriminator between response and nonresponse to celecoxib at the highest dose.

Chronic prenatal ethanol exposure (CPEE) can injure the developing brain, and may lead to the fetal alcohol syndrome (FAS). Previous studies have demonstrated that CPEE upregulates gamma-aminobutyric acid type A (GABA(A)) receptor expression in the cerebral cortex, and decreases functional synaptic plasticity in the hippocampus, in the adult guinea pig. This study tested the hypothesis that CPEE increases GABA(A) receptor expression in the hippocampus of guinea pig offspring that exhibit cognitive deficits in a hippocampal-dependent spatial learning task. Timed, pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight per day), isocaloric-sucrose/pair-feeding, or water throughout gestation. GABA(A) receptor subunit protein expression in the hippocampus was measured at two development ages: near-term fetus and young adult. In young adult guinea pig offspring, CPEE increased spontaneous locomotor activity in the open-field and impaired task acquisition in the Morris water maze. CPEE did not change GABA(A) receptor subunit protein expression in the near-term fetal hippocampus, but increased expression of the beta2/3-subunit of the GABA(A) receptor in the hippocampus of young adult offspring. CPEE did not change either [(3)H]flunitrazepam binding or GABA potentiation of [(3)H]flunitrazepam binding, but decreased the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam binding, to hippocampal GABA(A) receptors in adult offspring. Correlational analysis revealed a relationship between increased spontaneous locomotor activity and growth restriction in the hippocampus induced by CPEE. Similarly, an inverse relationship was found between performance in the water maze and the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam binding in the hippocampus. These data suggest that alterations in hippocampal GABA(A) receptor expression and pharmacological properties contribute to hippocampal-related behavioral and cognitive deficits associated with CPEE.

Objective: To evaluate the activation of clotting systems in patients with sickle cell disease (SCD) by measuring the plasma D-dimer level and to determine the effect of low-dose warfarin on D-dimer level during vaso-occlusive crisis., Methods: Plasma D-dimer level was measured in 65 blood samples of 37 adult patients with SCD who were hospitalized for vaso-occlusive painful crisis. D-dimer level of patients who were on low-dose warfarin was compared with those patients who were not on any anticoagulation treatment. Analysis of variance (anova) was carried out to determine factors significantly associated with low D-dimer level in patients with SCD. The following factors were included in the anova model; warfarin, homozygous hemoglobin S, history of blood transfusion in past 3 months, hydroxyurea, hemoglobin S%, hemoglobin F%, white blood cell counts, hemoglobin level, platelet count, and plasma fibrinogen level., Results: Overall median D-dimer level in 65 samples was 2.7 microg fibrinogen equivalent units (FEU)/mL (0.34-4). Patients who were on low-dose warfarin had a median D-dimer level of 0.81 microg FEU/mL (0.34-1.8) compared with 3.1 microg FEU/mL (0.94-4) in those patients who were not on anticoagulation treatment. Using anova to model D-dimer levels, only warfarin was significantly correlated with low D-dimer levels after controlling for other variables., Conclusions: Patients with SCD during vaso-occulsive painful crisis have an elevated D-dimer level. Low-dose anticoagulation treatment is associated with a significant reduction in the D-dimer levels.

Background: The superfamily of glutamate-gated ion channels mediates fast excitatory synaptic transmission in the central nervous system and is composed of the NMDA, AMPA, and kainate receptors. Binding studies have shown that chronic prenatal and/or neonatal ethanol exposure produces persistent effects on the numbers of some of these channels. However, whether or not this chronic ethanol exposure produces long-lasting effects on the expression of specific ionotropic receptor subunits remains an open question., Methods: Timed pregnant Dunkin-Hartley strain guinea pigs received oral administration of one of the following regimens between gestational days 2 and 67: (1) 4 g of ethanol per kilogram of maternal body weight per day with ad libitum access to pellet food and water (ethanol group), (2) isocaloric sucrose- and pair-feeding with ad libitum access to water (sucrose group), or (3) isovolumetric water with ad libitum access to food and water (water group). The maternal blood ethanol concentration produced by the ethanol regimen was 71 +/- 12 mM. Adult offspring were killed on postnatal day 61, and cerebral cortical tissue was analyzed for ionotropic glutamate receptor subunit expression by Western immunoblotting., Results: There was a statistically significant decrease in NR2B subunit protein expression and an increase in GluR2/3 subunit protein expression in the ethanol group. Expression of NR1, NR2A, NR2C, GluR1, GluR6/7, and KA2 subunit proteins was not affected., Conclusions: These results demonstrate that chronic prenatal ethanol exposure produces long-lasting effects on the subunit composition of NMDA and AMPA receptors in the cerebral cortex of the adult guinea pig.

Background: Significant interindividual variability exists following maternal alcohol consumption; not all children born to alcoholic women manifest the symptoms associated with foetal alcohol spectrum disorder (FASD)., Objective: To investigate the potential role of the placenta as a source of variability by determining if interindividual variability exists in the binding of acetaldehyde to human placenta., Methods: Acetaldehyde was added to ten different human placental homogenates and subjected to equilibrium dialysis. Homogenates of placentae obtained from guinea pigs chronically exposed to ethanol throughout gestation were also dialysed in the presence of acetaldehyde to look for alterations in binding after chronic alcohol exposure. Nonlinear least-squares regression analysis was used to characterize the binding system involved., Results: It was found that the amount of acetaldehyde bound to human placentae varied by as much as 3-fold among placentae. The binding profile of acetaldehyde was characterized as a two site binding system (Ka(1)=9.8 x 10(5)+/-0.7 x 10(5)l/mol, N(1)=1.1 x 10(-8)+/-0.7 x 10(-8)mol/g tissue; Ka(2)=1.6 x 10(4)+/-0.9 x 10(4)l/mol, N(2)=1.7 x 10(-7)+/-0.4 x 10(-7)mol/g tissue). Chronic alcohol exposure had no effect on the degree of acetaldehyde binding., Conclusion: This previously unidentified source of variability may partially explain why some foetuses are adversely affected by prenatal alcohol exposure while others are not.

The goal of this study was to develop a sensitive, simple, and widely applicable assay to measure copy numbers of specific mRNAs using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and identify a profile of gene expression closely associated with angiogenesis. We measured a panel of nine potential angiogenesis markers from a mouse transgenic model of prostate adenocarcinoma (TRAMP) and a mouse skin model of vascular endothelial growth factor (VEGF)-driven angiogenesis. In both models, expression of VEGF correlated with expression of mRNAs encoding other angiogenic cytokines (angiopoietin-1 and angiopoietin-2), endothelial cell receptor tyrosine kinases (Flt-1, KDR, Tie-1), and endothelial cell adhesion molecules (VE-cadherin, PECAM-1). Relative to control, in dermis highly stimulated by VEGF, the Ang-2 mRNA transcript numbers increased 35-fold, PECAM-1 and VE-cadherin increased 10-fold, Tie-1 increased 8-fold, KDR and Flt-1 each increased 4-fold, and Ang-1 increased 2-fold. All transcript numbers were correspondingly reduced in skin with less VEGF expression, indicating a relationship of each of these seven markers with VEGF. Thus, this study identifies a highly efficient method for precise quantification of a panel of seven specific mRNAs that correlate with VEGF expression and VEGF-induced neovascularization, and it provides evidence that real-time quantitative RT-PCR offers a highly sensitive strategy for monitoring angiogenesis.

Background: Access to high quality medical care and especially to complex procedures may be adversely affected in members of a minority ethnic group or a lower socioeconomic class. For example, Caucasians undergo coronary artery bypass grafting (CABG) or percutaneous transluminal coronary interventions (PTCI) twice as frequently as African-Americans. Data exist to suggest that African-Americans derive less benefit than Caucasians from CABG., Hypothesis: We investigated the possibility that outcomes of catheter-based coronary angioplasty might also be less favorable in minority populations., Methods: We analyzed in-hospital outcomes in 6,559 consecutive patients who underwent PTCI in our laboratory. In 37 ethnicity was classified as "other," 5,203 (79.8%) were identified as Caucasians, 863 (13.2%), as African-Americans, and 456 (7.0%), as Hispanics. Twelve baseline clinical, angiographic, and procedural characteristics were entered into a computerized data base. Hospital complications were identified by trained quality assurance nurses., Results: Substantial differences in baseline characteristics existed between the populations. Despite these differences, on univariate comparison of ethnicity and outcome, no differences between ethnic groups were found with a single exception. Mortality in Hispanics was higher than in the other two populations. (2.0 vs. 0.7 and 0.8%, respectively, p = 0.008). However, when this was adjusted for baseline characteristics, the difference was not significant., Conclusions: In contrast to previous studies suggesting less favorable outcomes of CABG in African-American patients, this analysis demonstrates an equal frequency of procedural success and rate of hospital complications for PTCI in that population, in Hispanics, and in Caucasians.