Radiofrequency ablation of Barrett's esophagus: outcomes of 429 patients from a multicenter community practice registry.

BACKGROUND AND STUDY AIMS: The use of radiofrequency ablation (RFA) for complete eradication of Barrett's esophagus has shown promise in trials conducted at predominantly tertiary academic centers; however less is known regarding outcomes in the community. We evaluated the safety and efficacy of RFA for Barrett's esophagus delivered in a community practice setting. PATIENTS AND METHODS: This was a multicenter registry conducted in community-based gastroenterology practices. Patients had confirmed intestinal metaplasia with or without dysplasia on biopsy of a Barrett's esophagus. Intervention was step-wise RFA with follow-up esophageal biopsies. Endpoints were histology-based; complete response was defined as all biopsies at most recent endoscopy negative for intestinal metaplasia (CR-IM) or dysplasia (CR-D). Three cohorts were reported: 1) safety cohort, all patients; 2) efficacy cohort A, patients with at least one biopsy session after initial treatment; 3) efficacy cohort B, patients with at least one biopsy session > or = 1 year after initial treatment. RESULTS: The safety cohort included 429 patients (71 % men, median age 59 years, median Barrett's segment 3.0 cm). There were no serious adverse events (bleeding, perforation, death), and a stricture occurred after 1.1 % of cases (2.1 % of patients). In efficacy cohort A (n = 338), CR-IM and CR-D were achieved in 72 % and 89 % of patients, respectively (median follow-up 9 months). In efficacy cohort B (n = 137), CR-IM and CR-D were achieved in 77 % and 100 % of patients, respectively (median follow-up 20 months). CONCLUSIONS: In this multicenter registry conducted at four community-based practices, the observed safety and efficacy outcomes associated with RFA for Barrett's esophagus are comparable to those previously reported in multicenter trials from predominantly tertiary academic centers.

Quantitative trait loci controlling allergen-induced airway hyperresponsiveness in inbred mice.

Identification of the genetic loci underlying asthma in humans has been hampered by variability in clinical phenotype, uncontrolled environmental influences, and genetic heterogeneity. To circumvent these complications, the genetic regulation of asthma-associated phenotypes was studied in a murine model. We characterized the strain distribution patterns for the asthma-related phenotypes airway hyperresponsiveness (AHR), lung eosinophils, and ovalbumin (OVA)-specific serum immunoglobulin (Ig) E induced by allergen exposure protocols in A/J, AKR/J, BALB/cJ, C3H/HeJ, and C57BL/6J inbred strains and in (C3H/HeJ x A/J)F1 mice. Expression of AHR differed between strains and was sometimes discordant with lung eosinophils or serum IgE. Furthermore, we identified two distinct quantitative trait loci (QTL) for susceptibility to allergen-induced AHR, Abhr1 (allergen-induced bronchial hyperresponsiveness) (lod = 4. 2) and Abhr2 (lod = 3.7), on chromosome 2 in backcross progeny from A/J and C3H/HeJ mice. In addition, a QTL on chromosome 7 was suggestive of linkage to this trait. These QTL differ from those we have previously found to control noninflammatory AHR in the same crosses. Elucidation of the genes underlying these QTL will facilitate the identification of biochemical pathways regulating AHR in animal models of asthma and may provide insights into the pathogenesis of human disease.

Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma.

The prevalence and severity of allergic asthma continue to rise, lending urgency to the search for environmental triggers and genetic substrates. Using microarray analysis of pulmonary gene expression and single nucleotide polymorphism-based genotyping, combined with quantitative trait locus analysis, we identified the gene encoding complement factor 5 (C5) as a susceptibility locus for allergen-induced airway hyperresponsiveness in a murine model of asthma. A deletion in the coding sequence of C5 leads to C5-deficiency and susceptibility. Interleukin 12 (IL-12) is able to prevent or reverse experimental allergic asthma. Blockade of the C5a receptor rendered human monocytes unable to produce IL-12, mimicking blunted IL-12 production by macrophages from C5-deficient mice and providing a mechanism for the regulation of susceptibility to asthma by C5. The role of complement in modulating susceptibility to asthma highlights the importance of immunoregulatory events at the interface of innate and adaptive immunity in disease pathogenesis.

Signal transducer and activator of transcription factor 6 (Stat6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production.

The pleiotropic cytokine interleukin 4 (IL-4) has been shown to regulate many processes thought to be important in the allergic diathesis. To determine the mechanism(s) by which IL-4 mediates allergic airway responses to inhaled allergens, we compared the effects of antigen sensitization and challenge on the development of allergic airway responses in mice in which the gene for the signal transducer and activator of transcription factor 6 (Stat6) was disrupted to those of their wild-type littermates. Strikingly, Stat6-deficient mice failed to develop airway hyperresponsiveness (AHR), which was observed in their wild-type littermates after allergen provocation. Moreover, antigen-induced increases in mucus-containing cells were found to be completely Stat6 dependent. Consistent with the lack of Th2 cytokine responses in Stat6-deficient mice, no ovalbumin-specific immunoglobulin (Ig)E was detected in their serum. In contrast, Stat6 signaling only partially mediated antigen-induced eosinophilia with no role in vascular adhesion molecule 1 expression. These results indicate that Stat6 signal transduction is critical in the development of allergen-induced AHR and that agents that specifically inhibit this pathway may provide a novel strategy for the treatment of allergic disorders.

Methamphetamine-induced hyperthermia in mice: examination of dopamine depletion and heat-shock protein induction.

Methamphetamine (METH) is a common drug of abuse and a clinical anoretic which is known to cause neurotoxicity in rodents as evidenced by a depletion of dopamine (DA) and by decreased numbers of DA uptake sites in the striatum. It is also known to cause hyperthermia which is believed to induce the production of the 72-kDa heat-shock protein (HSP-72). In the present study, we evaluated whether METH induced the production of HSP-72 in both the mouse hippocampus and striatum and also attempted to correlate this induction with monoamine depletion. Adult male C57BL/6N mice received METH (20 mg/kg, i.p.) in an ambient temperature of 27 degrees C and body temperatures were monitored up to 240 min after treatment. Animals were sacrificed 12, 18, 24, 39, and 48 h after treatment. One striatum was examined for DA, DOPAC, and HVA levels using HPLC-EC and the contralateral striatum, along with the hippocampus, was prepared for immunoblotting. HPLC-EC analysis revealed a significant depletion of DA, DOPAC, and HVA at all time points. There was, however, a significant increase in DA at 48 vs. 39 h. A biphasic production of HSP-72, in both the hippocampus and striatum, was detected by immunoblot. HSP-72 production was strong at 12 h which corresponds to neuronal induction. However, at 18 h in the striatum and 24 h in the hippocampus, the induction appears to be reduced. A second phase of HSP-72 induction occurred at 39 h in both regions. In a second experiment, mice were dosed according to the same paradigm and were perfused at 18 h after treatment for immunohistochemical analysis. HSP-72 immunoreactivity was found in neurons of the CA1 and CA4 regions of the hippocampus; however, no detectable response was evident in the striatum. In conclusion, these data demonstrate that a single injection of METH can lead to hyperthermia which may then result in both the induction of HSP-72 and depletion of DA concentration.

Myoelectric activity of the small intestine during morphine dependence and withdrawal in rats.

We investigated the effect of morphine dependence on the migrating myoelectric complex (MMC) of the small intestine, whether bacterial overgrowth developed in morphine-dependent rats, and the effect of naloxone, 0.5 mg/kg sc, and methylbromide naltrexone, 1.0 mg/kg sc, a peripheral opioid antagonist, on the MMC in morphine-naive and morphine-dependent rats. We also evaluated intestinal motility during naloxone-induced withdrawal in animals pretreated with clonidine, 100 micrograms/kg sc. Intestinal myoelectric activity was monitored by four indwelling electrodes in unanesthetized, fasted rats. D-[14C]xylose breath tests were performed before and after morphine-pellet implantation to evaluate the presence of bacterial overgrowth of the small intestine. Naloxone had no effect on myoelectric activity of the small intestine in morphine-naive rats. Cycling activity fronts were present in morphine-dependent animals, but there was a significant prolongation of activity front periodicity and slowing of the propagation velocity. No significant increase in 14CO2 excretion was noted in the morphine-dependent rats. After injection of naloxone, the morphine-dependent rats had a marked increase in spike activity with no identifiable activity fronts for 89 +/- 8 min. Similarly, methylbromide naltrexone disrupted activity fronts, but for a significantly shorter period. Clonidine prevented the marked increase in spike activity that occurred during naloxone-induced withdrawal. We conclude from our studies that myoelectric activity of the small intestine develops incomplete tolerance to morphine; bacterial overgrowth is not a feature of morphine dependence in the rat; alterations of intestinal myoelectric activity are a component of the opiate withdrawal syndrome, and they appear at least partially mediated by a peripheral mechanism that can be suppressed by an alpha 2-adrenergic agonist.