Functional Dyspepsia Treatment Trial (FDTT): a double-blind, randomized, placebo-controlled trial of antidepressants in functional dyspepsia, evaluating symptoms, psychopathology, pathophysiology and pharmacogenetics

BACKGROUND: Functional dyspepsia (FD) is a common problem affecting up to 10-25% of individuals. FD accounts for significant health care costs and affects quality of life but has no definitive treatment. OBJECTIVES: The Functional Dyspepsia Treatment Trial (FDTT) aims to test whether treatment with an antidepressant (amitriptyline or escitalopram) leads to improvement of symptoms in patients with moderate to severe FD. DESIGN: The FDTT is an international multicenter, parallel group, randomized, double-blind, placebo-controlled trial to evaluate whether 12 weeks of treatment with escitalopram or amitriptyline improves FD symptoms compared to treatment with placebo. Secondly, it is hypothesized that acceleration of solid gastric emptying, reduction of postprandial satiation, and enhanced gastric volume change with a meal will be significant positive predictors of short- and long-term outcomes for those on antidepressants vs. placebo. The third aim is to examine whether polymorphisms of GNβ3 and serotonin reuptake transporter influence treatment outcomes in FD patients receiving a tricyclic antidepressant, selective serotonin reuptake inhibitor therapy, or placebo. METHODS: The FDTT enrollment began in 2006 and is scheduled to randomize 400 patients by the end of 2012 to receive an antidepressant or placebo for 12 weeks, with a 6-month post-treatment follow-up. The study incorporates multiple validated questionnaires, physiological testing, and specific genetic evaluations. The protocol was approved by participating centers' Institutional Review Boards and an independent Data Safety Monitoring Board was established for monitoring to ensure patient safety and a single interim review of the data in December 2010 (ClinicalTrials.gov number NCT00248651).     

Differential cytotoxic response in keloid fibroblasts exposed to photodynamic therapy is dependent on photosensitiser precursor, fluence and location of fibroblasts within the lesion

Treatment of keloid disease (KD) is ill-defined and remains challenging. We previously reported successful clinical application of photodynamic therapy (PDT) in KD. The aim here was to evaluate cytotoxic effect of PDT using methyl aminolevulinate (M-ALA) and 5-aminolevulinic acid (5-ALA) on keloid fibroblasts (KF) (n?=?8) from different lesional sites (top, middle and margin) as compared to normal skin fibroblasts (n?=?3). The effect of protoporphyrin IX (PpIX) precursors was evaluated by fluorescence emission, LDH and WST-1 assay, reactive oxygen species (ROS) generation and qRT-PCR analysis. Apoptosis/necrosis differentiation and senescence were studied by fluorometric staining with Hoechst 33258/propidium iodide and β-galactosidase activity, respectively. Three hours post incubation with 4?mM precursors of photosensitisers, PpIX accumulation was site specific and higher with M-ALA. Cytotoxicity was also site specific (higher in fibroblasts from middle of the keloid as compared to cells from other sites) and increased proportionately to fluence rates post-PDT. Additionally, cytoproliferation was significantly decreased post-PDT depending on the light energy. Fluorescence analysis revealed that M-ALA instigated higher KF cytotoxicity at lower fluence (≤20?J/cm(2)) while 5-ALA instigated higher KF cytotoxicity at higher fluence, except in cells derived from middle of the keloid. ROS-mediated cytotoxicity was light energy dependent. Senescence was not observed at higher light energies (>10?J/cm(2)). Compared to other sites, fibroblasts from the middle were more prone to cell death post 5-ALA treatment. We conclude that cytotoxicity post-PDT in KD fibroblasts is dependent on the lesional site, precursor of intracellular photosensitiser and fluence. Thus, PDT may be used for site-targeted therapy of KD.     

Predicting bacteremic pneumonia in HIV-1–infected patients consulting the ED

Introduction

HIV-1–infected patients have higher incidence of community-acquired pneumonia (CAP) and risk of complications. Bacteremia has been associated with a higher risk of complications in such patients. We investigated factors associated with bacteremia in HIV-1–infected patients with CAP presenting at the emergency department.

Methods

We included HIV-1–infected patients with CAP for 3 years (March 2005-February 2008). Only patients in whom blood cultures were performed were finally included. Clinical data (age; sex; CD4⁺ count; serum HIV viral load; previous or current intravenous drug use and antiretroviral treatment; systolic blood pressure; and cardiac and respiratory rates), analytical data (leukocyte count, arterial oxygen content, C-reactive protein value, and urgent Streptococcus pneumoniae and Legionella spp antigen urine detection), and APACHE-II (Acute Physiology and Chronic Health Evaluation) score were compiled. The need for intensive care unit admission, mechanical ventilation, mortality, and for patients finally discharged, duration of admission were retrospectively obtained from the clinical history. A multivariate analysis using logistic regression was performed to find independent predictors of bacteremia.

Results

We diagnosed 129 HIV-1–infected patients with CAP. Blood cultures were performed in 118 cases (91%). Bacteremia was present in 28 (24%). Independent predictors of bacteremia were the detection of S pneumoniae antigen in urine (odds ratio, 9.0; 95% confidence interval, 1.9-42.0) and the absence of current antiretroviral treatment (odds ratio, 7.1; 95% confidence interval, 1.4-33.3). In-hospital mortality was higher in patients with bacteremia (15% vs 0%).

Conclusion

HIV-1–infected patients with CAP who are not on current antiretroviral therapy and have positive S pneumoniae antigenuria are at increased risk of having bacteremia. Bacteremic patients have a poor outcome.     

Impact of positive hepatitis B surface antigen on the outcome of IVF treatment

There has been controversy about the effect of hepatitis B virus (HBV) infection on pregnancy outcome after IVF treatment. A total of 1676 couples undergoing their first IVF cycle were included in this study. The prevalence of HBV infection in the female partners of the subfertile population seeking treatment with assisted reproductive technology was 7.8-9.6% during the study period. The ongoing pregnancy rate was not significantly different between couples with HBV-seropositive wives and seronegative ones (26.7% versus 30.2%). The ongoing pregnancy rate and the live-birth rate of couples with both partners being HBV surface antigen positive was not significantly different from couples with discordant HBV serostatus and those couples with both partners being HBV surface antigen negative (23% versus 29% versus 30%, respectively; 23% versus 27% versus 27%, respectively). The percentage of normal sperm morphology in HBV-seropositive husbands was significantly lower than that of seronegative counterparts (5.0% versus 10.0%, P=0.009). In conclusion, there was no adverse effect of HBV infection on the assisted reproduction outcomes. This study was the first report on the live-birth rate of hepatitis B (HBV) seropositive couples, revealing the effect on the pregnancy outcome of IVF. The prevalence of HBV infection in the female partners of subfertile population seeking treatment with ART was 7.8-9.6%. Both the ongoing pregnancy rate and live-birth rate were not significantly different among couples with both partners being positive for HBV surface antigen, couples with discordant HBV serostatus and those couples with both partners being negative for HBV surface antigen. The percentage of normal sperm morphology in HBV-seropositive husbands was significantly lower than that of seronegative counterparts.     

Detection of residual wall motion after myocardial infarction by gated technetium-99m tetrofosmin SPET: a comparison with contrast ventriculography

The differentiation of residual viability from necrotic myocardium in patients with a prior myocardial infarction is important when deciding whether revascularization is indicated. Myocardial viability can be assessed by studying perfusion and regional wall motion. Gated single-photon emission tomography (SPET) imaging allows the simultaneous assessment of perfusion and function through a single study. The aim of this study was to analyse the concordance between wall motion score derived by gated SPET and by contrast ventriculography. Furthermore, the agreement between myocardial perfusion and regional myocardial wall motion was analysed for both techniques. We studied a homogeneous group of 26 consecutive patients with a prior myocardial infarction, using both gated technetium-99m tetrofosmin SPET and contrast ventriculography. A seven-segment model of the left ventricle was employed to score regional myocardial wall motion on images obtained with gated SPET and contrast ventriculography using a four-point scale. Contrast ventriculography was performed within 2 weeks of the gated SPET study. Prevalence of abnormal wall motion (akinetic or dyskinetic) was 24/182 (13%) for gated SPET and 25/182 (14%) for contrast ventriculography (P=NS). There was a high agreement (80%) in wall motion score between gated SPET and contrast ventriculography (3=0.67, P<0.001). The agreement was better in segments with normal or mild to moderate hypoperfusion (82%, 3=0.69) than in those with severe hypoperfusion (67%, 3=0.56). The agreement between myocardial perfusion and myocardial wall motion was 89% (162/182), 3=0.57, for gated SPET and 80% (145/182), 3=0.21, for contrast ventriculography. The relation between the summed wall motion scores per patient on gated SPET and contrast ventriculography was excellent (y=0.81x+2.9, r=0.82, P<0.01). Thirteen (43%) out of 30 segments with severely diminished or no myocardial perfusion showed normal or hypokinetic wall motion on gated SPET, suggesting residual myocardial viability in malperfused regions. Our results suggest that gated SPET imaging is a reliable tool for the assessment of regional wall motion in post-myocardial infarction patients. Furthermore, in patients with a previous myocardial infarction, gated SPET imaging has the potential to detect preserved wall motion in regions with fixed perfusion defects, which might be indicative of residual myocardial viability.