Fluvoxamine in the treatment of binge-eating disorder: a multicenter placebo-controlled, double-blind trial

OBJECTIVE: The purpose of this study was to assess the efficacy of fluvoxamine in the treatment of binge-eating disorder. Binge-eating disorder is a newly described eating disorder characterized by recurrent episodes of binge eating but without purging behaviors. Uncontrolled reports have suggested that serotonin selective reuptake inhibitors (SSRIs) may be effective in treating this disorder. METHOD: Eighty-five outpatients with a DSM-IV diagnosis of binge-eating disorder were randomly assigned to receive either fluvoxamine (N=42) or placebo (N=43) in a 9-week, parallel-group, double-blind, flexible dose (50-300 mg) study at three centers. The primary outcome measures were frequency of binge eating, expressed as log ([binges/week]+1), and Clinical Global Impression (CGI) scale ratings. Secondary measures included the level of response (based on the percentage change in frequency of binges), body mass index, and Hamilton Rating Scale for Depression score. Except for the level of response, the outcome measures were analyzed by random regression methods; the treatment-by-time interaction was the measure of treatment effect. RESULTS: Compared with placebo, fluvoxamine was associated with a significantly greater rate of reduction in the frequency of binges, rate of reduction in CGI severity scores, rate of increase in CGI improvement scores, level of response for patients who completed the 9-week study, and rate of reduction in body mass index. There was no significant difference between placebo and fluvoxamine groups in the rate of decrease in Hamilton depression scale scores. A significantly greater proportion of patients receiving fluvoxamine than those receiving placebo discontinued treatment because of an adverse medical event. CONCLUSIONS: In this placebo-controlled trial, fluvoxamine was found to be effective according to most outcome measures in the acute treatment of binge-eating disorder.     

Two dual-specific (anti-IgG and anti-dsDNA) monoclonal autoantibodies derived from the NZB/NZW F1 recognize an epitope in the hinge region

The anti-IgG properties of two dual-specific (anti-dsDNA and anti-IgG) monoclonal NZB/NZW F1-derived autoantibodies, BV 17-45 and BV 16-13, were studied to resolve the location and possible commonality of the IgG epitope. To determine if BV 17-45 and BV 16-13 recognized the same IgG epitope, the relative temperature sensitivity of the conformational IgG epitopes were evaluated using the conformational sensitive immunoassay. Comparison of the temperature sensitivity of the conformational immunoglobulin epitopes over a temperature range of 25-100 degrees C suggested that the epitope recognized by BV 17-45 was the same as the IgG epitope recognized by BV 16-13. Further studies with papain- and pepsin-generated F(ab')2, Fab, and Fc fragments of BV 17-45 and BV 16-13 revealed that the dual-specific autoantibodies BV 17-45 and BV 16-13 both bound an epitope in the hinge region of the IgG molecule. The potential correlation between these studies and the pathogenic nature of dual-specific autoantibodies is discussed.     

Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation

OBJECTIVES: The purpose of this study was the investigation of the in vivo role of lipoprotein(a) [Lp(a)] and inflammatory infiltrates in the human coronary atherosclerotic plaque and their correlation with the clinical syndrome of presentation. BACKGROUND: Lipoprotein(a) is an atherogenic and thrombogenic lipoprotein, and has been implicated in the pathogenesis of acute coronary syndromes. Lipoprotein(a) induces monocyte chemoattraction and smooth muscle cell activation in vitro. Macrophage infiltration is considered one of the mechanisms of plaque rupture. METHODS: This study of atherectomy specimens investigated the in vivo role of Lp(a) at different stages of the atherogenic process, and its relationship with macrophage infiltration. We examined coronary atheroma removed from 72 patients with stable or unstable angina. Specimens were stained with antibodies specific for Lp(a), macrophages (KP-1), and smooth muscle cells (alpha-actin). Morphometric analysis was used to quantify the plaque areas occupied by each of the three antigens, and their colocalization. RESULTS: All specimens had localized Lp(a) staining; the mean fractional area was 58.2%. Ninety percent of the macrophage areas colocalized with Lp(a) positive areas, whereas 31.3% of the smooth muscle cell areas colocalized with Lp(a) positive areas. Patients with unstable angina (n = 46) had specimens with larger mean plaque Lp(a) areas than specimens from stable angina patients (n = 26): 64.4% versus 47.7% (p = 0.004). Unstable angina patients with rest pain (n = 28) had greater mean plaque Lp(a) area than unstable angina patients with crescendo exertional pain (n = 18): 71.1% versus 52.4% (p < 0.001). Mean KP-1 area was 31.2% in unstable rest angina versus 18.3% in stable angina (p = 0.05); alpha-actin area was greater in stable (48.5%) and crescendo exertional angina (48.8%) than in rest angina (30.4%). The strongest correlation between plaque KP-1 and Lp(a) area was in unstable rest angina (r = 0.88, p < 0.001), and between alpha-actin and Lp(a) areas in the crescendo exertional angina (r = 0.62, p < 0.01). CONCLUSIONS: Lipoprotein(a) is ubiquitous in human coronary atheroma. It is detected in larger amounts in tissue from culprit lesions in patients with unstable compared to stable syndromes, and has significant colocalization with plaque macrophages. A correlation of plaque alpha-actin and Lp(a) area suggests a role of Lp(a) in plaque growth.     

The granaticin biosynthetic gene cluster of Streptomyces violaceoruber Tü22: sequence analysis and expression in a heterologous host

BACKGROUND: The granaticins are members of the benzoisochromanequinone class of aromatic polyketides, the best known member of which is actinorhodin made by Streptomyces coelicolor A3(2). Genetic analysis of this class of compounds has played a major role in the development of hypotheses about the way in which aromatic polyketide synthases (PKSs) control product structure. Although the granaticin nascent polyketide is identical to that of actinorhodin, post-PKS steps involve different pyran-ring stereochemistry and glycosylation. Comparison of the complete gene clusters for the two metabolites is therefore of great interest. RESULTS: The entire granaticin gene cluster (the gra cluster) from Streptomyces violaceoruber T-22 was cloned on either of two overlapping cosmids and expressed in the heterologous host, Streptomyces coelicolor A3(2), strain CH999. Chemical analysis of the recombinant strains demonstrated production of granaticin, granaticin B, dihydrogranaticin and dihydrogranaticin B, which are the four known metabolites of S. violaceoruber. Analysis of the complete 39,250 base pair sequence of the insert of one of the cosmids, pOJ466-22-24, revealed 37 complete open reading frames (ORFs), 15 of which resemble ORFs from the act (actinorhodin) gene cluster of S. coelicolor A3(2). Among the rest, nine resemble ORFs potentially involved in deoxysugar metabolism from Streptomyces spp. and other bacteria, and six resemble regulatory ORFs. CONCLUSIONS: On the basis of these resemblances, putative functional assignments of the products of most of the newly discovered ORFs were made, including those of genes involved in the PKS and tailoring steps in the biosynthesis of the granaticin aglycone, steps in the deoxy sugar pathway, and putative regulatory and export functions.     

Interruption of a transforming growth factor alpha autocrine loop in Caco-2 cells by antisense oligodeoxynucleotides

BACKGROUND & AIMS: We have previously shown that Caco-2 cell proliferation is driven by basolateral membrane epidermal growth factor receptors. The aim of this study was to investigate whether autocrine production of transforming growth factor alpha (TGF-alpha) activates these receptors and stimulates proliferation using antisense oligodeoxynucleotides. METHODS: Caco-2 cells grown on microporous membranes or Jurkat cells were exposed to conventional or 5' cholesterol-modified oligodeoxynucleotides synthesized with random, antisense, or missense base sequences. Indices of proliferation were measured, including [3H]thymidine or [3H]uridine uptake for studies of short-term stimulation and the methylthiotetrazole assay as an index of cell number increase over longer periods. Secretion of TGF-alpha by cells was detected using a soft agar bioassay. RESULTS: Incubation with antisense oligodeoxynucleotides inhibited TGF-alpha secretion compared with controls. Random and missense oligodeoxynucleotides had no effect on proliferation. The TGF-alpha antisense oligodeoxynucleotides markedly inhibited proliferation, an effect that was abolished by adding TGF-alpha to the medium. Oligonucleotides had no effect on Jurkat cells, a lymphocytic cell line lacking epidermal growth factor receptors. Cholesterol-modified oligodeoxynucleotides were more effective and specific than unmodified oligodeoxynucleotides. CONCLUSIONS: Caco-2 cell proliferation is driven by autocrine stimulation of epidermal growth factor receptors by TGF-alpha. This mechanism may be effectively inhibited by antisense oligodeoxynucleotides, particularly those modified by the 5' attachment of cholesterol.     

Stability of traffic patterns in broadband networks

The control of telephony traffic is the task of network management and routing algorithms. In this paper, a study of two trunk groups carrying telephony traffic is used to show that instabilities can arise if there is a delay in getting feedback information for a network controller. The network controller seeks to balance the traffic in the two trunk groups, which may represent two paths from a source to a destination. An analysis shows how factors such as holding time, controller gain and feedback delay influence stability. Simulation of a two service case is also carried out to show that the same instabilities can arise.