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Biomedical subjects

E Schweizer

Publications and source records attributed to E Schweizer.

At least 55 records · Page 3Linked to original sources
PubMed1996

The long-term management of generalized anxiety disorder: issues and dilemmas.

Accumulating evidence suggests that a large proportion of patients diagnosed with generalized anxiety disorder suffer from a chronic or recurrent condition that is associated with a moderate amount of disability and impairment in quality of life. Acute drug therapy is well studied and appears to be highly effective in providing symptom relief, but relapse/recurrence is high. Little research has been reported that identifies predictors of recurrence or studies the clinical parameters of maintenance drug therapy, including benefit-risk assessments or optimal doses or durations of treatment.

Anti-Anxiety Agents↗
PubMed1996

[Significant value and therapeutic implications of routine gastroscopy before cholecystectomy].

Endoscopy of the upper digestive tract was performed in 338 consecutive patients undergoing cholecystectomy between January 1991 and December 1992. Pathological findings were seen in 160 (47.3%), 6.8% of the patients had peptic ulcers, 1.8% gastric erosions, 25.7% gastritis, 3.2% polyps, 4.7% hiatal hernias, 3.0% oesophagitis and 0.6% gastric cancer. In most patients the gastroscopic results did not correlate with the clinical symptoms. The therapy concept had to be changed in 8.3% of the patients due to gastroscopic findings, 23 patients with ulcers, 2 with erosions and 1 with oesophagitis had to be treated medically and so the cholecystectomy was postponed. Two patients with gastric cancer underwent gastrectomy. These results underline the importance of a routine gastroscopy before elective cholecystectomy.

Adolescent↗
PubMed1996

[Fatty acid synthases--strategic functions of multienzymes].

Several decades of biochemical research have led to our present detailed knowledge on cellular metabolism, is wealth of individual reactions, enzymes, and pathways, and their organization, interplay, and regulation. Although most metabolic reactions are simultaneous and occur in the same cell, they may also act independently of one other and without causing disturbing interferences. This demonstrates that the cellular interior is organized structurally and functionally and is not simply a "bag of enzymes." This organization ranges from distinct and functionally specialized organelles down to subtle or even hypothetical structures at the molecular level. The lowest level of structurally stable, supramolecular catalytic entities in the cell thus for known is that of the multienzyme complexes. Among the limited number of known multi-enzymes, fatty acid synthase is certainly one of the most complex and also best studied. Various structural and functional variants of this multienzyme system are known. These may be discussed in terms of specific requirements of the respective organisms.

Acyl Coenzyme A↗
PubMed1995

DNA binding site of the yeast heteromeric Ino2p/Ino4p basic helix-loop-helix transcription factor: structural requirements as defined by saturation mutagenesis.

The inositol/choline-responsive element (ICRE) is an 11 bp cis-activating sequence motif with central importance for the regulated expression of phospholipid biosynthetic genes in the yeast Saccharomyces cerevisiae. The ICRE containing the CANNTG core binding sequence (E-box) of basic helix-loop-helix (bHLH) regulatory proteins is recognized by the heteromeric bHLH transcription factor Ino2p/Ino4p. In this study, we define the Ino2p/Ino4p consensus binding sequence (5'-WYTTCAYR-TGS-3') based on the characterization of all possible single nucleotide substitutions. Interestingly, this analysis also identified a single functional deviation (CACATTC) from the CANNTG core recognition element of bHLH proteins. The DNA binding specificities of different yeast bHLH proteins may now be explained by distinct nucleotide preferences especially at two positions immediately preceding the CANNTG core motif.

Base Sequence↗
PubMed1995

Substrate and product binding sites of yeast fatty acid synthase. Stoichiometry and binding kinetics of wild-type and in vitro mutated enzymes.

The four known substrate binding sites of yeast fatty acid synthase (FAS), Ser819 (acetyltransferase, OHAC) and Ser5421 (malonyl/palmitoyl transferase, OHMa1) of subunit beta and Ser180 (pantetheine binding site, SHc) and Cys1305 (3-oxoacyl synthase, SHp) of subunit alpha were replaced, by targeted in vitro mutagenesis, by the non-acylatable amino acids glutamine, glycine or alanine. The four mutated FAS proteins together with two pairs of double mutants (OHAc/OHMa1 and SHc/SHp) were episomally expressed in appropriate delta fas1 or delta fas2 deletion strains. The purified enzymes isolated from these transformants were used for comparative acyl binding studies with the substrates [1-14C]acetyl-CoA and [2-14C]malonyl-CoA. Malonate was found to be transacylated to enzyme-bound pantetheine (SHc) exclusively by the Ser5421 hydroxyl group of malonyltransferase (OHMa1) while acetate could use both the acetyl (Ser819) and the malonyl (Ser5421) transferase active sites on its way to the SHc and SHp binding sites. Acylation of SHc with either substrate was unaffected by the absence of the 'peripheral' SH group (SHp) while binding of acetate to SHp was dependent on enzyme-bound pantetheine (SHc). These genetic data support a revised model regarding the intra-molecular channeling of acetate and malonate within yeast fatty acid synthase. Quantitative acyl binding studies revealed a maximum of 2-3 mol rather than the expected 12 mol of malonate and of 6-7 mol rather than 24 mol of acetate bound/mol hexameric yeast FAS. Only 20-30% of the malonyl-enzyme and 35-50% of the acetyl enzyme represented performic-acid-labile thioester bonds. The binding characteristics of both substrates, exhibiting Hill coefficients distinctly lower than 1, as well as their non-linear Lineweaver-Burk and Scatchard plots, point to a marked negative cooperativity among the 12 yeast FAS subunits. The observed sub-stoichiometric substrate binding characteristics of the enzyme are ascribed to this effect. An a priori asymmetry of the complex appears unlikely since the coenzyme-A:FAS transacylation equilibrium may be shifted towards the fully acetylated enzyme in the presence of N-ethylmaleimide. In contrast to the limited acylation capacity of the 'resting' enzyme, complete acylation of yeast FAS at all of its 12 SHc and SHp sites is observed under steady-state conditions of fatty acid biosynthesis. Under these conditions, the enzyme exhibits full-site reactivity at its SHp, SHc and OHAc sites, but a concomitant 18-fold increase in Km of the coenzyme-A:OHAc transacylation reaction keeps the acyl-O-ester content of the acylated enzyme at less than 5% of the total.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1995

Yeast transcriptional activator INO2 interacts as an Ino2p/Ino4p basic helix-loop-helix heteromeric complex with the inositol/choline-responsive element necessary for expression of phospholipid biosynthetic genes in Saccharomyces cerevisiae.

Coordinate transcriptional control of yeast genes involved in phospholipid biosynthesis is mediated by the inositol/choline-responsive element (ICRE) contained in the respective promoter regions. Regulatory genes INO2 and INO4, both encoding basic helix-loop-helix (bHLH) proteins, are necessary for ICRE-dependent gene activation. By the use of size variants and by heterologous expression in E. coli we demonstrate that Ino2p and Ino4p are both necessary and sufficient for the formation of the previously described FAS binding factor 1, Fbf1, interacting with the ICRE. Formation of a heteromeric complex between Ino2p and Ino4p by means of the respective bHLH domains was demonstrated in vivo by the interaction of appropriate two-hybrid constructs and in vitro by Far-Western analyses. Neither Ino2p nor Ino4p binds to the ICRE as a homodimer. When fused to the DNA-binding domain of Gal4p, Ino2p but not Ino4p was able to activate a UASGAL-containing reporter gene even in the absence of the heterologous Fbf1 subunit. By deletion studies, two separate transcriptional activation domains were identified in the N-terminal part of Ino2p. Thus, the bHLH domains of Ino2p and Ino4p constitute the dimerization/DNA-binding module of Fbf1 mediating its interaction with the ICRE, while transcriptional activation is effected exclusively by Ino2p.

Basic Helix-Loop-Helix Proteins↗
PubMed1995

Progesterone co-administration in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal severity and taper outcome.

Since recent research has suggested that the major metabolites of progesterone are barbiturate-like modulators of GABAergic function, we undertook a pilot study of the efficacy of micronized progesterone in attenuating withdrawal and facilitating discontinuation in benzodiazepine-dependent patients with a minimum of 1 year of continuous daily use. Forty-three patients taking a mean daily dose of 16.2 mg of diazepam (or its equivalent) were assigned, doubleblind, to treatment with either placebo (n = 13) or progesterone (n = 30). Progesterone was titrated to a mean daily dose of 1983 mg, and was co-administered for 3 weeks, after which the benzodiazepine was tapered by 25% per week. Progesterone (or placebo) was then continued for 4 weeks before being discontinued. There was no progesterone versus placebo difference in the severity of taper withdrawal. Withdrawal checklist change scores were 17.3 for progesterone and 16.5 for placebo (F 0.63; df 2.31; n.s.), and the Hamilton rating scale for anxiety change scores were 7.8 for progesterone and 6.3 for placebo (F 0.22; df 2.30; n.s.). There was no difference in ability to remain drug-free at 12 weeks post-taper, with 57% of progesterone-treated patients, and 58% of placebo-treated patients having a successful outcome.

Adult↗
PubMed1995

Relationships between age and symptom severity among women seeking medical treatment for premenstrual symptoms.

Age at the time of seeking treatment for premenstrual symptoms (PMS) was examined in a sample of 332 women who reported severe distress and met criteria for Late Luteal Phase Dysphoric Disorder (LLPDD). The mean age of the sample was 33.1 (+/- 5.3) years. Severity of symptoms decreased with age and was not associated with the duration of symptoms. Depression-related factors were associated with the severity of PMS, and together with the duration of symptoms, were the best discriminators between the younger (ages 20-35) and older (ages 36-44) women in this sample. These data suggest that the years of the late twenties through mid-thirties are the most vulnerable time for distressing PMS and fail to support the clinical premise that PMS worsens with age until menopause. Further longitudinal study should be conducted to confirm and extend these findings.

Adult↗
PubMed1995

A double-blind, placebo-controlled study of a CCK-B receptor antagonist, CI-988, in patients with generalized anxiety disorder.

This multicenter, double-blind, placebo-controlled, parallel-group, randomized study assessed the efficacy, safety, and tolerability of a novel CCK-B antagonist CI-988 in the treatment of generalized anxiety disorder (GAD). Patients received placebo or CI-988 (300 mg/day, thrice daily) for 4 weeks. Patients with a primary diagnosis of GAD according to DSM-III-R criteria were randomized. The study design included a 1- to 2-week single-blind placebo baseline phase, followed by a 4-week double-blind treatment phase. Efficacy was measured weekly by Hamilton Rating Scale for Anxiety (HAM-A), Clinical Global Impressions of Severity and Change, UCLA-Multi Dimensional Anxiety Scale, and Hamilton Rating Scale for Depression. Patients were also evaluated to determine whether they met criteria for irritable bowel syndrome (IBS) at screening and were evaluated with a gastrointestinal visual analog scale at each visit. Eighty-eight patients were randomized to CI-988 (N = 45) and placebo (N = 43) at three centers. CI-988 did not demonstrate an anxiolytic effect superior to placebo in this clinical trial. There was no significant difference in mean change in HAM-A total between placebo (-7.73) and CI-988 (-8.64). However, a significant treatment-by-center interaction and a highly variable placebo response rate among the three centers limit the interpretation of the results. CI-988 did not have an effect on symptoms of IBS other than diarrhea, which worsened in patients with IBS. Other than a higher incidence of some gastrointestinal symptoms (diarrhea, dyspepsia, flatulence, and nausea), CI-988 was well tolerated. Results suggest that testing higher oral doses of CI-988 may be warranted.

Adult↗
PubMed1995

Placebo-controlled comparison of the clinical effects of rapid discontinuation of ipsapirone and lorazepam after 8 weeks of treatment for generalized anxiety disorder.

One hundred and sixty patients (mean age 39.8 years; 67% female) diagnosed with generalized anxiety disorder (GAD) who had completed a prospective, 8 week, double-blind comparison of lorazepam (mean daily dose 4.2 mg) and ipsapirone (mean daily dose 19.5 mg) were rapidly tapered by a substitution of half-strength medication for 3 days, then substitution of matched placebo for an additional 11 days. Patients treated with ipsapirone showed no rebound anxiety on discontinuation, nor any other significant increase in withdrawal symptomatology compared to patients who had been prospectively treated with placebo. In contrast, patients treated with lorazepam showed significant emergent anxiety and/or withdrawal-related symptomatology by almost all clinical measures employed. Overall, 25% of patients treated with lorazepam showed rebound anxiety, and 40% of them utilized reserve medication because they found drug discontinuation to be intolerable. The clinical implications for discontinuation of benzodiazepines after short-term therapy are discussed.

Adult↗
PubMed1995

Expression of a functional fungal polyketide synthase in the bacterium Streptomyces coelicolor A3(2).

The multifunctional 6-methylsalicylic acid synthase gene from Penicillium patulum was engineered for regulated expression in Streptomyces coelicolor. Production of significant amounts of 6-methylsalicylic acid by the recombinant strain was proven by nuclear magnetic resonance spectroscopy. These results suggest that it is possible to harness the molecular diversity of eukaryotic polyketide pathways by heterologous expression of biosynthetic genes in an easily manipulated model bacterial host in which prokaryotic aromatic and modular polyketide synthase genes are already expressed and recombined.

Amino Acid Sequence↗
PubMed1995

Nefazodone: aspects of efficacy.

BACKGROUND: Nefazodone hydrochloride, a 5-HT2 receptor antagonist and serotonin (5-HT) uptake inhibitor, was evaluated in four Phase 3 double-blind, imipramine- and placebo-controlled studies involving outpatients with major depression. METHOD: Patients who qualified for well-controlled efficacy trials in major depression were enrolled in a series of active- and placebo-controlled trials to establish the comparative efficacy of nefazodone and a standard tricyclic antidepressant drug. The primary efficacy measures employed were the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and the Clinical Global Improvement (CGI) scale. Safety profiles were also compared as well as survival analyses of double-blind acute and continuation treatment of patients in efficacy trials. RESULTS: Three of four Phase 3 active- and placebo-controlled studies showed nefazodone to be an effective antidepressant drug with overall efficacy generally similar to that of imipramine. The remaining study did not differentiate either active drug from placebo controls. Superiority of nefazodone and imipramine over placebo was evidenced by greater improvement on core depression symptoms in addition to the primary outcome measures (HAM-D-17 and CGI). The incidence of side effects and premature treatment discontinuations for imipramine-treated patients was higher than for nefazodone therapy. Both drugs showed evidence of continuing efficacy during long-term treatment with significantly fewer dropouts (p < .05) than for placebo controls. CONCLUSION: Nefazodone, an antidepressant that modulates serotonin receptors and enhances serotonin-mediated neurotransmission, has been shown to be an effective and well-tolerated new antidepressant drug with greater patient acceptability and safety than imipramine.

Ambulatory Care↗
PubMed1995

Generalized anxiety disorder. Longitudinal course and pharmacologic treatment.

GAD generally is a fairly prevalent disorder occurring at a rate (even in its "pure" form) that equals or exceeds the other anxiety disorders such as panic disorder and social phobia. GAD tends to have an early age of onset and tends to exhibit a high degree of chronicity that frequently is complicated by comorbidity with other anxiety disorders as well as by depression and other Axis I and II disorders. The pharmacologic treatment of GAD should be conceptualized from the first day of treatment in terms of the long-term nature of the illness, in much the same way that treatment of affective disorders is now conceptualized. And yet an enormous amount of research remains to be done, as we know very little from controlled studies about how to optimize maintenance treatment of this relatively neglected disorder.

Anti-Anxiety Agents↗
PubMed1994

Importance of general regulatory factors Rap1p, Abf1p and Reb1p for the activation of yeast fatty acid synthase genes FAS1 and FAS2.

The fatty acid synthase genes FAS1 and FAS2 of the yeast Saccharomyces cerevisiae are under transcriptional control of pathway-specific regulators of phospholipid biosynthesis. However, site-directed mutagenesis of the respective cis-acting elements upstream of FAS1 and FAS2 revealed that additional sequences activating both genes must exist. A deletion analysis of the FAS1 promoter lacking the previously characterized inositol/choline-responsive-element motif defined a region (nucleotides -760 to -850) responsible for most of the remaining activation potency. Gel-retardation experiments and in-vitro DNase footprint studies proved the binding of the general regulatory factors Rap1p, Abf1p and Reb1p to this FAS1 upstream region. Mutation of the respective binding sites led to a drop of gene activation to 8% of the wild-type level. Similarly, we also demonstrated the presence of a Reb1p-binding site upstream of FAS2 and its importance for gene activation. Thus, in addition to the previously characterized FAS-binding factor 1 interacting with the inositol/choline-responsive-element motif, a second motif common to the promoter regions of both FAS genes could be identified. Transcription of yeast fatty acid synthase genes is therefore subjected to both the pathway-specific control affecting genes of phospholipid biosynthesis and to the activation by general transcription factors allowing a sufficiently high level of constitutive gene expression.

Base Sequence↗