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Biomedical subjects

E Schweizer

Publications and source records attributed to E Schweizer.

At least 91 records · Page 5Linked to original sources
PubMed1992

Coordinate genetic control of yeast fatty acid synthase genes FAS1 and FAS2 by an upstream activation site common to genes involved in membrane lipid biosynthesis.

A systematic search for upstream controlling elements necessary for efficient expression of the yeast fatty acid synthase genes FAS1 and FAS2 revealed identical activation sites, UASFAS, in front of both FAS genes. The individual element confers, in a heterologous yeast test system, an approximately 40-fold stimulation of basal gene expression. The UASFAS motifs identified have the consensus sequence TYTTCACATGY and function in either orientation. The same sequence motif is found in the upstream regions of all so far characterized yeast genes encoding enzymes of phospholipid biosynthesis. In gel retardation assays, a protein factor, Fbf1 (FAS binding factor), was identified which interacted with UASFAS. The UASFAS motif proved to be an inositol/choline responsive element (ICRE) conferring strict repression by exogenous inositol and choline on a heterologous reporter gene. Its core sequence perfectly matches the CANNTG motif typical of basic helix-loop-helix DNA-binding proteins. In contrast to the individual UASFAS element, the intact yeast FAS promoters are not significantly influenced by inositol and choline, and thus allow nearly constitutive fatty acid synthase production. Available evidence suggests that additional cis- and trans-acting elements, other than UASFAS and Fbf1, are involved in this constitutive FAS gene expression.

Base Sequence↗
PubMed1992

Molecular structure of the multifunctional fatty acid synthetase gene of Brevibacterium ammoniagenes: its sequence of catalytic domains is formally consistent with a head-to-tail fusion of the two yeast genes FAS1 and FAS2.

The Brevibacterium ammoniagenes fatty acid synthetase (FAS) gene was isolated from a series of overlapping clones by both immunological and plaque hybridization screening of two independent gene libraries. From the isolated DNA a contiguous segment of 10,549 bp was sequenced in both directions. The sequenced DNA contained a very long (9312 nucleotides) open reading frame coding for a protein of 3104 amino acids and with a molecular mass of 327,466 daltons. Based on characteristic sequence motifs known from other FAS systems, seven different FAS active centres were identified at distinct locations within the polypeptide chain. Only one component enzyme, the 3-hydroxydecanoyl beta, gamma-dehydratase, has not yet been localized definitively within the gene. Translation is presumed to start from a GUG triplet located 25 nucleotides downstream of the transcriptional initiation site. There is a canonical Shine-Dalgarno sequence just before this start codon. Comparison of the B. ammoniagenes FAS sequence with those of other known fatty acid synthetases revealed a particularly high degree of similarity to the products of the two yeast genes, FAS1 and FAS2 (30% identical and 46% identical plus closely related amino acids). This similarity extends over the entire length of the genes and involves not only the primary sequences of individual component enzymes but also their sequential order within the multifunctional proteins. These data, together with those on the structure of other fatty acid synthetases, are interpreted in terms of a contribution of both primary structure and subunit cooperation to a conserved topology of functional domains common to all type I FAS complexes.

Amino Acid Sequence↗
PubMed1992

An yeast nuclear mutation conferring temperature-sensitivity to the mitochondrial tryptophanyl-tRNA synthetase.

The conditional respiratory-deficient Saccharomyces cerevisiae mutant pet-ts2281 was complemented by an yeast genomic DNA library. The gene thus isolated was sequenced and proved to be identical to the known MSW1 sequence encoding mitochondrial tryptophanyl-tRNA synthetase (Myers and Tzagoloff 1985). Compared to the wild-type, the ts2281 mutant allele of MSW1 contained a single T----C transition leading to a Leu----Ser replacement at position 294 of the protein sequence. In addition to this mutational alteration, our sequence data for the wild-type gene differ from the originally published MSW1 sequence at five other DNA positions which affect two locally restricted regions of the polypeptide chain. As expected, at the non-permissive temperature ts2281 cells are specifically defective in mitochondrial trp-tRNA formation and, thus, in overall mitochondrial protein synthesis. In addition, the patterns of cytochrome b mRNA maturation intermediates were distinctly different in ts2281 and wild-type yeast cells. The mutational effect of the observed amino-acid substitution in ts2281 is discussed in terms of weakened hydrogen bonding in the C-terminal half of the MSW1-encoded protein.

Amino Acid Sequence↗
PubMed1992

Psychiatric inpatients' knowledge of medication at hospital discharge.

Results of a survey of 253 psychiatric inpatients on the day of discharge from a short-stay hospitalization indicated that more than half did not know the name and dosage of the psychiatric medications prescribed for them and why they were taking them, even though they had received both group and individual medication instruction during hospitalization. Sixty-eight percent of the patients knew the names of all their psychiatric medications, but only 53 percent knew when to take them. Sixty-three percent felt that they had some understanding of why the medications were prescribed, while 37 percent said they did not know. Younger, better-educated patients who had an affective illness (as opposed to schizophrenia) were more likely to have adequate knowledge of their medication regimen. Results suggest the need for more active forms of medication education, such as supervised self-administration in the final days of hospitalization.

Adolescent↗
PubMed1992

The efficacy and safety of paroxetine compared with placebo in outpatients with major depression.

Paroxetine, a phenylpiperidine derivative, is an antidepressant that selectively inhibits serotonin reuptake. In this study 111 outpatients with major depression diagnosed by DSM-III criteria were treated with either paroxetine or placebo in a 6-week, randomized, double-blind study. Paroxetine was significantly superior to placebo on six of the seven major efficacy variables. Significant differences in favor of paroxetine were apparent by Week 2. Paroxetine was also well tolerated. These results support the efficacy and safety of paroxetine as a treatment for patients with major depression.

Adult↗
PubMed1992

The use of low-dose intranasal midazolam to treat panic disorder: a pilot study.

BACKGROUND: Drug therapy of panic disorder, despite the intermittent nature of the panic attack, requires daily administration of antidepressants, which are often not tolerated, or benzodiazepines, which can result in physical dependence and withdrawal. The use of rapidly acting, low-dose intranasal midazolam to prevent incipient panic suggested itself to us as a novel alternative treatment strategy. METHOD: We conducted a 6-week double-blind, placebo-controlled, crossover-design pilot study of the safety and efficacy of p.r.n. low-dose intranasal midazolam in five patients diagnosed with DSM-III-R panic disorder. RESULTS: One to two drops of midazolam (approximately 0.25 to 0.5 mg) was well tolerated and highly effective in preventing incipient panic attacks and in reducing the overall weekly frequency of attacks. CONCLUSION: Intermittent intranasal midazolam shows promise as a novel alternative treatment for panic, but a controlled study of its efficacy and safety (including abuse potential) must be conducted.

Administration, Intranasal↗
PubMed1991

Isolation of a novel type-I fatty-acid synthetase from Euglena gracilis. Specific derepression in streptomycin-bleached cells.

A novel, high-molecular-mass fatty-acid synthetase (FAS) complex has been isolated from streptomycin-bleached Euglena gracilis cells. The enzyme was purified 250-fold from the crude cell homogenate and subsequently migrated upon SDS/PAGE as a single band of molecular mass 270 kDa. This apparent subunit size of the purified protein contrasted with a smaller size of only 200 kDa which was exhibited by the same protein upon immunoblotting of the crude cell extract. The purified Euglena FAS complex cosediments in a sucrose density gradient with yeast FAS and, from this, both enzymes were concluded to have the same overall molecular mass of 2.3 MDa. The enzyme described in this paper appears to be a typical type-I FAS multienzyme which clearly differs from the E. gracilis FAS so far described. Instead, it appears to be organized structurally similar to the type-I FAS multienzymes of lower fungi. In vitro, the purified Euglena FAS complex synthesizes mainly palmitic acid, or its CoA ester, from acetyl CoA and malonyl CoA as substrates. The Km values for acetyl CoA and malonyl CoA are 20 microM and 31 microM, respectively. Similar to the FAS enzymes of other lower eucaryotes, the Euglena type-I FAS is a flavoprotein. In contrast to yeast FAS, however, the flavin cofactor appears to be covalently attached to the enzyme protein. By immunological techniques, the enzyme was shown to be absent in green as well as in etiolated E. gracilis cells, while being rapidly induced upon streptomycin bleaching of heterotrophically growing green cells. The data suggest an inverse correlation between organellar development and derepression of this FAS complex.

Animals↗
PubMed1991

Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome.

Forty patients with a history of difficulty discontinuing long-term, daily benzodiazepine therapy were randomly assigned, under double-blind conditions, to treatment with carbamazepine (200 to 800 mg/d) or placebo. A gradual taper (25% per week reduction) off benzodiazepine therapy was then attempted. Five weeks after taper, significantly more patients who had received carbamazepine than placebo remained benzodiazepine free, this despite the fact that no statistically significant differences in withdrawal severity could be demonstrated. Patients receiving carbamazepine reported a larger reduction in withdrawal severity than patients receiving placebo, but only at a trend level, and only on the daily patient-rated withdrawal checklist. Eleven patients (28%) required antidepressant therapy for depression or panic when assessed at 12-weeks follow-up. The results of this pilot investigation suggest that carbamazepine might have promise as an adjunctive drug therapy for the benzodiazepine withdrawal syndrome, particularly in patients receiving benzodiazepines in daily dosages of 20 mg/d or greater of diazepam equivalents.

Benzodiazepines↗
PubMed1991

The pentafunctional FAS1 genes of Saccharomyces cerevisiae and Yarrowia lipolytica are co-linear and considerably longer than previously estimated.

The fatty acid synthetase (FAS) gene FAS1 of the alkane-utilizing yeast Yarrowia lipolytica was cloned and sequenced. The gene is represented by an intron-free reading frame of 6228 bp encoding a protein of 2076 amino acids and 229,980 Da molecular weight. This protein exhibits a 58% sequence similarity to the corresponding Saccharomyces cerevisiae FAS beta-subunit. The sequential order of the five FAS1-encoded enzyme The sequential order of the five FAS1-encoded enzyme domains, acetyl transferase, enoyl reductase, dehydratase and malonyl/palmityl-transferase, is co-linear in both organisms. This finding agrees with available evidence that the functional organization of FAS genes is similar in related organisms but differs considerably between unrelated species. In addition, previously reported conflicting data concerning the 3' end of S. cerevisiae FAS1 were re-examined by genomic and cDNA sequencing of the relevant portion of the gene. Thereby, the translational stop codon was shown to lie considerably downstream of both published termination sites. The S. cerevisiae FAS1 gene thus has a corrected length of 6153 bp and encodes a protein of 2051 amino acids and 228,667 Da molecular weight.

Amino Acid Sequence↗
PubMed1991

Properties of two nuclear pet mutants affecting expression of the mitochondrial oli1 gene of Saccharomyces cerevisiae.

This study details the characteristics of two temperature-conditional pet mutants of yeast, strains ts1860 and ts379, which at the non-permissive temperature show deficiencies in the formation of three mitochondrially encoded subunits of the ATP synthase complex. By analysis of mitochondrial translation products, and of mitochondrial transcription in temperature shift experiments from the permissive (22 degrees C) to the non-permissive (36 degrees C) temperature, it was concluded that the nuclear mutations in both mutants primarily inhibit synthesis of ATP synthase subunit 9, and that reductions in subunit 8 and 6 synthesis are secondary pleiotropic effects. Following transfer to 36 degrees C, cells of mutant ts379 display a near complete inhibition of subunit 9 synthesis within 1 h, coincident with a marked reduction in the level of the cognate oli1 mRNA. On the other hand, near complete inhibition of subunit 9 synthesis in strain ts1860 occurs after 3 h at 36 degrees C, at which time there is little change in the level of subunit 9 mRNA. In both mutants the mRNA levels for subunits 6 and 8 are not significantly affected at the time of inhibition of subunit 9 synthesis. Provision of an alternative source of subunit 8, translated extra-mitochondrially for import into the organelle, does not overcome the mutant phenotype of either mutant at 36 degrees C, confirming that subunit 8 is not the sole or primary deficiency in each mutant. The mutants indicate that the products of a least two nuclear genes (designated AEP1 and AEP2) are required for the expression of the mitochondrial oli1 gene and the synthesis of subunit 9. (ABSTRACT TRUNCATED AT 250 WORDS)

Cell Nucleus↗
PubMed1991

Long-term benzodiazepine users 3 years after participation in a discontinuation program.

OBJECTIVE: Clinical status and use of benzodiazepines and other psychotropic drugs at follow-up were assessed in patients who had been chronically dependent on benzodiazepines and had been referred for participation in a discontinuation study. METHOD: Of 123 benzodiazepine-dependent patients screened for entry into a tapered discontinuation program, 48 had completed the program, 38 had not, and 37 had not undergone drug tapering. Follow-up information was obtained through a structured telephone interview and a mail questionnaire that included a global severity scale assessing anxiety and depression and the Hopkins Symptom Checklist. The time to follow-up was 2.7-5.0 years, and the mean +/- SD interval between screening and follow-up was 2.9 +/- 0.9 years. RESULTS: Outcome at follow-up significantly favored the patients who had completed the discontinuation program; 73% were not using benzodiazepines, compared to 39% in the unsuccessful taper group and 14% in the no-taper group. Moderate or marked anxiety was still reported by 35% of the patients who were taking benzodiazepines and 25% of those who were not. At follow-up, 22% of the patients were being treated with nonbenzodiazepine psychotropic agents, primarily antidepressants. CONCLUSIONS: The high percentage of patients who were benzodiazepine-free at follow-up and the continued anxiety and depression present in many patients suggest that some patients may have been taking benzodiazepines because of chronic or recurrent anxiety or depression, not physical dependence.

Anxiety Disorders↗
PubMed1991

Placebo-controlled trial of venlafaxine for the treatment of major depression.

Results are presented of the first double-blind, placebo-controlled trial of a novel antidepressant venlafaxine, which preclinically has demonstrated serotonin, norepinephrine, and dopamine reuptake inhibiting effects. Sixty outpatients meeting DSM-III-R criteria for major depression were randomized to receive 6 weeks of treatment with one of three fixed doses of venlafaxine--25 mg three times a day, 75 mg three times a day, or 125 mg three times a day--or placebo. Significant improvement was observed in depression scores at all doses, with the high dose resulting in earlier improvement, by week 2. For the combined venlafaxine treatment groups, 68% achieved a moderate or marked improvement on the Clinical Global Impression scale, compared with only 31% for the placebo group. Venlafaxine was well tolerated, and nervousness, sweating, and nausea were the only adverse effects observed more frequently with drug compared with placebo.

Adult↗
PubMed1991

Buspirone in major depression: a controlled study.

One hundred and fifty-five outpatients suffering from major depression with moderate anxiety entered a double-blind study comparing 8 weeks of treatment with buspirone or placebo. Thirty-four percent of buspirone and 41% of placebo patients discontinued treatment before 8 weeks. Results were consistent across all physician- and patient-completed outcome measures, with treatment response to buspirone significantly better than to placebo at treatment endpoint. Seventy percent of buspirone and 35% of placebo patients (p less than .01) were rated moderately or markedly improved after 8 weeks of therapy. Initial levels of anxiety and depression had no significant effect on treatment outcome. Buspirone was found to be safe and well tolerated at doses of up to 90 mg/day.

Adolescent↗