The core particle (CP) of the yeast proteasome is composed of four heptameric rings of subunits arranged in a hollow, barrel-like structure. We have found that the CP is autoinhibited by the N-terminal tails of the outer (alpha) ring subunits. Crystallographic analysis showed that deletion of the tail of the alpha3 subunit opens a channel into the proteolytically active interior chamber of the CP, thus derepressing peptide hydrolysis. In the latent state of the particle, the tails prevent substrate entry by imposing topological closure on the CP. Inhibition by the alpha subunit tails is relieved upon binding of the regulatory particle to the CP to form the proteasome holoenzyme. Opening of the CP channel by assembly of the holoenzyme is regulated by the ATPase domain of Rpt2, one of 17 subunits in the RP. Thus, open-channel mutations in CP subunits suppress the closed-channel phenotype of an rpt2 mutant. These results identify a specific mechanism for allosteric regulation of the CP by the RP.

Adenosine Triphosphatases↗

PubMedDate not supplied

Selective modulation of thyroid hormone receptor action.

Thyroid hormones have some actions that might be useful therapeutically, but others that are deleterious. Potential therapeutically useful actions include those to induce weight loss and lower plasma cholesterol levels. Potential deleterious actions are those on the heart to induce tachycardia and arrhythmia, on bone to decrease mineral density, and on muscle to induce wasting. There have been successes in selectively modulating the actions of other classes of hormones through various means, including the use of pharmaceuticals that have enhanced affinities for certain receptor isoforms. Thus, there is reason to pursue selective modulation of thyroid hormone receptor (TR) function, and several agents have been shown to have some beta-selective, hepatic selective and/or cardiac sparring activities, although development of these was largely not based on detailed understanding of mechanisms for the specificity. The possibility of selectively targeting the TRbeta was suggested by the findings that there are alpha- and beta-TR forms and that the TRalpha-forms may preferentially regulate the heart rate, whereas many other actions of these hormones are mediated by the TRbeta. We determined X-ray crystal structures of the TRalpha and TRbeta ligand-binding domains (LBDs) complexed with the thyroid hormone analog 3,5,3'-triiodithyroacetic acid (Triac). The data suggested that a single amino acid difference in the ligand-binding cavities of the two receptors could affect hydrogen bonding in the receptor region, where the ligand's 1-position substituent fits and might be exploited to generate beta-selective ligands. The compound GC-1, with oxoacetate in the 1-position instead of acetate as in Triac, exhibited TRbeta-selective binding and actions in cultured cells. An X-ray crystal structure of the GC-1-TRbeta LBD complex suggests that the oxoacetate does participate in a network of hydrogen bonding in the TR LBD polar pocket. GC-1 displayed actions in tadpoles that were TRbeta-selective. When administered to mice, GC-1 was as effective in lowering plasma cholesterol levels as T(3), and was more effective than T(3) in lowering plasma triglyceride levels. At these doses, GC-1 did not increase the heart rate. GC-1 was also less active than T(3) in modulating activities of several other cardiac parameters, and especially a cardiac pacemaker channel such as HCN-2, which may participate in regulation of the heart rate. GC-1 showed intermediate activity in suppressing plasma thyroid stimulating hormone (TSH) levels. The tissue/plasma ratio for GC-1 in heart was also less than for the liver. These data suggest that compounds can be generated that are TR-selective and that compounds with this property and/or that exhibit selective uptake, might have clinical utility as selective TR modulators.

Animals↗

PubMedDate not supplied

Antibody-antigen flexibility.

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Antibodies↗

PubMedDate not supplied

Relationship between right-to-die and satisfaction with life.

To examine the relationship between right-to-die attitudes and satisfaction with life, 108 institutionalized elderly residents in a random sample were interviewed in the summer of 1990. Overall, 55 percent responded Yes or Probably Yes to a question pertaining to the legalization of some form of control of death circumstances. Those who were moderately or most satisfied with their lives more often responded Yes or Probably Yes to the legalization question. The purpose of this article is to discuss findings from a random sample of 108 institutionalized elderly concerning the relationship between their responses to right-to-die questions and their self-reported satisfaction with life.

Adult↗

PubMedDate not supplied

Comparison of the pharmacodynamics and pharmacokinetics of pantoprazole (40 mg) as compared to omeprazole MUPS (20 mg) after repeated oral dose administration.

The effects on intragastric p11 and gastrin secretion of once daily pantoprazole (40 mg) and a new formulation omeprazole (20 mg) in a Multiple Unit Pellet System (MUPS) were investigated during two treatment periods of 7 days each in a randomized crossover study with 16 healthy Helicobacter pylori-negative male volunteers. Intragastric pH was measured using continuous 24 hour pH-metry on days 1 and 7. The results were compared to the baseline curves obtained before each treatment period. On day 1, pantoprazole raised the intragastric pH significantly higher and more quickly than omeprazole MUPS (pH median 1.9 vs. 1.6, baseline pH 1.4). After 7 days, the 24 h gastric pH medians were still in favor of pantoprazole (pH 3.0 vs. 2.8). With respect to the basal gastrin concentration, both treatments resulted in similar increases. For pantoprazole, no differences were observed in AUC and Cmax after single and repeated dosing. However, the new omeprazole MUPS formulation still showed the well-known effect of initial low bioavailability increasing after repeated dosing. Pantoprazole and omeprazole were well tolerated. There seems to be no advantage in the new omeprazole formulation compared with the conventional capsule with regard to bioavailability and increase in intragastric pH. The results of this study confirm former results in which pantoprazole (40 mg) was shown to be significantly superior to omeprazole (20 mg) in elevating intragastric pH.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMedDate not supplied

Bioavailability of a crushed pantoprazole tablet after buffering with sodium hydrogencarbonate or magaldrate relative to the intact enteric coated pantoprazole tablet.

The aim of this study was to determine the bioavailability of orally administered, crushed pantoprazole tablets after buffering with either 1.4% sodium hydrogencarbonate or 1600 mg magaldrate relative to the intact enteric coated pantoprazole tablet. A single dose, three-period crossover study was performed with 18 healthy male volunteers. The crushed pantoprazole suspension, together with either sodium hydrogencarbonate or magaldrate, was administered via a nasogastral tube. Tmax of crushed pantoprazole was earlier as compared to the intact tablet (0.5 h vs. 3 h) and Cmax was approximately 10% higher due to faster absorption. The bioavailability of the crushed pantoprazole tablet relative to the intact pantoprazole tablet was 93% when using sodium hydrogencarbonate as the buffering agent, and 88% when using magaldrate. Based on the internationally approved confidence intervals for AUC (0.80-1.20) and Cmax (0.70-1.43), the crushed tablet buffered with sodium hydrogencarbonate was shown to be bioequivalent with the intact tablet (point estimates for AUC or Cmax: 0.93 or 1.10). For the crushed tablet buffered with magaldrate (point estimates for AUC or Cmax: 0.88 or 1.12) bioequivalence with the intact tablet could not be formally demonstrated, although the lower confidence limit for AUC of 0.78 was only slightly below the lower limit of the equivalence range of 0.80.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMedDate not supplied

The role of Se, Mo and Fe in the structure and function of carbon monoxide dehydrogenase.

CO dehydrogenase (EC 1.2.99.2) catalyzes the oxidation of CO according to the following equation: CO + H2O-->CO2 + 2 e- + 2 H+. It is a selenium-containing molybdo-iron-sulfur-flavoenzyme, which has been crystallized and structurally characterized in its oxidized state from the aerobic CO utilizing bacteria Oligotropha carboxidovorans and Hydrogenophaga pseudoflava. Both CO dehydrogenase structures show only minor differences, and the enzymes are dimers of two heterotrimers. Each heterotrimer is composed of a molybdoprotein, a flavoprotein, and an iron-sulfur protein. CO oxidation takes place at the molybdoprotein which contains a 1:1 mononuclear complex of molybdopterin-cytosine dinucleotide and a Mo-ion, along with a catalytically essential S-selanylcysteine. The latter is appropriately positioned in the SeMo-active site by a unique VAYRCSFR active site loop. In H. pseudoflava the arginine preceeding the cysteine in the active site loop is modified to a Cgamma-hydroxy arginine residue which has no obvious function. The substituents in the first coordination sphere of the Mo-ion are the enedithiolate sulfur atoms of the molybdopterin-cytosine dinucleotide, two oxo- and a sulfido-group. Extended X-ray absorption fine structure spectroscopy (EXAFS), along with the crystal structure of CO dehydrogenase (23.2 U mg(-1)) at 1.85 A resolution, have identified a sulfur atom at 2.3 A from the Mo-ion. The sulfur reacts with cyanide yielding thiocyanate. The corresponding inactive desulfo-CO dehydrogenase shows a typical desulfo inhibited-type of Mo-electron paramagnetic resonance (EPR) spectrum. Structural changes at the SeMo-site during catalysis are suggested by the Mo to Se distance of 3.7 A and the Mo-S-Se angle of 113 degrees in the oxidized enzyme which increase to 4.1 A, and 121 degrees, respectively, in the reduced enzyme. The intramolecular electron transport chain in CO dehydrogenase involves the following prosthetic groups and minimal distances: CO-->[Mo of the molybdenum cofactor] - 14.6 A - [2Fe-2S]I - 12.4 A - [2Fe-2S]II - 8.7 A - [FAD].

Aldehyde Oxidoreductases↗

PubMedDate not supplied

Anticancer activity of a lectin-rich mistletoe extract injected intratumorally into human pancreatic cancer xenografts.

BACKGROUND: In single case observations, tumour remissions after intratumoral injections of mistletoe extracts have been described. MATERIALS AND METHODS: We investigated the antitumour activity of intratumorally (i.t.)-injected lectin-rich mistletoe extract at different dosages and i.t.-injected mistletoe lectin I in comparison to intravenous (i.v.) Gemcitabine and i.t. treatment with placebo in a human pancreatic cancer xenograft. RESULTS: In a preliminary dose-response experiment, the most marked tumour inhibition was induced when mistletoe extract was given at 8 mg/kg body weight (BW) and mistletoe lectin I at 5.3 microg/kg BW. In a second experiment, bi-weekly i.t. injections of mistletoe extract over 8 weeks resulted in a very high antitumour activity with an optimal T/C value (=median relative tumour volume of the test group vs. the control) of 0.4% combined with 3/8 partial and 3/8 complete remissions. Gemcitabine was less active with 2/8 partial and 1/8 complete remissions and an optimal TIC of 4.6%. CONCLUSION: I.t.-injected lectin-rich mistletoe extract should be further evaluated in patients with inoperable locally advanced pancreatic cancer.

Adenocarcinoma↗

PubMedDate not supplied

[Clergy's viewpoint; prolonging of life, ethics and geriatrics].

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Aged↗

PubMedDate not supplied

[Conservative therapy of urolithiasis].

Some common conservative treating methods of urolithiasis are critically discussed. Based on physico-chemical relationships of solubility and cristallisation of stone-forming compounds our own methods of conservative treatment of urolithiasis is presented.

Crystallization↗

PubMedDate not supplied

[Induction of liver microsomal enzymes in epileptics under treatment with carbamazepine].

Serum gamma-GT activity was significantly (0.01 greater than P greater than 0.001) elevated in 18 out of 30 epileptics receiving carbamazepine (CBZ), i.e. in 60%. The incidence of abnormal gamma-GT levels in the control group (25 neurotic patients taking minor tranquilizers) was lower (12%). The possible relationships between the enzyme induction or chronic hepatic toxicity and the elevation of serum gamma-GT activity in epileptics taking CBZ are discussed.

Adolescent↗