The temporal organization of functional brain connectivity is abnormal in schizophrenia but does not correlate with symptomatology.

Previous work employing graph theory and nonlinear analysis has found increased spatial and temporal disorder, respectively, of functional brain connectivity in schizophrenia. We present a new method combining graph theory and nonlinear techniques that measures the temporal disorder of functional brain connections. Multichannel electroencephalographic data were windowed and functional networks were reconstructed using the minimum spanning trees of correlation matrices.

Isoflurane anesthesia does not satisfy the homeostatic need for rapid eye movement sleep.

Background: Sleep and general anesthesia are distinct states of consciousness that share many traits. Prior studies suggest that propofol anesthesia facilitates recovery from rapid eye movement (REM) and non-REM (NREM) sleep deprivation, but the effects of inhaled anesthetics have not yet been studied. We tested the hypothesis that isoflurane anesthesia would also facilitate recovery from REM sleep deprivation.

Integration of optimized substituent patterns to produce highly potent 4-aryl-pyridine glucagon receptor antagonists.

Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-hydroxyethyl] and a 2'-hydroxy group. Due to restricted rotation of the phenyl-pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC(50)=10-25 nM.

Optimization of the 4-aryl group of 4-aryl-pyridine glucagon antagonists: development of an efficient, alternative synthesis.

A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.

Discovery of 5-hydroxyalkyl-4-phenylpyridines as a new class of glucagon receptor antagonists.

5-Hydroxyalkyl-4-phenylpyridines have been identified as a novel class of glucagon antagonists with potential utility for the treatment of diabetes. A lead structure with moderate activity was discovered through a high throughput screening assay. Structure-activity relationships led to the discovery of a potent antagonist, IC(50)=0.

Acyclic structural variants of growth hormone secretagogue L-692,429.

Systematic investigation of acyclic analogs of L-692,429, the prototype benzolactam growth hormone secretagogue, has helped to further define the structural requirements for the release of growth hormone from rat pituitary cells for this class of secretagogues.

A potent, orally bioavailable benzazepinone growth hormone secretagogue.

The identification of L-739,943 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L-692,429 through modification of its amino acid side chain and replacement of the acidic 2'-tetrazole with the neutral and potency enhancing 2'-(N-methylaminocarbonylamino)methyl substituent. L-739,943 is orally active for the release of growth hormone in beagle dogs at doses as low as 0.5 mg/kg.

Variant preexcitation syndrome: a true nodoventricular mahaim fiber or an accessory atrioventricular pathway with decremental properties?

Introduction: The differentiation between a nodoventricular fiber and an accessory atrioventricular (AV) pathway with long conduction times and decremental properties could be very difficult even at detained electrophysiologic study.

Methods And Results: A 20-year-old male with a history of a wide QRS tachycardia underwent electrophysiologic study. Baseline intervals were normal.

Radiofrequency ablation for the fast pathway of atrioventricular node reentry. Evidence for partial damage to the fast and lower common pathways.

Radiofrequency ablation was attempted in a 30-year-old woman with atrioventricular (AV) node reentry of the common variety. Energy was delivered to ablate a fast pathway. After energy delivery, the atrio-His interval prolonged following transient AV node block.

Effects of acute and repeated intravenous administration of L-692,585, a novel non-peptidyl growth hormone secretagogue, on plasma growth hormone, IGF-1, ACTH, cortisol, prolactin, insulin, and thyroxine levels in beagles.

L-692,585 is a 2-hydroxypropyl derivative of L-692,429, both novel non-peptidyl growth hormone (GH) secretagogues. The effects of single and repeated intravenous administration of L-692,585 on serum or plasma GH and other hormones in beagles were evaluated. In a balanced 8-dog dose-ranging study, compared to the saline control with a mean (+/- S.

[Treatment of AV-nodal reentry tachycardia by transcatheter radiofrequency ablation].

A case history is presented of a patient in whom an AV-nodal reentrant tachycardia was cured by the selective transcatheter ablation of the extranodal slow pathway. Recent anatomical and electrophysiological findings connected with the mechanism of AV-nodal reentrant tachycardia are presented, which permitted development of the transcatheter radio frequency AV-nodal modification. The Hungarian introduction of this therapeutic modality is recommended.

N-glucuronidation reactions. II. Relative N-glucuronidation reactivity of methylbiphenyl tetrazole, methylbiphenyl triazole, and methylbiphenyl imidazole in rat, monkey, and human hepatic microsomes.

The relative intrinsic in vitro N-glucuronidation reactivity of three classes of heterocyclic compounds was compared using model compounds incubated with UDP-glucuronic acid-enriched liver microsomes from rats, monkeys, and humans. These compounds, all methylbiphenyl (MB) derivatives, represent three classes of N-containing heterocycles commonly used in the design of new drug entities [i.e MB-tetrazole, MB-triazole, (1,2,3- and 1,2,4-), and MB-imidazole (C2- and C4-substituted)].

Atrioventricular node re-entry of the common variety. Unusual location for the fast pathway.

Radiofrequency ablation was attempted in a 17-year-old man with atrioventricular node re-entry of the common variety. Energy was delivered to three sites around the ostium of the coronary sinus. The third attempt resulted in a sudden increase in AH interval with loss of retrograde conduction.

A novel 3-substituted benzazepinone growth hormone secretagogue (L-692,429).

The 3-substituted benzazepinone, L-692,429 (compound 1), is the prototype compound of a novel class of compounds that stimulate release of growth hormone (GH). The molecule evolved from efforts to identify a non-peptide mimic of the growth hormone-releasing hexapeptide, GHRP-6. Compound 1 is prepared by sequential attachment of dimethyl-beta-alanine and 2'-biphenylyltetrazole side chains to a chiral 3-aminobenzolactam nucleus.

Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles.

L-692,429 is a substituted benzolactam that has recently been shown to stimulate GH secretion from rat pituitary cells in vitro with an ED50 of 60 nM. In the current studies, we evaluated the efficacy and specificity of L-692,429 as a GH secretagogue in beagles. L-692,429 at 0.

A nonpeptidyl growth hormone secretagogue.

A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6).

Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue.

L-692,429, a benzolactam derivative, stimulated GH release from rat primary pituitary cells in a dose-dependent manner. The concentration of L-692,429 required for half-maximal stimulation were 59.6 +/- 7.

A new class of potent, slowly reversible dehydropeptidase inhibitors.

Dehydrodipeptide analogs whose scissile carboxamide has been replaced with a PO(OH)CH2 group have been found to be potent inhibitors of the zinc protease dehydrodipeptidase 1 (DHP-1, renal dipeptidase, EC 3.4.13.

Conflict in the parameters defining life and death in Missouri statutes.

Over the last twenty years, state legislatures have enacted statutes incorporating medically and legally established criteria to be utilized in the determination of death. Similarly consistent criteria for determining the onset of life have yet to be established. As a result, unacceptably conflicting statutory language defining life and the state's interest in that life exists.

Phosphinic acid inhibitors of D-alanyl-D-alanine ligase.

We report the synthesis of a series of phosphinic acid dipeptide analogues, NH2CH(R1)PO(OH)CH2CH(R2)CO2H, related to DAla-DAla. The best of these compounds are potent, essentially irreversible inhibitors of DAla-DAla ligase, and their preferred stereochemistry was shown by chiral synthesis of (1(S)-aminoethyl)(2(R)-carboxy-1-n-propyl)phosphinic acid, 12b, and by X-ray crystallography of its derivative benzyl [1(S)-[(benzyloxycarbonyl)-amino]ethyl](2(R)-carbomethoxy-1-propyl) phosphinate, 13, to correspond to the stereochemical configuration of DAla-DAla at both centers. A mechanism for the inhibition of DAla-DAla ligase by these compounds is proposed to involve an ATP-dependent formation of phosphorylated inhibitor within the enzyme's active site.

Statement on the nomenclature of dog C4 allotypes.

As a collaborative work of three laboratories the polymorphism of the canine fourth complement component (C4) was studied in a total of 131 unrelated dogs from different breeds and mongrels. Using high voltage electrophoresis followed by an immunoblotting technique, we detected eight distinct variants. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of canine C4 showed an additional heterogeneity of the alpha and gamma chains which resulted in a total of 11 variants in the population studied.