Non-peptide cholecystokinin-B/gastrin receptor antagonists based on bicyclic, heteroaromatic skeletons.

A series of potent and selective cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane (BCO) skeleton which have recently been described were found to show species-dependent behavior when examined in rat and dog models.

The assessment of diagnostic imaging technologies: a policy perspective.

Diagnostic imaging technologies are essential in health care but have high costs and poorly defined benefits. Formulation and implementation of policy on their procurement and use is made difficult by the complexity of the diagnostic process, and the limitations of available data and assessment methodology. Informed policy decisions will need to be based on a synthesis of imperfect data from a variety of perspectives, and supplemented by effective dissemination and feedback of information.

Depletion of estrogen receptor in human breast tumor cells by a novel substituted indole that does not bind to the hormone binding domain.

Steroidal antiestrogens appear to have at least two major modes of action in breast cancer cells, direct antagonism of estrogen binding to its receptor and depletion of estrogen receptors (ER) due to inhibition of dimerization of the receptor and a resultant destabilization of the receptor protein. In a search for other classes of compounds which would act as dimerization inhibitors, a novel substituted indole (8-{2-[1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-1H-indol-3-yl]-acetylamino} octanoic acid butyl-methyl amide, MDL 101,906) was synthesized. Binding of the ER to its consensus response element (ERE) was apparently decreased in nuclear extracts from MCF-7 human breast cancer cell treated with MDL 101,906.

Mortality soon after discharge from a major teaching hospital: linking mortality and morbidity.

In this pilot study, data held by the Registrar of Births, Deaths and Marriages was linked to the Patient Master Index at St Vincent's Hospital Melbourne in order to identify early post discharge deaths, and inpatient records were linked with the Victorian Inpatient Minimum Database. Between July 1991 and December 1993 there were 831 deaths within 28 days of discharge. Injuries and poisoning were the commonest cause of death in younger patients who had attended the emergency department.

Linking mortality data with hospital morbidity data--a pilot study.

Record linkage is becoming an increasingly important technique in moni toring health outcomes. In this study we wought to examine the feasibility of linking mortality data held by the Registry of Birth, Deaths and Marriages with the Patient Master Index (PMI) at St. Vincent's Hospital, Melbourne, in order to document deaths soon after hospital discharge.

Improving the affinity and selectivity of a nonpeptide series of cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane skeleton.

We have recently described a novel series of nonpeptidic cholecystokinin-B (CCKB)/gastrin receptor antagonists based on a dibenzobicyclo[2.2.2]octane skeleton.

Factors affecting the electroporation of Bacillus subtilis.

Bacillus subtilis 168 trp- was found to be transformable with the tetracycline resistance plasmid pAB124 by electroporation of whole cells, inconsistently and at very low frequencies. Supplementation of the growth medium with glycine, or particularly DL-threonine, produced cells that could be electrotransformed much more efficiently at frequencies up to 2.5 x 10(3) transformants per microgram plasmid DNA.

The application of hydrogen bonding analysis in X-ray crystallography to help orientate asparagine, glutamine and histidine side chains.

Protein X-ray crystallography produces an electron density map that rarely detects individual hydrogen atoms or distinguishes between carbon, nitrogen and oxygen atoms in the electron density. This makes it difficult to orientate the side chains of Asn, Gln and His, which appear symmetrical in the electron density; their orientation is usually judged on the basis of hydrogen bonding. Based on the observation that almost all buried donors and acceptors are satisfied, we have developed a simple algorithm to compare the alternative conformations of these residues and, where possible, identify the most favourable.

Detection of methanotrophic bacteria in environmental samples with the PCR.

We designed PCR primers by using the DNA sequences of the soluble methane monooxygenase gene clusters of Methylosinus trichosporium OB3b and Methylococcus capsulatus (Bath), and these primers were found to be specific for four of the five structural genes in the soluble methane monooxygenase gene clusters of several methanotrophs. We also designed primers for the gram-negative methylotroph-specific methanol dehydrogenase gene moxF. The specificity of these primers was confirmed by hybridizing and sequencing the PCR products obtained.

Quantification of mitral regurgitation by integrated Doppler backscatter power.

Objectives: We attempted to determine whether continuous wave Doppler backscatter power could be used to quantify mitral regurgitation.

Background: The power of a Doppler backscatter signal is proportional to the number of scatterers insonated and, hence, to the moving volume of blood. The relative power of the continuous wave Doppler signals from mitral inflow and aortic outflow is therefore proportional to the relative volumes of blood in motion.

Prediction of delayed neurological deficit after subarachnoid haemorrhage: a CT blood load and Doppler velocity approach.

The predictive value of cranial computed tomography (CT) blood load and serial transcranial Doppler sonography for the development of delayed ischaemic neurological deficit was assessed in 121 patients following subarachnoid haemorrhage. Of the 121 patients, 81 (67%) had thick layers of blood or haematoma, including intraventricular bleeding. The proportion of patients who developed delayed deficit was higher with increasing amounts of subarachnoid blood on the admission CT (51% of 53 cases in Fisher grade 3; 35% of 33 cases in grade 2; 28% of 7 cases in grade 1, P < 0.

Amino/aromatic interactions in proteins: is the evidence stacked against hydrogen bonding?

We investigate the suggestion that aromatic rings can act as hydrogen-bond acceptors in proteins, by an analysis of 55 non-homologous high-resolution protein chain structures. Approximately 10% of interactions between sp2 hybridized nitrogen atoms, from either side-chains or main-chains, and phenylalanine or tyrosine rings have the nitrogen atom positioned above the ring. In these instances, however, the sp2 nitrogen atoms tend to form stacked interactions with the aromatic rings, these geometries outnumbering amino/aromatic hydrogen bonds by around 2.

Satisfying hydrogen bonding potential in proteins.

We have analysed the frequency with which potential hydrogen bond donors and acceptors are satisfied in protein molecules. There are a small percentage of nitrogen or oxygen atoms that do not form hydrogen bonds with either solvent or protein atoms, when standard criteria are used. For high resolution structures 9.

Haloallylamine inhibitors of MAO and SSAO and their therapeutic potential.

Based on mechanistic understandings, molecular modeling and extensive quantitative structure-activity relationships, appropriately substituted haloallylamine derivatives were designed as potential mechanism-based inhibitors of MAO and/or SSAO. Potent inhibition of MAO-B and SSAO occurred with fluoroallylamines whereas chloroallylamines, such as MDL 72274A ((E)-2-phenyl-3-chloroallylamine hydrochloride), were selective and potent inhibitors of SSAO. MDL 72974A (E)-2-(4-fluorophenethyl)-3-fluoroallylamine hydrochloride is a potent (IC50 = 10(-9) M) inhibitor of both MAO-B and SSAO, with 190-fold lower affinity for MAO-A.

Adrenalectomy and steroid replacement in a small macropodid marsupial, the quokka (Setonix brachyurus): metabolic and renal effects.

Contrary to previously accepted observations, the quokka (Setonix brachyurus), a small macropodid marsupial, survival bilateral adrenalectomy indefinitely if injected with appropriate doses of cortisol and aldosterone, either singly or combined. Normal behavior and plasma solute concentrations could be maintained indefinitely by daily i.m.

Use of transcranial Doppler sonography to predict development of a delayed ischemic deficit after subarachnoid hemorrhage.

Blood flow velocity was recorded from the middle or anterior cerebral and extracranial internal carotid arteries using transcranial Doppler sonography (TCD) in 121 unselected consecutive patients with acute aneurysmal subarachnoid hemorrhage (SAH). Recordings were made daily or every 2nd day after SAH for a 14-day period. The highest recorded velocity was greater in the 47 patients who developed a delayed ischemic neurological deficit (186 +/- 6 cm sec-1; mean +/- standard error of the mean) than in the 74 patients who did not develop a neurological deficit (149 +/- 5 cm sec-1) (p < 0.

Angiographic and Doppler diagnosis of cerebral artery vasospasm following subarachnoid haemorrhage.

Angiographic middle and anterior cerebral artery diameter and transcranial ultrasound flow velocity measurements were performed within 24 h of each other in 102 patients with recent aneurysmal subarachnoid haemorrhage. There was a significant inverse correlation between middle cerebral artery diameter and flow velocity (r = -0.54, p < 0.

MDL 72,974A: a selective MAO-B inhibitor with potential for treatment of Parkinson's disease.

MDL 72,974A [(E)-2-(4-fluorophenethyl)-3-fluoroallylamine, hydrochloride] was designed to be a selective, mechanism-based irreversible inhibitor of monoamine oxidase type B (MAO-B). The compound is a potent, selective MAO-B inhibitor in vitro and in vivo. In vitro studies revealed an IC50 value (MAO-B) of 3.

Left ventricular energy in mitral regurgitation: a preliminary report.

Energy exchange based on Newtonian principles is the most appropriate way to express the function of any pump--including the heart. Using information obtained at cardiac catheterisation, we have measured the total work energy (ET) of the left ventricle (LV) (mean 1.63 F) in patients with severe mitral regurgitation (mean regurgitant fraction 0.