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A novel 1,4-homofragmentation which complicated the conversion of an alpha,alpha-dichloroester to the corresponding alpha-keto acid, was investigated. The results showed a mechanism involving an [alpha]-lactone intermediate, which can lead to both the desired [alpha]-keto acid and the 1,4-homofragmentation with the product distribution being dependent upon reaction conditions.

Research has been conducted on the diamine dioxime ligands' technetium complexes. The substitution of these complexes at the central carbon of the propylene bridge has been examined and the results are discussed.

The conditions under which the Mitsunobu procedure for sulfonating a secondary alcohol with stereochemical inversion is performed were modified in the context of cis-mesyloxy proline derivative synthesis from L-hydroxyproline. The modifications, which eliminate the use of zinc salts, isolate the product via crystallization and removal of the Mitsunobu redox byproducts to eliminate the need for purification via column chromatography.

A study was conducted on the regioselective coupling of tetraalkylammonium salts of 6-iodo-2-aminopurine to a cyclobutly triflate. Mild coupling conditions were attained through a Mitsunobu-type strategy with yields ranging from 23%-78%. However, product purification posed constant problems. Results showed that tetraalkylammonium salts of 6-iodo-2-aminopurine coupled easily with equimolar quantities of the corresponding protected cyclobutly triflate at room temperature in methylene chloride.

A novel pathway for the preparation of substituted seven-membered lactams facilitates the stereoslective introduction of substituents at the C-7 site of the azepinone ring and alpha to the acetic acid side chain. The associated bicyclic fused lactams result in good yield and high stereoselectivity from dehydrative cyclization of dipeptidyl aldehydes.

The macrocyclic amino carboxylate complexes, DOTA and DO3A, serve as contrast agents for magnetic resonance imaging. Fe(DO3A).3H2O is synthesized by the reaction of Fe(OH)3 and H3DO3A in water. The resulting suspension, on being stirred and heated at 90 degree celsius for 1 hour, yields a yellow-green solid on evaporation of the solvent. Crystallographic studies of this compound reveals the molecular structure of the neutral Fe(DO3A), which shares identity with the heptacoordinate face-capped trigonal prismatic structure of In(DO3A).

Hydrogenolysis and deformylation of 10-formyl-1,4, 7-tris(benzyloxycarbonylmethyl)- 1,4,7,10-tetraazacyclododecane affords the synthesis of (1R,4R,7R)-alpha,alpha',alpha''-trimethyl-1,4,7,10- tetraazacyclododecane-1,4,7-triacetic acid (DO3MA). A pure Gd(III) chelate, Gd(DO3MA), is formed by the complex with gadolinium acetate. Structural analysis shows that the chelate crytals have three asymmetric carbons with alpha-methyl groups in (R)-configuration. The x-ray crystallographic and physicochemical properties of the chelates are discussed.

The psychological effects of long-term aerobic training were assessed in 87 sedentary older group and compared with a nonexercising control group. The exercising group were found to have had bettercardiovascular fitness and a positive disposition in a self-reported survey after a 12-month period. The difference in cognitive function measures was found to be insignificant in the light of the decline in performance from pre- to post-testing in the control group.

An increased level of high-density lipoprotein (HDL) is associated with a lower risk of coronary heart disease. In humans, HDL cholesterol consists of two principal fractions, HDL2 and HDL3, and HDL2 has been linked to protection from heart disease. Hence it is important to determine the factors that control HDL2 cholesterol levels. The relation between HDL2 cholesterol levels and various metabolic and physical characteristics was examined in 146 healthy subjects, who were between 60 and 70 years old. Covariates such as body weight, fatness, distribution of fat, diet, fitness, blood levels of insulin, and glucose tolerance, the ability of the tissue to use glucose, were measured, and the relationships between these covariates and HDL2 levels were determined in a mathematical model. The level of HDL2 cholesterol was inversely related to waist-to-hip circumference, and blood levels of insulin; in other words, increased HDL2 cholesterol levels were associated with decreases in waist-to-hip circumference and blood insulin levels. HDL2 cholesterol levels were associated with the degree of glucose tolerance, but not with body mass and fat, oxygen uptake, diet and sex. Thus, HDL2 cholesterol levels are inversely correlated with fat in the waist and hip region, blood insulin levels, and the presence of glucose intolerance, and are not associated with sex or body fat. (Consumer Summary produced by Reliance Medical Information, Inc.)

The number of children speaking more than one language as well as the number of languages spoken in Ireland has increased significantly posing a problem for timely identification of children with language disorder. The current study aims to profile performance of monolingual and multilingual children on language processing tasks: non-word repetition (NWR) and sentence repetition (SR). We used: (1) Crosslinguistic (CL) and English Language-Specific (LS) NWR and (2) SR in English, Polish and Russian. Children's socioeconomic status, language emergence, the age of exposure (AoE) to English and the percentage of English spoken at home were recorded. The study included 88 children age 5–8 attending a school in a disadvantaged area. CL and LS NWR yielded similar distribution of scores for monolinguals and multilinguals. The tasks identified small number of children who performed significantly lower than the mean while there were no significant differences between the groups. In English SR, monolinguals significantly outperformed multilinguals. Comparison of SR in English and Polish/Russian indicated that some children showed balanced performance in both of their languages while others showed marked differences performing better in either Polish/Russian or English depending on their AoE to English and percentage of English spoken at home. The pilot study suggests that CL-NWR is a promising screening tool for identifying monolingual and multilingual children with language disorder while SR provides more detailed information on children's language performance relative to their language exposure. SR task is recommended to be used only if comparable tasks are available in all of children's languages. [ABSTRACT FROM AUTHOR]

A commodious one-pot synthesis of N,N'-distributed ketene animals from activated methylene compounds and isothiocyanates is described. According to results, the rotamers are stabilized by intramolecular hydrogen bonding both in solution and solid states.

This paper examines interaction at a midwives' ante-natal clinic from the perspective of both participants and illustrates how speech and silence interact to construct the experience of ante-natal care in contemporary Ireland. Using a discourse analysis approach, the perspectives of the professionals and that of the women using the service are described, as are contrasting elements of these perspectives. Silence is defined as issues left unspoken, and three main issues are identified: the active role of women in labour, the possibility of alternatives and choices within and to the current system, and women's subjective experience of pregnancy and birth. Challenges to the status quo through attempts to introduce topics usually left unspoken are also described. Women are shown to be adept at both introducing their perspective and at attempting to introduce a plurality of voices in the discourse. As midwives conduct the tasks at hand, challenges are quickly relinquished and ultimately the status quo of contemporary antenatal care in which the medical model prevails, is left intact. [ABSTRACT FROM AUTHOR]

Abstract: Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models. [Copyright &y& Elsevier]

Abstract: The cannabinoid CB1 G protein-coupled receptor has been shown to be a regulator of food consumption and has been studied extensively as a drug target for the treatment of obesity. To advance understanding of the receptor''s three-dimensional structure, we performed mutagenesis studies at human cannabinoid CB1 receptor residues F200 and S383 and measured changes in activity and binding affinity of compounds from two recently discovered active chemotypes, arylsulfonamide agonists and tetrahydroquinoline-based inverse agonists, as well as literature compounds. Our results add support to previous findings that both agonists and inverse agonists show varied patterns of binding at the two mutated residue sites, suggesting multiple subsites for binding to the cannabinoid CB1 receptor for both functional types of ligands. We additionally find that an F200L mutation in the receptor largely restores binding affinity to ligands and significantly decreases constitutive activity when compared to F200A, resulting in a receptor phenotype that is closer to the wild-type receptor. The results downplay the importance of aromatic stacking interactions at F200 and suggest that a bulky hydrophobic contact is largely sufficient to provide significant receptor function and binding affinity to cannabinoid CB1 receptor ligands. [Copyright &y& Elsevier]

The purpose of this quality improvement initiative was to improve oropharyngeal dysphagia screening and reduce aspiration pneumonia rates on 3 inpatient hospital medical units. Guided by a Plan-Do-Study-Act methodology, an interdisciplinary health team developed and implemented a systematic process for oropharyngeal dysphagia screening and management. As a result, use of the screening protocol increased, timely initiation of speech language pathology consultations increased, and aspiration pneumonia rates decreased.

The first stereoselective synthesis of the hexahydroimidazo[1,5b]isoquinoline (HHII) scaffold as a surrogate for the steroidal A-B ring system is described. The structure-activity relationships of the analogs derived from this scaffold show that the basic imidazole moiety is tolerated by the glucocorticoid receptor (GR) in terms of binding affinity, although the partial agonist activity in the transrepressive assays depends on the substitution pattern on the B-ring. More importantly, most compounds in the HHII series bearing a tertiary alcohol moiety on the B-ring are either inactive or significantly less active in inducing GR-mediated transactivation, thus displaying a "dissociated" pharmacology in vitro.

Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.

A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.

LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.