Two-generation reproductive toxicity study of dietary bisphenol A in CD-1 (Swiss) mice.

Dietary bisphenol A (BPA) was evaluated in a mouse two-generation study at 0, 0.018, 0.18, 1.

Two-generation reproductive toxicity evaluation of dietary 17beta-estradiol (E2; CAS No. 50-28-2) in CD-1 (Swiss) mice.

No information exists on reproductive/developmental effects in mice exposed to dietary 17beta-estradiol (E2) over multiple generations. Therefore, under OECD Test Guideline 416 with enhancements, CD-1 mice (F0 generation, 25 mice/sex/group) were exposed to dietary E2 at 0, 0.001, 0.

Carbamate-appended N-alkylsulfonamides as inhibitors of gamma-secretase.

The synthesis and gamma-secretase inhibition data for a series of carbamate-appended N-alkylsulfonamides are described. Carbamate 54 was found to significantly reduce brain Abeta in transgenic mice. 54 was also found to possess markedly improved brain levels in transgenic mice compared to previously disclosed 1 and 2.

Nitrogen-appended N-alkylsulfonamides as inhibitors of gamma-secretase.

The synthesis and gamma-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11-47) are described. Inhibition of brain Abeta in transgenic mice was demonstrated by two of these compounds (23 and 44).

Conformationally restricted homotryptamines. Part 4: Heterocyclic and naphthyl analogs of a potent selective serotonin reuptake inhibitor.

A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1S,2S)-2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding.

Sequential linezolid-resistant Staphylococcus epidermidis isolates with G2576T mutation.

We report on an analysis of sequential isolates of Staphylococcus epidermidis from cultures of blood obtained from a patient with acute myeloid leukemia while the patient was receiving linezolid treatment. All 12 isolates had a linezolid MIC of 32 microg/ml. A 420-bp domain V region of the 23S rRNA gene from all isolates was amplified, and their nucleotide sequences were determined.

N-(5-chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides as gamma-secretase inhibitors.

A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.

Conformationally restricted homotryptamines 3. Indole tetrahydropyridines and cyclohexenylamines as selective serotonin reuptake inhibitors.

A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a.

Persistent organic pollutants in outmigrant juvenile chinook salmon from the Lower Columbia Estuary, USA.

Although chemical contaminants are recognized as a potential factor contributing to the salmon declines in the Pacific Northwest, United States, information on contaminant concentrations in threatened and endangered salmon from the Columbia Estuary is limited. In this study we monitored exposure to several persistent organic pollutants [polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethanes (DDTs) and other organochlorine pesticides] in outmigrant juvenile fall chinook salmon (Oncorhynchus tschawytscha) in the Lower Columbia River, and evaluated the potential for adverse effects on salmon and the estuarine food web. Contaminants were measured in whole bodies and stomach contents of subyearling to yearling chinook collected in 2001 and 2002 from sites near the confluence of the Columbia and Willamette Rivers, Longview, and within the lower Estuary.

In vitro and in vivo metabolism of a gamma-secretase inhibitor BMS-299897 and generation of active metabolites in milligram quantities with a microbial bioreactor.

BMS-299897 is a gamma-secretase inhibitor that has the potential for treatment of Alzheimer's disease. The metabolism of [(14)C]BMS-299897 was investigated in human liver microsomes, in rat, dog, monkey and human hepatocytes and in bile duct cannulated rats. Seven metabolites (M1-M7) were identified from in vitro and in vivo studies.

CYP2E1-catalyzed oxidation contributes to the sperm toxicity of 1-bromopropane in mice.

1-bromopropane (1-BrP) induces dose- and time-dependent reproductive organ toxicity and reduced sperm motility in rodents. The contribution of cytochrome P4502E1 (CYP2E1) to both 1-BrP metabolism and the induction of male reproductive toxicity was investigated using wild-type (WT) and Cyp2e1-/- mice. In gas uptake inhalation studies, the elimination half-life of [1,2,3-(13)C]-1-BrP was longer in Cyp2e1-/- mice relative to WT (3.

Three-generation evaluation of dietary para-nonylphenol in CD (Sprague-Dawley) rats.

This study evaluated the potential for dietary para-nonylphenol (NP; CAS No. 84852-15-3) to affect parental fertility and growth and development of three offspring generations in CD (Sprague-Dawley [SD]) rats, including sperm counts across generations to determine the validity of equivocal reductions observed in the F2 generation by R. E.

Allosteric inhibitors of Bcr-abl-dependent cell proliferation.

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library.

Anti-inflammatory influence of P-selectin on human mononuclear cells.

The purpose of this study was to determine if P-selectin, an adhesion molecule involved in the transendothelial movement of leukocytes, might also have a direct influence on the function of cells that come into contact with it. Human peripheral blood mononuclear cells were incubated on immobilized P-selectin or a control substrate (bovine serum albumin, BSA) and stimulated with bacterial lipopolysaccharide (LPS). After 24 h, the concentrations of proinflammatory cytokines in the supernatants of LPS-stimulated cells incubated on P-selectin were <50% of those produced by cells incubated on BSA (interleukin-1beta: P=0.

Aryl hydrocarbon receptor-independent toxicity of weathered crude oil during fish development.

Polycyclic aromatic hydrocarbons (PAHs), derived largely from fossil fuels and their combustion, are pervasive contaminants in rivers, lakes, and nearshore marine habitats. Studies after the Exxon Valdez oil spill demonstrated that fish embryos exposed to low levels of PAHs in weathered crude oil develop a syndrome of edema and craniofacial and body axis defects. Although mechanisms leading to these defects are poorly understood, it is widely held that PAH toxicity is linked to aryl hydrocarbon receptor (AhR) binding and cytochrome P450 1A (CYP1A) induction.

Modulation of conventional outflow facility by the adenosine A1 agonist N6-cyclohexyladenosine.

Purpose: Studies have shown that the activation of adenosine A(1) receptors lower intraocular pressure primarily by increasing total outflow facility. The purpose of this study was to investigate the actions of the adenosine A(1) agonist N(6)-cyclohexyladenosine (CHA) on conventional outflow facility.

Methods: Conventional outflow facility was evaluated in isolated bovine anterior segments, perfused at a constant pressure of 10 mm Hg.

Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors.

A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis.

Escherichia coli: development of carbapenem resistance during therapy.

A 76-year-old woman had recurrent urosepsis due to extended-spectrum beta -lactamase-positive Escherichia coli. Imipenem resistance was detected after long-term imipenem-meropenem therapy. The carbapenem-hydrolyzing enzyme gene was identified as blaKPC-3.

Hydroxytriamides as potent gamma-secretase inhibitors.

Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.

Indanyl piperazines as melatonergic MT2 selective agents.

Optimization of a benzyl piperazine pharmacophore produced N-acyl-4-indanyl-piperazines that bind with high affinity to melatonergic MT(2) receptors. (R)-4-(2,3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine-carboxamide fumarate (13) is a water soluble, selective MT(2) agonist, which produces advances in circadian phase in rats at doses of 1-56 mg/kg that are no different from those of melatonin at 1 mg/kg. Unlike melatonin, 13 produced only weak contractile effects in rat tail artery.

Development of a presynaptic 5-HT1A antagonist.

A new 5-HT(1A) silent antagonist 14 (5-HT(1A) IC(50)=2.2 nM) antagonizes the effects of agonists on reciprocal forepaw treading behavior, on neuronal firing in the rat dorsal raphé, and on 5-HT(1A) release in the raphé and hippocampus. While 14 alone was inactive in the social interaction paradigm, it completely reversed the social interaction activity of the serotonergic compounds (buspirone, 1, and 2).

Review of the reliability and validity of myometry with children.

Pediatric occupational therapists and physical therapists often measure muscle strength, and muscle strength frequently is cited as an indicator of function in clinical practice and in research. A reliable measure to quantify strength is necessary to accurately assess muscle strength so the values can be used for comparison, study, and indication of change. The hand-held myometer provides an alternative to traditional methods of manual muscle testing, and its reliability and validity have been examined in adults.

Estrogen-dependent growth of a rat pituitary tumor involves, but does not require, a high level of vascular endothelial growth factor.

Long-term (10-week) treatment of Fischer 344 (F344) rats with the synthetic estrogen diethylstilbestrol (DES) increases the level of vascular endothelial growth factor (VEGF) in the pituitary. This is concurrent with the development of a large tumor of the pituitary of F344 rats. A role for VEGF in estrogen-dependent pituitary tumor growth is also supported by the fact that pituitary VEGF level is not increased by estrogen treatment in rats of the tumor-resistant Brown Norway (BN) strain.

High dose rate afterloading 192 iridium prostate brachytherapy.

Since the evolution of prostate-specific antigen testing for prostate cancer, men have been diagnosed with earlier staged disease. Earlier staged cancer is amenable to local therapy. Over the last decade, new technology has evolved in the treatment of localized prostate cancer.

Density and population structure of owl monkeys (Aotus azarai) in the Argentinean Chaco.

Owl monkeys are small monogamous primates ranging over a wide area extending from Panama to the Chaco region of northern Argentina. The Chaco, an alluvial plain covering over one million km2 of Argentina, Bolivia, Brazil, and Paraguay, consists of a mosaic of grasslands, savannas, xeric thorn forests, and gallery forests. The region shows significant seasonal variation in climate, rainfall, and food availability.