Parallel synthesis of 3-aryloxy-2-propanolamines and evaluation as dual affinity 5-HT(1A) and 5-HT re-uptake ligands

A solution phase synthesis for the preparation of 3-aryloxy-2-propanolamine libraries has been developed. This resulted in the identification of 5 as a ligand with dual affinity for 5-HT1A and serotonin reuptake receptors which shows excellent pharmacokinetic parameters.     

Lilac alcohol epoxide: a linalool derivative in Actinidia arguta flowers

Lilac alcohol epoxide (2-(5-methyl-5-(oxiran-2-yl)-tetrahydrofuran-2-yl)propan-1-ol), a previously unreported monoterpene, was identified in the solvent extract of the flowers of seven Actinidia arguta genotypes. The diastereomeric lilac alcohol epoxides co-occurred with the lilac aldehydes and alcohols. Another compound, the lilac diol (2-(5-(1-hydroxyethyl)-5-methyl-tetrahydrofuran-2-yl)propan-1-ol) was synthesised as part of our efforts to identify the lilac alcohol epoxide.     

Evaluation of 23S rRNA PCR primers for use in phylogenetic studies of bacterial diversity

The availability of a diverse set of 23S rRNA gene sequences enabled evaluation of the specificity of 39 previously published and 4 newly designed primers specific for bacteria. An extensive clone library constructed using an optimized primer pair resulted in similar gene richness but slightly differing coverage of some phylogenetic groups, compared to a 16S rRNA gene library from the same environmental sample.     

Baroreflex responsiveness during ventilatory acclimatization in humans

We tested the hypothesis that the decline in muscle sympathetic activity during and after 8 h of poikilocapnic hypoxia (Hx) was associated with a greater sympathetic baroreflex-mediated responsiveness. In 10 healthy men and women (n=2), we measured beat-to-beat blood pressure (Portapres), carotid artery distension (ultrasonography), heart period, and muscle sympathetic nerve activity (SNA; microneurography) during two baroreflex perturbations using the modified Oxford technique before, during, and after 8 h of hypoxia (84% arterial oxygen saturation). The integrated baroreflex response [change of SNA (DeltaSNA)/change of diastolic blood pressure (DeltaDBP)], mechanical (Deltadiastolic diameter/DeltaDBP), and neural (DeltaSNA/Deltadiastolic diameter) components were estimated at each time point. Sympathetic baroreflex responsiveness declined throughout the hypoxic exposure and further declined upon return to normoxia [pre-Hx, -8.3+/-1.2; 1-h Hx, -7.2+/-1.0; 7-h Hx, -4.9+/-1.0; and post-Hx: -4.1+/-0.9 arbitrary integrated units (AIU) x min(-1) x mmHg(-1); P<0.05 vs. previous time point for 1-h, 7-h, and post-Hx values]. This blunting of baroreflex-mediated efferent outflow was not due to a change in the mechanical transduction of arterial pressure into barosensory stretch. Rather, the neural component declined in a similar pattern to that of the integrated reflex response (pre-Hx, -2.70+/-0.53; 1-h Hx, -2.59+/-0.53; 7-h Hx, -1.60+/-0.34; and post-Hx, -1.34+/-0.27 AIU x min(-1) x microm(-1); P < 0.05 vs. pre-Hx for 7-h and post-Hx values). Thus it does not appear as if enhanced baroreflex function is primarily responsible for the reduced muscle SNA observed during intermediate duration hypoxia. However, the central transduction of baroreceptor afferent neural activity into efferent neural activity appears to be reduced during the initial stages of peripheral chemoreceptor acclimatization.     

Cyclin-dependent kinases and cell-cycle transitions: does one fit all?

Cell-cycle transitions in higher eukaryotes are regulated by different cyclin-dependent kinases (CDKs) and their activating cyclin subunits. Based on pioneering findings that a dominant-negative mutation of CDK1 blocks the cell cycle at G2-M phase, whereas dominant-negative CDK2 inhibits the transition into S phase, a model of cell-cycle control has emerged in which each transition is regulated by a specific subset of CDKs and cyclins. Recent work with gene-targeted mice has led to a revision of this model. We discuss cell-cycle control in light of overlapping and essential functions of the different CDKs and cyclins.     

Colorectal cancer cases and relatives of cases indicate similar willingness to receive and disclose genetic information

Context: Recent developments in genetic testing allow us to detect individuals with inherited susceptibility to some cancers. Genetic testing to identify carriers of cancer-related mutations may help lower risk by encouraging preventive behaviors and surveillance. This study assessed willingness of colon cancer cases and relatives to receive genetic information that may indicate an increased risk for cancer, to whom they would disclose genetic information, and whether receiving genetic test results may influence future prevention behaviors among individuals enrolled in the Seattle Colorectal Cancer Family Registry. Methods: Incident invasive colorectal cancer cases were identified from the Puget Sound Surveillance Epidemiology and End Results (SEER) registry. In 2007, a sequential sample of cases and relatives (n = 147) were asked to respond to a questionnaire addressing study aims. The questionnaire was administered during a baseline or 5-year follow-up interview. Results: Patterns of response to each statement were similar between colorectal cancer cases and relatives. Both colorectal cases (95%) and relatives (95%) reported willingness to receive genetic information. Nearly all participants would tell their doctor the results of a genetic test (99% of cases; 98% of relatives), and all married participants would tell their spouses. Cases (96%) anticipated being slightly more likely than relatives (90%) to change their cancer screening behavior, but this difference was not statistically significant (p = 0.33). Conclusions: A high percentage of both colorectal cancer cases and relatives sampled from the Seattle Colorectal Cancer Family Registry are interested in identifying their genetic status, discussing their genetic status with their family and doctor, and adopting behavioral changes that may reduce cancer risk.     

Apparent Efficacy of Food-Based Calcium Supplementation in Preventing Rickets in Bangladesh

To determine whether increased Ca intakes can prevent rickets in a susceptible group of children living in a rickets-endemic area of Bangladesh, we conducted a 13-month long, double-blind, clinical trial with 1-to 5-year-old children who did not present with rickets but ranked in the upper decile of plasma alkaline phosphatase (AP) activity of a screening cohort of 1,749 children. A total of 158 children were randomized to a milk-powder-based dietary supplement given daily, 6 days/week, and providing either 50, 250, or 500 mg Ca, or 500 mg Ca plus multivitamins, iron, and zinc. Upon initial screening, 194 healthy children presented with no rachitic leg signs and had serum AP in the upper decile (>260 u/dl) of the cohort. When 183 of those subjects were re-screened after a 7-month pre-trial period, 23 (12.6%) had developed rachitic leg signs, suggesting an annual risk of 21.5% in this cohort. Of those still not presenting with leg signs and completing 13 months of dietary intervention, none showed rachitic leg signs, none showed significant radiological evidence of active rickets, and all showed carpal ossification normal for age after that intervention. These results are consistent with even the lowest amount of supplemental Ca (50 mg/day) being useful in supporting normal bone development in this high-risk population.