Comparison of blood volume characteristics in anemic patients with low versus preserved left ventricular ejection fractions

Anemia is a significant co-morbidity in patients with heart failure (HF) irrespective of the ejection fraction and is routinely quantified by hemoglobin concentration. Hemodilution as a cause of anemia has been described in systolic HF. The aim of this study was to further investigate the effects of plasma volume in patients with HF by (1) assessing the prevalence of dilutional anemia in patients with anemia and preserved ejection fractions and (2) exploring the relation between hemoglobin and red cell volume in these patients. Forty-six patients with anemia (as determined by standard hemoglobin measurement), 22 with HF and low ejection fractions (HFLEF) and 24 with HF and preserved ejection fractions (HFPEF), all underwent plasma volume measurement with iodine-131-labeled albumin. Hemoglobin values did not differ between subjects with HFLEF and those with HFPEF (10.8 +/- 1.0 vs 11.0 +/- 1.0 g/dl, p = 0.55), but a red cell deficit was found in 88% of patients with HFPEF compared with 59% of those with HFLEF (p = 0.04). This was the result of a higher prevalence of an expansion of plasma volume in patients with HFLEF (100%) compared with those with HFPEF (71%). Among all patients, no correlation was found between hemoglobin and red cell volume (r = 0.09, p = 0.54), but a correlation did exist in patients with normal blood volumes (r = 0.55, p = 0.02). In conclusion, dilutional anemia caused by an expansion in plasma volume without a red cell deficit occurs more commonly in patients with HFLEF than those with HFPEF, and hemoglobin does not correlate with red cell volume in patients with anemia and HF.     

Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor

A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.     

Structure-activity relationships of C-17 cyano-substituted estratrienes as anticancer agents

The synthesis, SAR, and preclinical evaluation of 17-cyanated 2-substituted estra-1,3,5(10)-trienes as anticancer agents are discussed. 2-Methoxy-17beta-cyanomethylestra-1,3,5(10)-trien-3-ol ( 14), but not the related 2-ethyl derivative 7, and the related 3- O-sulfamates 8 and 15 display potent antiproliferative effects (MCF-7 GI 50 300, 60 and 70 nM, respectively) against human cancer cells in vitro. Investigation of the SAR reveals that a sterically unhindered hydrogen bond acceptor attached to C-17 is most likely key to the enhanced activity. Compound 8 displayed significant in vitro antiangiogenic activity, and its ability to act as a microtubule disruptor was confirmed. Inhibitory activity of the sulfamate derivatives against steroid sulfatase and carbonic anhydrase II (hCAII) was also observed, and the interaction between 15 and hCAII was investigated by protein crystallography. The potential of these multimechanism anticancer agents was confirmed in vivo, with promising activity observed for both 14 and 15 in an athymic nude mouse MDA-MB-231 human breast cancer xenograft model.     

Effects of PRX-00023, a novel, selective serotonin 1A receptor agonist on measures of anxiety and depression in generalized anxiety disorder: results of a double-blind, placebo-controlled trial

PRX-00023, a serotonin 1A receptor agonist, was designed to provide high potency and selectivity for its target. To assess the possible therapeutic utility in anxiety, a randomized, double-blind, placebo-controlled trial was conducted in 311 subjects who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for generalized anxiety disorder. All subjects underwent a 1-week placebo run-in and were randomized to receive once-daily capsules containing either PRX-00023 (80 mg/d) or placebo for an additional 8 weeks. The primary outcome measure was the Hamilton Anxiety Scale (HAM-A). The Montgomery-Asberg Depression Rating Scale was used as a secondary endpoint to measure depressive symptoms. Statistical testing was performed with analysis of covariance, between baseline and week 8, with baseline values as a covariate. The anxiolytic effect of PRX-00023, compared with placebo, showed trends across all anxiolytic measures but failed to reach significance on the primary endpoint (HAM-A total score). Among the components of the HAM-A total score, the anxious mood item was significantly different from placebo in the PRX-00023-treated group (-1.015 vs -0.748; P = 0.02). The scores of the Montgomery-Asberg Depression Rating Scale were significantly improved compared with placebo at week 8 (-4.5 vs -1.6; P = 0.0094 in the last observation carried forward analysis). PRX-00023 was well tolerated; of note, there were no drug-related serious adverse events, and more patients discontinued due to adverse events in the placebo group (2.9%) than in the PRX-00023 group (1.4%). The most common adverse event was headache, observed in 15.7% and 10.9% of PRX-00023- and placebo-treated patients, respectively. Furthermore, there was no evidence of impaired sexual function, as measured by the Massachusetts General Hospital Sexual Function Scale. Collectively, these results support further clinical investigation of higher doses of PRX-00023 in anxiety and depression.     

Outcomes of root canal treatment and restoration, implant-supported single crowns, fixed partial dentures, and extraction without replacement: a systematic review

STATEMENT OF PROBLEM: Dentists and patients are regularly confronted by a difficult treatment question: should a tooth be saved through root canal treatment and restoration (RCT), be extracted without any tooth replacement, be replaced with a fixed partial denture (FPD) or an implant-supported single crown (ISC)? PURPOSE: The purpose of this systematic review was to compare the outcomes, benefits, and harms of endodontic care and restoration compared to extraction and placement of ISCs, FPDs, or extraction without tooth replacement. MATERIAL AND METHODS: Searches performed in MEDLINE, Cochrane, and EMBASE databases were enriched by hand searches, citation mining, and expert recommendation. Evidence tables were developed following quality and inclusion criteria assessment. Pooled and weighted mean success and survival rates, with associated confidence intervals, were calculated for single implant crowns, fixed partial dentures, and initial nonsurgical root canal treatments. Data related to extraction without tooth replacement and psychosocial outcomes were evaluated by a narrative review due to literature limitations. RESULTS: The 143 selected studies varied considerably in design, success definition, assessment methods, operator type, and sample size. Direct comparison of treatment types was extremely rare. Limited psychosocial data revealed the traumatic effect of loss of visible teeth. Economic data were largely absent. Success rates for ISCs were higher than for RCTs and FPDs, respectively; however, success criteria differed greatly among treatment types, rendering direct comparison of success rates futile. Long-term survival rates for ISCs and RCTs were similar and superior to those for FPDs. CONCLUSIONS: Lack of comparative studies with similar outcomes criteria with comparable time intervals limited comparison of these treatments. ISC and RCT treatments resulted in superior long-term survival, compared to FPDs. Limited data suggested that extraction without replacement resulted in inferior psychosocial outcomes compared to alternatives. Long-term, prospective clinical trials with large sample sizes and clearly defined outcomes criteria are needed.