Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects

Objective: To evaluate the efficacy and safety of the selective dopamine D1/D5 antagonist ecopipam for the treatment of obesity. Research Methods and Procedures: Four randomized, double‐blind, multicenter trials compared ecopipam (n = 1667) and placebo (n = 1118) in obese subjects including type 2 diabetic subjects. Subjects received oral ecopipam 10, 30, or 100 mg daily for 12 weeks (Phase 2) or 50 or 100 mg daily for 52 weeks (Phase 3) combined with a weight loss program. Primary efficacy variables were the proportion of subjects with ≥5% weight loss from baseline at 12 weeks (Phase 2) or the distribution of percentage weight loss from baseline at 52 weeks (Phase 3). Results: In the Phase 2 study, 26% of subjects administered ecopipam 100 mg vs. 6% of placebo subjects achieved ≥5% weight loss after 12 weeks (p < 0.01). In the Phase 3 studies, ecopipam 100 mg produced a 3.1% to 4.3% greater weight loss than placebo at 52 weeks. More subjects administered ecopipam vs. placebo achieved a 5% to 10% or >10% weight loss in two non‐diabetic phase 3 trials. Ecopipam‐treated subjects also maintained more weight loss compared with placebo subjects at 52 weeks. Phase 3 studies were discontinued because of unexpected psychiatric adverse events (ecopipam 31% vs. placebo 15%), including depression, anxiety, and suicidal ideation. Discussion: Ecopipam was effective for achieving and maintaining weight loss in obese subjects, including type 2 diabetic subjects; however, the adverse effects on mood observed in the Phase 3 studies exclude its projected use in weight management.     

NPY5R antagonism does not augment the weight loss efficacy of orlistat or sibutramine

Objective: Central counter‐regulatory mechanisms, including those related to the orexigenic hormone neuropeptide Y (NPY), may limit the weight loss observed with conventional pharmacological monotherapy. This study evaluated whether blockade of the NPY Y5 receptor (NPY5R) with the selective antagonist MK‐0557 potentiates sibutramine and orlistat weight loss effects. Research Methods and Procedures: Obese patients (497, BMI 30 to 43 kg/m²) were randomized to 1 of 5 treatment arms [placebo, n = 101; sibutramine 10 mg/d, n = 100; MK‐0557 1 mg/d plus sibutramine 10 mg/d, n = 98; orlistat 120 mg TID, n = 99; MK‐0557 1 mg/d plus orlistat 120 mg TID, n = 99] in conjunction with a hypocaloric diet for 24 weeks. The all‐patients‐treated population, imputing missing data using last observation carried forward, was used to assess weight loss from baseline. Results: The study was completed by 71% of patients in placebo, 76% in sibutramine alone, 79% in MK‐0557 + sibutramine, 69% in orlistat alone, and 76% in MK‐0557 + orlistat groups. Least squares (LS) mean difference [95% confidence interval (CI)] in weight change from baseline between MK‐0557 + sibutramine and sibutramine alone was ?0.1 (?1.6, 1.4) kg (p = 0.892) and between MK‐0557 + orlistat and orlistat alone was ?0.9 (?2.4, 0.6) kg (p = 0.250). Sibutramine alone induced a LS mean weight loss of ?5.9 (?6.9, ?4.9) kg vs. ?4.6 (?5.7, ?3.6) kg for orlistat (p = 0.097). There were no serious drug‐related adverse events and MK‐0557 was well tolerated. Discussion: Blockade of the NPY5R with the potent antagonist MK‐0557 did not significantly increase the weight loss efficacy of either orlistat or sibutramine monotherapy.     

Applying Fuzzy and Probabilistic Uncertainty Concepts to the Material Flow Analysis of Palladium in Austria

Material flow analysis (MFA) is a widely applied tool to investigate resource and recycling systems of metals and minerals. Owing to data limitations and restricted system understanding, MFA results are inherently uncertain. To demonstrate the systematic implementation of uncertainty analysis in MFA, two mathematical concepts for the quantification of uncertainties were applied to Austrian palladium (Pd) resource flows and evaluated: (1) uncertainty ranges expressed by fuzzy sets and (2) uncertainty ranges defined by normal distributions given as mean values and standard deviations. Whereas normal distributions represent the traditional approach for quantifying uncertainties in MFA, fuzzy sets may offer additional benefits in relation to uncertainty quantification in cases of scarce information. With respect to the Pd case study, the fuzzy representation of uncertain quantities is more consistent with the actual data availability in cases of incomplete databases, and fuzzy sets serve to highlight the effect of uncertainty on resource efficiency indicators derived from the MFA results. For both approaches, data reconciliation procedures offer the potential to reduce uncertainty and evaluate the plausibility of the model results. With respect to Pd resource management, improved formal collection of end‐of‐life (EOL) consumer products is identified as a key factor in increasing the recycling efficiency. In particular, the partial export of EOL vehicles represents a substantial loss of Pd from the Austrian resource system, whereas approximately 70% of the Pd in the EOL consumer products is recovered in waste management. In conclusion, systematic uncertainty analysis is an integral part of MFA required to provide robust decision support in resource management.     

The Arabidopsis SUVR4 protein is a nucleolar histone methyltransferase with preference for monomethylated H3K9

Proteins containing the evolutionarily conserved SET domain are involved in regulation of eukaryotic gene expression and chromatin structure through their histone lysine methyltransferase (HMTase) activity. The Drosophila SU(VAR)3-9 protein and related proteins of other organisms have been associated with gene repression and heterochromatinization. In Arabidopsis there are 10 SUVH and 5 SUVR genes encoding proteins similar to SU(VAR)3-9, and 4 SUVH proteins have been shown to control heterochromatic silencing by its HMTase activity and by directing DNA methylation. The SUVR proteins differ from the SUVH proteins in their domain structure, and we show that the closely related SUVR1, SUVR2 and SUVR4 proteins contain a novel domain at their N-terminus, and a SUVR specific region preceding the SET domain. Green fluorescent protein (GFP)-fusions of these SUVR proteins preferably localize to the nucleolus, suggesting involvement in regulation of rRNA expression, in contrast to other SET-domain proteins studied so far. A novel HMTase specificity was demonstrated for SUVR4, in that monomethylated histone H3K9 is its preferred substrate in vitro.     

Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans

Adiponectin is an adipose tissue-specific protein that is abundantly present in the circulation and suggested to be involved in insulin sensitivity and development of atherosclerosis. Because cytokines are suggested to regulate adiponectin, the aim of the present study was to investigate the interaction between adiponectin and three adipose tissue-derived cytokines (IL-6, IL-8, and TNF-alpha). The study was divided into three substudies as follows: 1) plasma adiponectin and mRNA levels in adipose tissue biopsies from obese subjects [mean body mass index (BMI): 39.7 kg/m2, n = 6] before and after weight loss; 2) plasma adiponectin in obese men (mean BMI: 38.7 kg/m2, n = 19) compared with lean men (mean BMI: 23.4 kg/m2, n = 10) before and after weight loss; and 3) in vitro direct effects of IL-6, IL-8, and TNF-alpha on adiponectin mRNA levels in adipose tissue cultures. The results were that 1) weight loss resulted in a 51% (P < 0.05) increase in plasma adiponectin and a 45% (P < 0.05) increase in adipose tissue mRNA levels; 2) plasma adiponectin was 53% (P < 0.01) higher in lean compared with obese men, and plasma adiponectin was inversely correlated with adiposity, insulin sensitivity, and IL-6; and 3) TNF-alpha (P < 0.01) and IL-6 plus its soluble receptor (P < 0.05) decreased adiponectin mRNA levels in vitro. The inverse relationship between plasma adiponectin and cytokines in vivo and the cytokine-induced reduction in adiponectin mRNA in vitro suggests that endogenous cytokines may inhibit adiponectin. This could be of importance for the association between cytokines (e.g., IL-6) and insulin resistance and atherosclerosis.     

Production of N(2) through anaerobic ammonium oxidation coupled to nitrate reduction in marine sediments

In the global nitrogen cycle, bacterial denitrification is recognized as the only quantitatively important process that converts fixed nitrogen to atmospheric nitrogen gas, N(2), thereby influencing many aspects of ecosystem function and global biogeochemistry. However, we have found that a process novel to the marine nitrogen cycle, anaerobic oxidation of ammonium coupled to nitrate reduction, contributes substantially to N(2) production in marine sediments. Incubations with (15)N-labeled nitrate or ammonium demonstrated that during this process, N(2) is formed through one-to-one pairing of nitrogen from nitrate and ammonium, which clearly separates the process from denitrification. Nitrite, which accumulated transiently, was likely the oxidant for ammonium, and the process is thus similar to the anammox process known from wastewater bioreactors. Anaerobic ammonium oxidation accounted for 24 and 67% of the total N(2) production at two typical continental shelf sites, whereas it was detectable but insignificant relative to denitrification in a eutrophic coastal bay. However, rates of anaerobic ammonium oxidation were higher in the coastal sediment than at the deepest site and the variability in the relative contribution to N(2) production between sites was related to large differences in rates of denitrification. Thus, the relative importance of anaerobic ammonium oxidation and denitrification in N(2) production appears to be regulated by the availability of their reduced substrates. By shunting nitrogen directly from ammonium to N(2), anaerobic ammonium oxidation promotes the removal of fixed nitrogen in the oceans. The process can explain ammonium deficiencies in anoxic waters and sediments, and it may contribute significantly to oceanic nitrogen budgets.     

Location of DNA damage by charge exchanging repair enzymes: effects of cooperativity on location time

Background  

How DNA repair enzymes find the relatively rare sites of damage is not known in great detail. Recent experiments and molecular data suggest that individual repair enzymes do not work independently of each other, but interact with each other through charges exchanged along the DNA. A damaged site in the DNA hinders this exchange. The hypothesis is that the charge exchange quickly liberates the repair enzymes from error-free stretches of DNA. In this way, the sites of damage are located more quickly; but how much more quickly is not known, nor is it known whether the charge exchange mechanism has other observable consequences.     

Gonococcal Tonsillar Infections

Neisseria gonorrhoeae were cultured from tonsillar swabs in six men and six women out of 161 consecutive, unselected, Danish patients (95 men and 66 women) suffering from urogenital or rectal gonorrhoea. Gonococci were found in the tonsils in only one out of 49 foreign men with gonorrhoea. Eleven of the Danish patients admitted orogenital contact at their most recent intercourse. The gonococcal complement fixation test was negative in all except two cases. Standard singledose treatment cured the urogenital and rectal infections promptly but failed to cure the tonsillar infection in five cases, and in recalcitrant cases the organisms were demonstrable for some months.