Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease.

BACKGROUND: Sirtuin 1 (Sirt1) is suppressed in non-alcoholic fatty liver disease (NAFLD), while its' stimulation or overexpression results in reduced disease severity in pre-clinical NAFLD models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin and sildenafil (NS-0200), which was effective in a mouse model of non-alcoholic steatohepatitis (NASH). AIM: To report the results from a Phase 2, randomised clinical trial of of NS-0200 in 91 subjects with NAFLD (liver fat ≥15% by magnetic resonance imaging-proton-density fat fraction (MRI-PDFF)). METHODS: Subjects were randomised to placebo, low-dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high-dose NS-0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI-PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35). RESULTS: In the full cohort, active treatments did not separate from placebo. High dose NS-0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P < 0.005) while low dose NS-0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose-responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up-regulation of fatty acid oxidation. CONCLUSION: These data support further evaluation of high-dose NS-0200 for treating NASH, especially in those with elevated ALT (NCT 02546609).

Sources of variability in livestock water quality over 5 years in the Northern Great Plains.

Concentrated dissolved minerals in naturally occurring water accessible to livestock grazing semiarid landscapes can negatively influence animal productivity and well-being. Twelve indicators of water quality (Ca, Cl, Fe, F, Mg, Mn, Na, nitrate N, pH, SO4, total dissolved solids [TDS], and temperature) were measured at 45 livestock water sites over 5 yr from 2009 through 2013 at the 22,257-ha USDA-ARS Fort Keogh Livestock and Range Research Laboratory (Miles City, MT) to estimate variation. Water was sampled from 4 sources: 1) flowing surface water, 2) groundwater, 3) reservoirs, and 4) springs. The sampled area was classified by 3 cardinal compass bearings (locations): 1) north, 2) southeast, and 3) southwest of the Yellowstone River. Samples were collected twice yearly in 2 seasons, May (wet) and September (dry). Year, location, source, and season and their interactions were analyzed as a 5 × 3 × 4 × 2 factorial arrangement of treatments. A location × year interaction (P < 0.04) was found for Mg, Na, SO4, and TDS. The southwest location had the greatest concentrations in 2012 of Na, SO4, and TDS. A source × year interaction (P < 0.02) was found for Ca, Fe, F, Mg, Mn, Na, SO4, TDS, and temperature. Iron, Mg, and Mn had the greatest concentrations in flowing surface water in 2012. Greater and then lower precipitation in 2011 followed by below-average precipitation in 2012 was associated with elevated mineral concentrations in sources in the southwest location and flowing surface water sources demonstrating sources of water quality variability within time and space at the study site. Average concentrations of Ca, Cl, Mg, and nitrate N and pH levels across sources and locations did not exceed the upper maximum intake level for beef cattle. In contrast, concentrations of F, Fe, Na, SO4, and TDS at times exceeded the upper maximum level for beef cattle, indicating these minerals may negatively impact range beef cattle performance.

Population densities and tree diameter effects associated with verbenone treatments to reduce mountain pine beetle-caused mortality of lodgepole pine.

Mountain pine beetle, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae: Scolytinae), is among the primary causes of mature lodgepole pine, Pinus contorta variety latifolia mortality. Verbenone is the only antiaggregant semiochemical commercially available for reducing mountain pine beetle infestation of lodgepole pine. The success of verbenone treatments has varied greatly in previous studies because of differences in study duration, beetle population size, tree size, or other factors. To determine the ability of verbenone to protect lodgepole pine over long-term mountain pine beetle outbreaks, we applied verbenone treatments annually for 3 to 7 yr at five western United States sites. At one site, an outbreak did not develop; at two sites, verbenone reduced lodgepole pine mortality in medium and large diameter at breast height trees, and at the remaining two sites verbenone was ineffective at reducing beetle infestation. Verbenone reduced mountain pine beetle infestation of lodgepole pine trees in treated areas when populations built gradually or when outbreaks in surrounding untreated forests were of moderate severity. Verbenone did not protect trees when mountain pine beetle populations rapidly increase.

Managing soil nitrogen to restore annual grass-infested plant communities: effective strategy or incomplete framework?

Theoretical and empirical work has established a positive relationship between resource availability and habitat invasibility. For nonnative invasive annual grasses, similar to other invasive species, invader success has been tied most often to increased nitrogen (N) availability. These observations have led to the logical assumption that managing soils for low N availability will facilitate restoration of invasive plant-dominated systems. Although invasive annual grasses pose a serious threat to a number of perennial-dominated ecosystems worldwide, there has been no quantitative synthesis evaluating the degree to which soil N management may facilitate restoration efforts. We used meta-analysis to evaluate the degree to which soil N management impacts growth and competitive ability of annual and perennial grass seedlings. We then link our analysis to current theories of plant ecological strategies and community assembly to improve our ability to understand how soil N management may be used to restore annual grass-dominated communities. Across studies, annual grasses maintained higher growth rates and greater biomass and tiller production than perennials under low and high N availability. We found no evidence that lowering N availability fundamentally alters competitive interactions between annual and perennial grass seedlings. Competitive effects of annual neighbors on perennial targets were similar under low and high N availability. Moreover, in most cases perennials grown under competition in high-N soils produced more biomass than perennials grown under competition in low-N soils. While these findings counter current restoration and soil N management assumptions, these results are consistent with current plant ecological strategy and community assembly theory. Based on our results and these theories we argue that, in restoration scenarios in which the native plant community is being reassembled from seed, soil N management will have no direct positive effect on native plant establishment unless invasive plant propagule pools and priority effects are controlled the first growing season.

Factors associated with sustained virological response in liver transplant recipients with recurrent hepatitis C.

BACKGROUND: Antiviral therapy has achieved sustained virological response (SVR) in less than one third of orthotopic liver transplantation (OLT) patients with recurrent hepatitis C. AIM: The aim of this study was to identify predictors of SVR in OLT patients treated with pegylated interferon and ribavirin (PEG+RBV) for recurrent hepatitis C virus (HCV). METHODS: We analyzed data from our transplantation database for 62 subjects treated with PEG+RBV between August 2001 and September 2008. After univariate examination for factors known to be associated with SVR, significant associations (P < .05) were probed using multivariate logistic regression. Kaplan-Meier patient and graft survival analyses were compared between patients with (n = 19; 30.6%) versus without SVR. RESULTS: On univariate analysis, longer duration of therapy, low pretreatment HCV RNA (<1 million IU/mL), and early virological response (EVR) were associated with SVR. On multivariate analysis, only low pretreatment HCV RNA predicted SVR. Patient survival was significantly higher in the SVR group. CONCLUSIONS: Covariates associated with SVR among OLT patients with recurrent HCV were similar to the pretransplantation group. Potentially modifiable risk factors, such as obesity, diabetes mellitus, and metabolic syndrome, were not significant predictors of treatment response. Patient survival was associated with SVR, highlighting the impact of successful HCV therapy on long-term post-OLT outcomes.

[Associating Serenoa repens, Urtica dioica and Pinus pinaster. Safety and efficacy in the treatment of lower urinary tract symptoms. Prospective study on 320 patients]. / Associazione di Serenoa repens, Urtica dioica e Pinus pinaster. Sicurezza ed efficacia nel trattamento dei sintomi del basso tratto urinario. Studio prospettico su 320 pazienti.

INTRODUCTION: Serenoa repens (saw palmetto) has been employed for the treatment of lower urinary tract symptoms (LUTS) for several years. Its mechanism of action is believed to be due to antiandrogenic, antiproliferative and antinflammatory properties. An association of Serenoa with the nettle "Urtica dioica" showing antiproliferative activity and the pine "Pinus pinaster" derivative, showing antinflammatory action, has been proposed in recent years. Such an action is hoped to act not only by reducing LUTS but also by preventing the development of prostate cancer. MATERIAL AND METHODS: During the years 2007 and 2008, 320 patients suffering from LUTS were treated with an association of Serenoa repens 320 mg, Urtica dioica 120 mg and Pinus pinaster 5 mg, named IPBTRE. This treatment was administered to all patients for a minimal duration of 30 days to a maximum of a year, either alone or in association with antibiotics or alpha-blockers, if needed. Outcome analysis was based on evaluation of symptoms, prostate volume and maximum flow rate (Qmax). RESULTS: From a careful analysis of the data collected in our database, the following observations can be made: ages varied between 19 and 78 years. The patients were affected by BPH in 46% of cases, chronic prostatitis syndrome in 43%, chronic genital-pelvic pain in 7% and other conditions in 4%, the absolute numbers being 147, 138, 22 and 7 patients, respectively. No untoward side effect was reported in any case. Variations in symptom score could be fully evaluated only in 80 of 320 patients (25%), of whom 68 (85%) reported a significant benefit, with special reference to an improvement of pain, urgency, strangury and nocturia. Data on variations in prostate volume, as measured by digital rectal examination, were available in 84 (26.5%) patients. No significant change was observed. Qmax after treatment was measured in 83 (26%) patients. It did not show significant changes from the initial values. DISCUSSION: The association tested in our study appeared to be safe and well tolerated. No changes in flow rate and prostate volume were observed, but a marked reduction of LUTS was observed in 85% of evaluable cases, especially with regard to pain and irritative symptoms. Whether or not such an association may display a prevention of prostate cancer, may be investigated in additional studies.

Inundative release of Aphthona spp. flea beetles (Coleoptera: Chrysomelidae) as a biological "herbicide" on leafy spurge in riparian areas.

Inundative releases of beneficial insects are frequently used to suppress pest insects but not commonly attempted as a method of weed biological control because of the difficulty in obtaining the required large numbers of insects. The successful establishment of a flea beetle complex, mixed Aphthona lacertosa (Rosenhauer) and Aphthona nigriscutus Foundras (87 and 13%, respectively), for the control of leafy spurge, Euphorbia esula L., provided an easily collectable source of these natural enemies that enabled us to attempt inundative release as a possible leafy spurge control method in a sensitive riparian ecological zone where chemical control is restricted. Our target weed populations were small isolated patches of leafy spurge along three streams in southwestern, central, and northeastern Idaho. This study assessed leafy spurge and associated vegetation responses to inundative releases of 10 and 50 beetles per spurge flowering stem over two consecutive years. Releasing 10 beetles per flowering stem had inconclusive effects on spurge biomass, crown, stem, and seedling density. Alternatively, releasing 50 beetles per flowering stem resulted in a reduction of biomass, crown and stem density in the range of 60-80% at all three study sites, and about an approximately 60% reduction of seedling density at one site, compared with untreated plots. In contrast to leafy spurge, associated vegetation did not conclusively respond to beetle release, indicating that it may take more than two years for desired riparian vegetation to respond to reductions in leafy spurge competition.

Body mass index as a predictor of hepatic steatosis in living liver donors.

Evaluation of the living donor for liver transplantation is a complex process involving such invasive studies as liver biopsy and angiography. It is important to establish the likelihood and extent of hepatic steatosis in living donors by clinical, imaging, and biochemical parameters to avoid performing a liver biopsy, if possible. In this study, the predictive value of body mass index (BMI), liver chemistry tests, and imaging studies was compared with liver histological examination in 33 potential living donors. Patients were grouped and compared based on their BMI (<25, 25 to 28, >28). No patient with a BMI less than 25 had hepatic steatosis. Of patients with a BMI of 25 to 28, steatosis was found on biopsy in 3 of 9 patients. Thirteen of 17 patients (76%) with a BMI greater than 28 had hepatic steatosis on liver biopsy. There was a significant correlation between BMI and overall grade of steatosis (R = 0.49). All subjects with steatosis detected on magnetic resonance imaging (MRI) or computed tomography (CT) had steatosis on biopsy, and all but 2 such patients had greater than 10% steatosis on biopsy. Conversely, 30% of patients in the MRI group and 24% of patients in the CT group failed to show hepatic steatosis when it was present on biopsy. Thus, it appears that liver biopsy could be avoided in subjects with a normal BMI and absence of risk factors. Individuals with a high BMI should undergo liver biopsy because biochemical and imaging data are currently inadequate to determine the extent of steatosis. Future studies should aim at improving the sensitivity of imaging techniques in the diagnosis of steatosis.