No abstract

Liver cirrhosis represents a worldwide health problem and is a major cause of mortality. Cirrhosis is the result of extensive hepatocyte death and fibrosis induced by chronic alcohol abuse and hepatitis B and C viruses. Successful gene therapy approaches to this disease may require both reversal of fibrosis and stimulation of hepatocyte growth. Urokinase-type plasminogen activator (uPA) may serve this function, as it is an initiator of the matrix proteolysis cascade and induces hepatocyte growth factor expression. In a rat cirrhosis model, a single iv administration of a replication-deficient adenoviral vector encoding a nonsecreted form of human uPA resulted in high production of functional uPA protein in the liver. This led to induction of collagenase expression and reversal of fibrosis with concomitant hepatocyte and improved liver function. Thus, uPA gene therapy may be an effective strategy for treating cirrhosis in humans.

Fire is considered the main cause for the patchy distribution of high‐montane tropical forests growing below the upper limit of tree growth, but there are little quantitative data on the impacts of burning on the respective tree populations. This study compares adult tree survival as well as sapling (0.05–1.3 m) and seedling (<0.05 m) recruitment of Polylepis incana, and the coexisting Gynoxis acostae in burned and unburned forest stands in the Páramo de Guamaní, central Ecuador. In P. incana, adult survival after burning was low, whereas all G. acostae individuals survived through resprouting. Two years after fire, the density of P. incana seedlings and saplings was higher than that of G. acostae, but still not sufficient for forest recovery. A sowing experiment revealed a significantly lower seedling emergence of both species in the burned than in the unburned plots. Seedling emergence was comparable to laboratory studies performed under optimal conditions, suggesting there was no evidence for climate constraining emergence at the given altitude. Interactions between seedling survival and burning for P. incana indicate higher seedling survival after burning, which could not be shown for G. acostae. Our data imply that single fire events strongly decrease adult and seedling population sizes in P. incana and thus may be the main reason for the discontinuous forest distribution below the upper distribution limit of the species. In contrast, the high resprouting potential of G. acostae explains its relatively high percentage in the remaining Ecuadorian P. incana stands.

Human urokinase-type plasminogen activator (uPA) gene administration via an adenoviral (Ad)-vector induced cirrhosis regression and ameliorated hepatic dysfunction in a model of experimental liver cirrhosis. The administration of a single dose of 6 x 10(11) viral particles per kilogram of a clinical-grade Ad-vector was evaluated after the onset of rat liver cirrhosis via degradation of deposited collagen and a substantial decrease of alpha-sma-positive cells. Also, gene expression for pro-fibrogenic molecules (Col I, III, IV, TIMP-1 and PAI-1) was clearly down-regulated. In contrast, gene expression for collagen-degrading enzymes such as MMP-13 and MMP-2 was up-regulated. These events correlated with increased amounts of proteic free-TIMP-1, i.e. non-complexed with metalloproteinases (MMPs), indicating the presence of higher amounts of active MMPs inside the liver of cirrhotic animals treated with Ad-huPA. The harmonized and concerted expression of HGF and c-met resulted in exacerbated hepatocyte proliferation, although these events did not induce an abnormal liver growth. Angiogenesis, i.e. formation of new blood vessels, was evaluated by vascular endothelial growth factor (VEGF) expression which was notably detected to be 10 times higher during the first 6 days after Ad-huPA-treatment in cirrhotic animals as compared with controls. These events provide a clearer rationale as to how Ad-huPA-induced liver regeneration on CCl(4)-induced liver fibrosis takes place.

Soil hydraulic properties control the provision of hydrological services. Vegetation and topography influence these properties by altering soil structure and porosity. The underlying mechanisms are not yet fully understood for the high Andean region. In this study, we examined how vegetation and topographic attributes are related to soil hydraulic properties and soil pore structure in young volcanic ash soils, and further correlated them to soil texture, organic carbon, and root characteristics to explain these relationships. In a 0.7 km 2 study site located in the Andean páramo of northern Ecuador, we measured soil water retention, saturated hydraulic conductivity, bulk density (BD), and pore size distribution parameters on eight soil profiles with contrasting vegetation types (cushion-forming plants vs. tussock grasses) and topographic positions (summit vs. hillslope). We observed significant differences in soil hydraulic properties and soil pore structure in the uppermost horizons by vegetation type, whereas topography had a minor effect. In the A horizons, we found higher water retention at saturation and field capacity (10%-14%), higher total available water (8%-15%), and higher saturated hydraulic conductivity (4-12 times) under cushion-forming plants compared to tussock grasses. The elevated values under cushion plants were attributed to the presence of larger pores, lower soil BD, and higher soil organic carbon content as a result of coarser root systems. Total available water was generally high (0.34-0.40 cm 3 cm À3 ), and locally not associated with any soil property. The higher water retention in soils under cushion vegetation can enhance soil water storage for plants and the regulation of water flows during prolonged

Despite widely published speculation regarding a potential potency advantage of short-wavelength (blue-appearing) light for Seasonal Affective Disorder (SAD) treatment, there have been few systematic studies. Those comparing short-wavelength to broad-wavelength (white) light under actual clinical conditions suggest equivalent effectiveness. This multicenter, parallel-group design trial was undertaken to compare the effects of light therapy on SAD using blue (~465nm) versus blue-free (595–612nm) LED lights. Fifty-six medication-free subjects aged 21–64 years who met DSM-IV-TR criteria for recurrent major depression with winter-type seasonal pattern were enrolled in this blinded study at 5 participating centers between January and March 2012. Thirty-five subjects met criteria for randomization to 30 minutes of either blue (~465nm) or blue-free (595–612nm) daily morning light therapy. Twenty-nine subjects completed the study; three subjects withdrew due to treatment-related adverse events, including migraines, and three withdrew for non-study-related reasons. The primary effectiveness variable was depression score (SIGH-ADS) after six weeks of daily light treatment. Secondary effectiveness variables included Quality of Life and suicidality ratings. Using an intent-to-treat analysis, mean depression scores were different at baseline for the blue group (29±5 vs. 26±5, p=0.05 blue vs. blue-free, respectively), and initial score was used as a covariate. Baseline scores were not significantly different between treatment groups among those who completed the study, and no significant differences in depression scores were observed after 6 weeks (mean ± s.d. scores at 6 weeks: 5.6±6.1 vs. 4.5±5.3, p=0.74, blue vs. blue-free, respectively). In addition, the proportion of subjects who met remission criteria, defined as a depression score ≤8, was not significantly different between the two groups (p=0.41); among the 29 subjects who completed the study, 76% of subjects experienced remission by the end of the trial, which coincided with the beginning of spring. Quality of Life and suicidality ratings were also significantly improved from pre- to post-treatment, with no significant difference between treatments. No subject experienced worsening or non-improved symptoms over the 6-week trial. The main finding of this study is that subjects treated with blue light did not improve more than subjects treated with blue-free light; both showed substantial improvement on multiple measures. Failure to find differences may have resulted from methodological constraints, including a small sample size. Recruitment began mid-winter during an unusually mild season, and the trial was terminated earlier than planned by the study sponsor due to a failure to detect difference. However, if confirmed in a larger randomized sample, these results suggest that blue wavelengths are not necessary for successful SAD treatment.

Gene therapy may represent a new avenue for the development of multimodal treatment for diverse forms of cirrhosis. This study explores the potential benefits of combining adenovirus-mediated human urokinase-plasminogen activator (AdHuPA) gene delivery and biliodigestive anastomosis to enhance the therapeutic efficacy of each treatment alone for cholestatic disorders resulting in secondary biliary cirrhosis. In an experimental model of secondary biliary cirrhosis, application of 6 x 10(11) vp/kg AdHuPA adenovirus vector resulted in 25.8% liver fibrosis reduction and some improvement in liver histology. The relief of bile cholestasis by a surgical procedure (biliodigestive anastomosis) combined with AdHuPA hepatic gene delivery rendered a synergistic effect, with a substantial 56.9 to 42.9% fibrosis decrease. AdHuPA transduction resulted in clear-cut expression of human uPA protein detected by immunohistochemistry and induction of up-regulation in the expression of metalloproteinases MMP-3, MMP-9, and MMP-2. Importantly, functional hepatic tests, specifically direct bilirubin, were improved. Also, hepatic cell regeneration, rearrangement of hepatic architecture, ascites, and gastric varices improved in cirrhotic rats treated with AdHuPA but not in counterpart AdGFP cirrhotic animals. We believe this might represent a novel therapeutic strategy for human cholestatic diseases.

No abstract