A Double Blind, Placebo-Controlled, Randomized Crossover Study of the Acute Metabolic Effects of Olanzapine in Healthy Volunteers

Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18-30 years old, BMI 18.5-25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.ClinicalTrials.gov NCT00741026

Anxious/depressed symptoms are related to microstructural maturation of white matter in typically developing youths

AbstractThere are multiple recent reports of an association between anxious/depressed (A/D) symptomatology and the rate of cerebral cortical thickness maturation in typically developing youths. We investigated the degree to which anxious/depressed symptoms are tied to age-related microstructural changes in cerebral fiber pathways. The participants were part of the NIH MRI Study of Normal Brain Development. Child Behavior Checklist A/D scores and diffusion imaging were available for 175 youths (84 males, 91 females; 241 magnetic resonance imagings) at up to three visits. The participants ranged from 5.7 to 18.4 years of age at the time of the scan. Alignment of fractional anisotropy data was implemented using FSL/Tract-Based Spatial Statistics, and linear mixed model regression was carried out using SPSS. Child Behavior Checklist A/D was associated with the rate of microstructural development in several white matter pathways, including the bilateral anterior thalamic radiation, bilateral inferior longitudinal fasciculus, left superior longitudinal fasciculus, and right cingulum. Across these pathways, greater age-related fractional anisotropy increases were observed at lower levels of A/D. The results suggest that subclinical A/D symptoms are associated with the rate of microstructural development within several white matter pathways that have been implicated in affect regulation, as well as mood and anxiety psychopathology.</jats:p

Eucalyptus

The Eucalyptus genus yields high rates of productivity and can be grown across a wide range of site types and climates for products such as pulp, fuelwood, or construction lumber. In addition, many eucalypts have the ability to coppice, making this genus an ideal candidate for use as a biofuel feedstock. However, the water use of Eucalyptus is a controversial issue, and the impacts of these fast-growing trees on water resources are well documented. Regardless, the demand for wood products and water continues to rise, providing a challenge to increase the productivity of forest plantations within water constraints. This is of particular relevance for water-limited countries such as South Africa which relies on exotic plantations to meet its timber needs. Research results from water use studies in South Africa are well documented and legislation restrictions limit further afforestation. This paper outlines techniques used to quantify the water use of eucalypt plantations and provides recommendations on where to focus future research efforts. Greater insights into the water use efficiency of clonal material are needed, as certain eucalypt clones show fast growth and low water use. To better understand water use efficiency, estimates should be combined with monitoring of stand canopy structure and measurements of physiological processes

Eucalyptus and Water Use in South Africa

The Eucalyptus genus yields high rates of productivity and can be grown across a wide range of site types and climates for products such as pulp, fuelwood, or construction lumber. In addition, many eucalypts have the ability to coppice, making this genus an ideal candidate for use as a biofuel feedstock. However, the water use of Eucalyptus is a controversial issue, and the impacts of these fast-growing trees on water resources are well documented. Regardless, the demand for wood products and water continues to rise, providing a challenge to increase the productivity of forest plantations within water constraints. This is of particular relevance for water-limited countries such as South Africa which relies on exotic plantations to meet its timber needs. Research results from water use studies in South Africa are well documented and legislation restrictions limit further afforestation. This paper outlines techniques used to quantify the water use of eucalypt plantations and provides recommendations on where to focus future research efforts. Greater insights into the water use efficiency of clonal material are needed, as certain eucalypt clones show fast growth and low water use. To better understand water use efficiency, estimates should be combined with monitoring of stand canopy structure and measurements of physiological processes

Autolysis: mechanisms of action in the removal of devitalised tissue

Chronic wounds affect millions of people worldwide. In the UK alone, the cost of their treatment is estimated to be between £4.5bn and £5.1bn. The implementation of wound-bed preparation strategies remove the barriers to healing and wound debridement is a key component in preparing the wound bed for wound progression. This article aims to review one of the several debridement methods available to clinicians: autolytic debridement. Autolysis (i.e. autolytic debridement) uses the body's own enzymatic mechanisms to remove devitalised tissue in order to remove the barriers to healing. This review aims to provide clinicians working in wound care with a better understanding of the mechanisms and implications of autolytic debridement

Time-Dependent Inhibition and Estimation of CYP3A Clinical Pharmacokinetic Drug-Drug Interactions Using Plated Human Cell Systems

ABSTRACT: The current studies assessed the utility of freshly plated hepatocytes, cryopreserved plated hepatocytes, and cryopreserved plated HepaRG cells for the estimation of inactivation parameters k inact and K I for CYP3A. This was achieved using a subset of CYP3A time-dependent inhibitors (fluoxetine, verapamil, clarithromycin, troleandomycin, and mibefradil) representing a range of potencies

Effect of Inhibition of the Lysophosphatidic Acid Receptor 1 on Metastasis and Metastatic Dormancy in Breast Cancer

Background Previous studies identified the human nonmetastatic gene 23 (NME1, hereafter Nm23-H1) as the first metastasis suppressor gene. An inverse relationship between Nm23-H1 and expression of lysophosphatidic acid receptor 1 gene (LPAR1, also known as EDG2 or hereafter LPA1) has also been reported. However, the effects of LPA1 inhibition on primary tumor size, metastasis, and metastatic dormancy have not been investigated. Methods The LPA1 inhibitor Debio-0719 or LPA1 short hairpinned RNA (shRNA) was used. Primary tumor size and metastasis were investigated using the 4T1 spontaneous metastasis mouse model and the MDA-MB-231T experimental metastasis mouse model (n = 13 mice per group). Proliferation and p38 intracellular signaling in tumors and cell lines were determined by immunohistochemistry and western blot to investigate the effects of LPA1 inhibition on metastatic dormancy. An analysis of variance-based two-tailed t test was used to determine a statistically significant difference between treatment groups. Results In the 4T1 spontaneous metastasis mouse model, Debio-0719 inhibited the metastasis of 4T1 cells to the liver (mean = 25.2 liver metastases per histologic section for vehicle-treated mice vs 6.8 for Debio-0719-treated mice, 73.0% reduction, P < .001) and lungs (mean = 6.37 lesions per histologic section for vehicle-treated mice vs 0.73 for Debio-0719-treated mice, 88.5% reduction, P < .001), with no effect on primary tumor size. Similar results were observed using the MDA-MB-231T experimental pulmonary metastasis mouse model. LPA1 shRNA also inhibited metastasis but did not affect primary tumor size. In 4T1 metastases, but not primary tumors, expression of the proliferative markers Ki67 and pErk was reduced by Debio-0719, and phosphorylation of the p38 stress kinase was increased, indicative of metastatic dormancy. Conclusion The data identify Debio-0719 as a drug candidate with metastasis suppressor activity, inducing dormancy at secondary tumor site

Nitrogen forms affect root structure and water uptake in the hybrid poplar

The study analyses the effects of two different forms of nitrogen fertilisation (nitrate and ammonium) on root structure and water uptake of two hybrid poplar (Populus maximowiczii x P. balsamifera) clones in a field experiment. Water uptake was studied using sap flow gauges on individual proximal roots and coarse root structure was examined by excavating 18 whole-root systems. Finer roots were scanned and analyzed for architecture. Nitrogen forms did not affect coarse-root system development, but had a significant effect on fine-root development. Nitrate-treated trees presented higher fine:coarse root ratios and higher specific root lengths than control or ammonium treated trees. These allocation differences affected the water uptake capacity of the plants as reflected by the higher sapflow rate in the nitrate treatment. The diameter of proximal roots at the tree base predicted well the total root biomass and length. The diameter of smaller lateral roots also predicted the lateral root mass, length, surface area and the number of tips. The effect of nitrogen fertilisation on the fine root structure translated into an effect on the functioning of the fine roots forming a link between form (architecture) and function (water uptake)

Individual tree and stand-level carbon and nutrient contents across one rotation of loblolly pine plantations on a reclaimed surface mine

While reclaimed loblolly pine (Pinus taeda L.) plantations in east Texas, USA have demonstrated similar aboveground productivity levels relative to unmined forests, there is interest in assessing carbon (C) and nutrients in aboveground components of reclaimed trees. Numerous studies have previously documented aboveground biomass, C, and nutrient contents in loblolly pine plantations; however, similar data have not been collected on mined lands. We investigated C, N, P, K, Ca, and Mg aboveground contents for first-rotation loblolly pine growing on reclaimed mined lands in the Gulf Coastal Plain over a 32-year chronosequence and correlated elemental rates to stand age, stem growth, and similar data for unmined lands. At the individual tree level, we evaluated elemental contents in aboveground biomass components using tree size, age, and site index as predictor variables. At the stand-level, we then scaled individual tree C and nutrients and fit a model to determine the sensitivity of aboveground elemental contents to stand age and site index. Our data suggest that aboveground C and nutrients in loblolly pine on mined lands exceed or follow similar trends to data for unmined pine plantations derived from the literature. Diameter and height were the best predictors of individual tree stem C and nutrient contents (R ≥ 0.9473 and 0.9280, respectively) followed by stand age (R ≥ 0.8660). Foliage produced weaker relationships across all predictor variables compared to stem, though still significant (P ≤ 0.05). The model for estimating stand-level C and nutrients using stand age provided a good fit, indicating that contents aggrade over time predictably. Results of this study show successful modelling of reclaimed loblolly pine aboveground C and nutrients, and suggest elemental cycling is comparable to unmined lands, thus providing applicability of our model to related systems

Morphology and foliar chemistry of containerized Abies fraseri (Pursh) Poir. seedlings as affected by water availability and nutrition

• We present the results of a two-year (2007–2008) greenhouse study investigating the effect of water availability and nitrogen fertilization on the growth, biomass partitioning, and foliar nutrient content of Abies fraseri (Pursh) Poir. • Fertilizer and moisture content (irrigation) were varied in a factorial experiment combining four levels of irrigation and three levels of fertilization to evaluate growth and foliar nutrient content. In addition, a numerical optimization was used to estimate appropriate levels of each factor necessary to achieve simulated goals for response variables. • Irrigation increased the height growth by 12 to 35% depending on the fertilization treatment (p = 0.0001). Fertilization increased height growth by 10 to 26% (p = 0.02). A similar response was observed for stem diameter growth (SDG). Total biomass accumulation increased as result of positive response of stem and root biomass development, and foliar nitrogen content was positively affected by nitrogen fertilization and negatively affected by irrigation. The numerical optimization for simulated target growth and nitrogen content responses produced levels of input combinations with high desirability factors to achieve the target responses. • These results suggest that nutrient addition is a strong determining factor for early development of this species. The improved growth efficiency in this study is likely attributed to a combination of factors including, improved photosynthetic capacity, decreased stomatal limitations, or increased resource allocation to stems