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The present study (NCT01446276, ClinicalTrials.gov) assessed long-term effects of high-dose Resveratrol (RSV) on basal and insulin-mediated very low-density lipoprotein triglyceride (VLDL-TG), palmitate and glucose kinetics, and liver fat content in men with nonalcoholic fatty liver disease (NAFLD). Participants (n = 16) were non-diabetic, upper-body obese (BMI > 28 kg/m2 , WHR > 0.9) men with NAFLD who were randomized (1:1) in a double-blinded, placebo-controlled clinical trial to either RSV or placebo (500 mg 3 times daily) for 6 months. Magnetic resonance (MR) spectroscopy, dual-X-ray absorptiometry and MR imaging assessed liver fat content and body composition, respectively. 14 C-labeled VLDL-TG and 3 H-labeled glucose and palmitate tracers, in combination with indirect calorimetry and breath samples, were used to assess kinetics and substrate oxidations during basal and hyperinsulinaemic euglycaemic clamp conditions. RSV did not improve either basal or insulin-mediated VLDL-TG secretion, oxidation or clearance rates, nor did it affect palmitate or glucose turnover. Likewise, no changes in body composition or liver fat content occurred following RSV compared with placebo treatment. Therefore, RSV cannot be recommended for treatment of metabolic abnormalities in NAFLD.

Introduction: Low-grade chronic inflammation is common in hemodialysis (HD) patients. Previous studies suggest an anti-inflammatory effect of angiotensin II receptor blocker (ARB) treatment. The aim of this study was to compare the effect of ARB vs. placebo on plasma concentrations of inflammatory markers in HD patients. Methods: Adult HD patients were randomized for double-blind treatment with the ARB irbesartan 150–300 mg/day or placebo. At baseline, 1 week, 3, 6, 9, and 12 months plasma high sensitivity C-reactive protein (hsCRP), interleukin (IL)−1β, IL-6, IL-8, IL-18, and transforming growth factor-β (TGF-β) were measured using Luminex and enzyme-linked immunosorbent assay (ELISA) technology. Findings: Eighty-two patients were randomized (placebo/ARB: 41/41). The groups did not differ in initial levels of any of the inflammatory markers (placebo/ARB median(range)): hsCRP 3.3(0.2–23.4)/2.7(0.2–29.6) μg/mL; IL-1β 1.1(0.0–45.9)/1.1(0.0-7.2) pg/mL; IL-6 10(1–90)/12(1–84) pg/mL; IL-8 31(9–134)/34(5–192) pg/mL; IL-18 364(188–1343)/377(213–832) pg/mL; TGF-β 3.2(0.8–13.9)/3.6(1.3–3.8) ng/mL. Overall, there was no significant difference in hsCRP, IL-6, IL-8, and TGF-β between placebo and ARB-treated patients during the study period, and hsCRP, IL-6, IL-8, and TGF-β were relatively stable during the study period (P ≥ 0.18 in all tests for parallel curves, equal levels, and constant levels). The IL-1β level was slightly different in the two groups over time, but not significantly (P = 0.09 in test for parallel curves) and it was also relatively stable during the study period (P ≥ 0.49 in tests for equal levels and constant level). IL-18 was the only inflammatory marker which was not constant during the study period (P = 0.001 in test for constant level), but there was no significant difference between placebo and ARB-treated (P ≥ 0.51 in tests for parallel curves and equal levels). Discussion: Inflammatory biomarkers were neither acutely, nor in the long-term significantly affected by the ARB irbesartan. Our findings suggest that ARB treatment in HD patients does not offer protective anti-inflammatory effects.

BACKGROUND & AIMS Macrophage activation plays a key pathogenic role in experimental non-alcoholic fatty liver disease (NAFLD) and contributes to the progression of steatohepatitis (NASH) and fibrosis. We studied macrophage activation in human NAFLD by measuring soluble (s)CD163, a specific macrophage activation marker, hypothesizing that sCD163 would be associated with the patients' morphological disease grade. Furthermore, we investigated an association between sCD163 and the apoptosis marker cytokeratin-18 (CK-18) to explore a link between macrophage activation and apoptosis. METHODS sCD163 associations with biochemical and histological measures of NAFLD were investigated in two independent cohorts of 157 Australian and 174 Italian NAFLD patients, with liver biopsies graded for NAFLD severity, steatosis and fibrosis. sCD163 and CK-18 were measured by enzyme-linked immunosorbent assay. RESULTS In both cohorts sCD163 increased in parallel with the patients' morphological disease grading, being independently associated with the Kleiner fibrosis score (P < 0.001). A high sCD163 predicted advanced fibrosis {F ≥ 3; Australian cohort: area under receiver-operating characteristics curve 0.77 [95% confidence interval (CI): 0.76-0.87], Italian cohort: 0.80 (95% CI: 0.72-0.88)}. In both groups, sCD163 was independently associated with CK-18 (P < 0.001). CONCLUSION Soluble CD163 reflecting macrophage activation is associated with morphological features of NAFLD suggesting their involvement in the pathogenesis of NAFLD, NASH and particularly fibrosis. An independent association between sCD163 and cytokeratin-18 suggests that apoptosis may contribute to macrophage activation in NAFLD/NASH.

OBJECTIVE: To investigate the response of serum fibroblast growth factor 21 (FGF21) to a meal and to insulin infusion in haemodialysis (HD) patients.DESIGN AND PATIENTS: Meal study: in a cross-over design, 12 non-diabetic HD patients were randomly assigned to: 1) a non-HD day with one meal served, 2) a HD day with one meal served during HD, and 3) a HD day with two meals served during and after HD, respectively. Twelve healthy controls participated in an experiment identical to the non-HD day. Insulin infusion study: in a cross-over design, 11 non-diabetic HD patients were randomly assigned to receive a 4-h HD session with either: 1) no infusion, 2) glucose infusion, or 3) glucose-insulin infusion. A meal was served 2 h before HD start.RESULTS: Meal study: serum FGF21 was 23-fold higher in HD patients than controls (P < 0∙001). Postprandial FGF21 decreased on all four study days (P ˂ 0∙006), but the relative reductions from baseline were significantly greater in controls (P < 0∙008). Postprandial changes in FGF21 were inversely related with triglycerides (P = 0∙042) and positively related with insulin-like growth factor binding protein-1 (IGFBP-1) (P < 0∙001). Serum FGF21 was only associated with changes in adiponectin (P = 0∙001) and free fatty acids (P = 0∙04) in the healthy controls. Insulin infusion study: as compared with no infusion, glucose and glucose-insulin infusion prevented the postprandial decrease in FGF21 and resulted in higher FGF21 concentrations by up to 25% (P = 0∙003).CONCLUSIONS: Serum FGF21 was highly elevated in HD patients but the response of serum FGF21 to meal intake and insulin infusion seemed to be intact. Our results indicate that FGF21 may play an important role in short-term metabolic homeostasis. This article is protected by copyright. All rights reserved.

OBJECTIVE: Patients on maintenance haemodialysis (HD) have reduced circulating free and bioactive insulin-like growth factor I (IGF-I) due to increased IGF-binding proteins (IGFBPs). This study investigated the postprandial response of the IGF system in HD patients compared with matched healthy subjects.DESIGN AND PATIENTS: In a crossover study, twelve nondiabetic HD patients were assigned in a random order to three 10-h study days: (1) a non-HD day with one meal served at baseline (NHDM1), (2) an HD day with one meal served during HD (HDM1) and (3) an HD day with two meals served during and after HD, respectively (HDM2). Twelve healthy controls conducted session 1.RESULTS: After the baseline meal, insulin concentrations changed similarly in HD patients and controls, whereas hyperglycaemia was more prolonged in HD patients (P < 0·001). Postprandial IGFBP-1 showed greater reductions from baseline in controls (-76% [-81; -70%], mean [95% confidence intervals], P < 0·001) than in patients on non-HD days (-45% [-57; -30%], P < 0·001). In the latter group, the response was even more attenuated during HD (-22% [-38; -1%] and -24% [-40; -4%], P ≤ 0·041). After the second meal on HDM2 days, IGFBP-1 further decreased (-50% [-61; -37%], P < 0·001), whereas IGFBP-1 returned to baseline levels on the other study days. Consistently, at the end of the study days, bioactive IGF-I was significantly above baseline only on HDM2 days (+22% [+5; +43%], P = 0·012).CONCLUSIONS: HD patients were unable to suppress IGFBP-1 to the same extent as healthy controls, which may increase the risk of protein-energy wasting in maintenance HD. A second meal after HD, however, effectively suppressed IGFBP-1 and increased bioactive IGF-I.

Kidney transplantation from a large donor to a small recipient, as in pediatric transplantation, is associated with an increased risk of thrombosis and DGF. We established a porcine model for renal transplantation from an adult donor to a small or size-matched recipient with a high risk of DGF and studied GFR, RPP using MRI, and markers of kidney injury within 10 h after transplantation. After induction of BD, kidneys were removed from ∼63-kg donors and kept in cold storage for ∼22 h until transplanted into small (∼15 kg, n = 8) or size-matched (n = 8) recipients. A reduction in GFR was observed in small recipients within 60 min after reperfusion. Interestingly, this was associated with a significant reduction in medullary RPP, while there was no significant change in the size-matched recipients. No difference was observed in urinary NGAL excretion between the groups. A significant higher level of HO-1 mRNA was observed in small recipients than in donors and size-matched recipients indicating cortical injury. Improvement in early graft perfusion may be a goal to improve short- and long-term GFR and avoid graft thrombosis in pediatric recipients.

Silver is a metal with well-known antibacterial effects. This makes silver an attractive coating material for medical devices for use inside the body, e.g. orthopaedic prostheses and catheters used in neurosurgery as it has been found to reduce the high risk of infections. Lately, the use of nano-silver particles in the industry, e.g. woven into fabrics and furniture has increased, and thus the exposure to silver particles in daily life increases. To study the effect of metallic silver particles on nervous tissue, we injected micron-sized silver particles into the mouse brain by stereotactic procedures. After 7, 14 days and 9 months, the silver-exposed animals had considerable brain damage seen as cavity formation and inflammation adjacent to the injected metallic silver particles. The tissue loss involved both cortical and hippocampal structures and resulted in enlargement of the lateral ventricles. Autometallographic silver enhancement showed silver uptake in lysosomes of glia cells and neurons in the ipsilateral cortex and hippocampus alongside a minor uptake on the contralateral side. Silver was also detected in ependymal cells and the choroid plexus. After 9 months, spreading of silver to the kidneys was seen. Cell counts of immunostained sections showed that metallic silver induced a statistically significant inflammatory response, i.e. increased microgliosis (7 days: p < 0.0001; 14 days: p < 0.01; 9 months: p < 0.0001) and TNF-α expression (7 and 14 days: p < 0.0001; 9 months: p = 0.91). Significant astrogliosis (7, 14 days and 9 months: p < 0.0001) and increased metallothionein (MT I + II) expression (7 and 14 days: p < 0.0001; 9 months: p < 0.001) were also seen in silver-exposed brain tissue. We conclude that metallic silver implants release silver ions causing neuroinflammation and a progressive tissue loss in the brain.

Mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2) are two kinases phosphorylated by both ERK1/2 and p38 MAPK. Recently, MSK1 and 2 have been reported to act as negative regulators of acute inflammation. In this study, we investigated the role of MSK1/2 in chronic skin inflammation using an oxazolone-induced allergic contact dermatitis model in MSK1/2 knockout mice and wild-type mice. MSK1/2 knockout mice were demonstrated to have significantly increased inflammation compared with wild-type mice. This was measured by an increased ear thickness, elevated infiltration of neutrophils in the skin and increased inflammatory histological changes. Furthermore, we found significantly elevated levels of the proinflammatory cytokines Tumor necrosis factor-α (TNF-α), IL-1β and IL-6 at both mRNA and protein levels in MSK1/2 knockout mice compared with wild-type mice after oxazolone treatment. In addition, the mRNA expression of the chemokine Thymus and activation regulated chemokine (TARC) was demonstrated to be significantly elevated in oxazolone-treated MSK1/2 knockout mice compared with wild-type mice. The increased expression of TARC was paralleled by increased infiltration of cells positive for the TARC receptor, CCR4, in the dermis of MSK1/2 knockout mice. Our results indicate that MSK1/2 are involved in the activation of feedback mechanisms that dampen oxazolone-induced skin inflammation.

In six field experiments it was investigated whether row spacing, timing, direction and orientation of post-emergence weed harrowing in spring barley influenced the selectivity and whether it is important that increasing intensities of harrowing are generated either by increasing number of passes or increasing driving speed. Selectivity was defined as the relationship between crop burial in soil immediately after treatment and weed control. To estimate crop burial, digital image analysis was used in order to make the estimations objective. The study showed that narrow row spacing decreased selectivity in a late growth stage (21) whereas row spacing in the range of 5.3 cm to 24 cm had no effects in an early growth stage (12). Harrowing across rows decreased selectivity in one out of two experiments. Whether repeated passes with the harrowing were carried out in the same orientation along the rows or in alternative orientations forth and back was unimportant. There were indications that high driving speed decreases selectivity and that repeated passes with low driving speed are better than single treatments with high driving speed. Impacts on selectivity, however, were small and only significant at high degrees of weed control. Timing had no significant impact on selectivity.

In diabetic patients, reduced renal oxygen availability is associated with a higher risk of diabetic nephropathy (DN) [1]. Recently, dynamic nuclear polarization hyperpolarized [1-13C]pyruvate has ...

We consider estimating functions for discretely observed diffusion processes of the following type: for one part of the parameter of interest we propose to use a simple and explicit estimating function of the type studied by Kessler (2000); for the remaining part of the parameter we use a martingale estimating function. Such an approach is particularly useful in practical applications when the parameter is high-dimensional. It is also often necessary to supplement a simple estimating function by another type of estimating function because only the part of the parameter on which the invariant measure depends can be estimated by a simple estimating function. Under regularity conditions the resulting estimators are consistent and asymptotically normal. Several examples are considered in order to demonstrate the idea of the estimating procedure. The method is applied to two data sets comprising wind velocities and stock prices. In one example we also propose a general method for constructing diffusion models with a prescribed marginal distribution which have a flexible dependence structure.

Germination characteristics are important for the establishment success of grass species. The objective of this study was to study the variation in germination characteristics within and among cultivars in three grass species by use of a curve-fitting procedure. The study included 20 seed lots of slender creeping red fescue (Festuca rubra L. var. littoralis Vasey), 19 lots of perennial ryegrass (Lolium perenne L.), and 16 lots of Kentucky bluegrass (Poa pratensis L.), and the seed lots represented four, four, and five cultivars, respectively. Seeds of each seed lot were germinated in standard tests, and germination was recorded daily. Germination time courses were described for each replicate of each seed lot, using a generalized hyperbolic multinomial distribution. The function efficiently described all observed germination time courses, and germination was summarized as three characteristics of biological significance: final germination percentage (FGP), mean germination time (MGT), and time from 25 to 75% germination (T 25-75 ). For each of the characteristics, an ANOVA was performed. Cultivar differences were tested against variation between seed lots within cultivars. Within all three species, there were significant cultivar differences in FGP, and cultivars of red fescue and Kentucky bluegrass also differed significantly in MGT and T 25-75 . Cultivar variation was 53 to 99% larger than seed lot variation within cultivars, but in some cases, seed lots within cultivars differed considerably in germination characteristics. Cultivars should, therefore, be represented by more than one seed lot and cultivar differences should be tested against seed lot differences to get valid test results.