Advancing environmental risk assessment of regulated products under EFSA's remit

The pre‐market environmental risk assessment (ERA ) of regulated products such as genetically modified organisms, plant protection products and feed additives is an important process to safeguard the desired level of protection of the environment and biodiversity. ERA evaluates the potential adverse effects on the environment of certain actions, and is an important analytical scientific tool to support regulatory decision‐making. Significant advances have been made in the field in recent years. Potential avenues to the further advancement of ERA of regulated products under EFSA 's remit were discussed during the breakout session ‘Advancing environmental risk assessment’ held at the EFSA 2nd Scientific Conference ‘Shaping the Future of Food Safety, Together’ (Milan, Italy, 14–16 October 2015). The value of ERA and its relevance to decision‐making can be increased by: (1) using the ecosystem services approach to make protection goals operational; (2) relying on problem formulation to enhance the relevance of ERA studies; (3) complying with quality standards to warrant the reliability of ERA studies; (4) making ERA more contextual by accounting for multiple stressors and environmental benefits; and (5) acknowledging the strengths and limitations of post‐market environmental monitoring as a tool to resolve scientific uncertainties

Role of Esrrg in the Fibrate-Mediated Regulation of Lipid Metabolism Genes in Human ApoA-I Transgenic Mice

We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and β-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.National Institutes of Health (HL48739 and HL68216); European Union (LSHM-CT-2006-0376331, LSHG-CT-2006-037277); the Biomedical Research Foundation of the Academy of Athens; the Hellenic Cardiological Society; the John F Kostopoulos Foundatio

Gait abnormalities in people with Dravet syndrome: A cross-sectional multi-center study

Objective: To quantify gait abnormalities in people with Dravet syndrome (DS). Methods: Individuals with a confirmed diagnosis of DS were enrolled, and stratified according to knee flexion at initial contact (IC) and range of motion (ROM) during stance (atypical crouch: knee flexion >20\ub0 at IC and knee ROM >15\ub0 during stance; straight: knee flexion <20\ub0 at IC). A 1D ANOVA (\u3b1 = 0.05) was used to test statistical differences among the joint kinematics and spatio\u2013temporal parameters of the cohort and an age-matched control group. Clinical (neurological and orthopaedic evaluation) and anamnestic data (seizure type, drugs, genetic mutation) were collected; distribution between the two gait phenotypes was assessed with the Fisher exact test and, for mutation, with the chi-squared test (p < 0.05). Linear regression between maximum knee flexion and normalised walking speed was calculated. Results: Seventy-one subjects were enrolled and evaluated with instrumented gait analysis. Fifty-two were included in final analysis (mean age 13.8 \ub1 7.3; M 26). Two gait patterns were detected: an atypical crouch gait (34.6%) with increased ankle, knee and hip flexion during stance, and reduced walking speed and stride length not associated with muscle-tendon retractions; and a pattern resembling those of healthy age-matched controls, but still showing reduced walking speed and stride length. No differences in clinical or anamnestic data emerged between the two groups. Significance: Objectively quantified gait in DS shows two gait patterns with no clear-cut relation to clinical data. Kinematics abnormalities may be related to stabilization issues. These findings may guide rehabilitative and preventive measures

Rats selectively bred for low aerobic capacity have reduced hepatic mitochondrial oxidative capacity and susceptibility to hepatic steatosis and injury

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65411/1/jphysiol.2009.169060.pd

The Sirt1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression

Aims The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture. Methods and results Apolipoprotein E-deficient (Apoe−/−) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg−1 diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr−/− mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis. Conclusion We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosi

Dose-Dependent Effect of Rosuvastatin on VLDL–Apolipoprotein C-III Kinetics in the Metabolic Syndrome

OBJECTIVE—Dysregulated apolipoprotein (apo)C-III metabolism may account for hypertriglyceridemia and increased cardiovascular risk in the metabolic syndrome. This study investigated the dose-dependent effect of rosuvastatin on VLDL apoC-III transport in men with the metabolic syndrome

Performance of two questionnaires to measure treatment adherence in patients with Type-2 Diabetes

<p>Abstract</p> <p>Background</p> <p>Most valid methods to measure treatment adherence require time and resources, and they are not easily applied in highly demanding Primary Health Care Clinics (PHCC). The objective of this study was to determine sensitivity, specificity, predictive values, likelihood ratios, and post-test probabilities of two novel questionnaires as proxy measurements of treatment adherence in Type-2 diabetic patients.</p> <p>Methods</p> <p>Two questionnaires were developed by a group of experts to identify the patient's medical prescription knowledge (knowledge) and their attitudes toward treatment adherence (attitudes) as proxy measurements of adherence. The questionnaires were completed by patients receiving care in PHCC pertaining to the Mexican Institute of Social Security in Aguascalientes (Mexico). Pill count was used as gold standard. Participants were selected randomly, and their oral hypoglycemic prescriptions were studied. The main outcome measures for each questionnaire were sensitivity, specificity, predictive values, likelihood ratios, and post-test probabilities, all as an independent questionnaire test and in a serial analysis.</p> <p>Results</p> <p>Adherence prevalence was 27.0% using pill count. Knowledge questionnaire showed the highest sensitivity (68.1%) and negative predictive value (82.2%), the lowest negative likelihood ratio (0.58) and post-test probability for a negative result (0.16). Serial analysis showed the highest specificity (77.4%) and positive predictive value (40.1%) as well as the highest positive likelihood ratio (1.8) and post-test probability for a positive result (0.39).</p> <p>Conclusion</p> <p>Medical Prescription Knowledge questionnaire showed the best performance as proxy measurement to identify non-adherence in type 2 diabetic patients regarding negative predictive value, negative likelihood ratio, and post-test probability for a negative result. However, Medical Prescription Knowledge questionnaire performance may change in contexts with higher adherence prevalence. Therefore, more research is needed before using this method in other contexts.</p

Canine leishmaniasis: the key points for qPCR result interpretation

Background: Diagnosis and follow up of CanL is difficult since the range of clinical signs is varied and seroprevalence is high in endemic areas. The aims of this study were: i) demonstrate the advantages of Leishmania qPCR to diagnose and control CanL and highlight its prognostic value and ii) propose guidelines for tissue selection and infection monitoring. Findings: This study included 710 dogs living in an endemic area of leishmaniasis. Forty percent (285/710) exhibited clinical signs consistent with CanL. Infection was detected in 36.3% (258/710) of the dogs of which 4.5% (32/710) were detected by qPCR, 16.2% (115/710) detected by ELISA and 15.6% (111/710) tested positive for both tests. Only 17.9% (127/710) of the dogs were classified sick (affected) with CanL. All symptomatic dogs with medium or high ELISA titers were qPCR-positive in blood samples. All dogs with inconclusive or low ELISA results with high or medium qPCR parasitemia values developed the disease. Seventy one percent of asymptomatic ELISA-positive dogs confirmed by qPCR (medium to high parasitemia) developed the disease. Bone marrow or lymph node aspirate should be selected to ensure the absence of the parasite in asymptomatic dogs: 100-1,000 parasites/ml in bone marrow are detectable in blood, whereas lower parasite loads are usually negative. Almost 10% of negative samples in blood were positive in conjunctival swabs. Conclusions: Because qPCR allows parasite quantification, it is an effective tool to confirm a diagnosis of CanL in (i) cases of inconclusive ELISA results, (ii) when the dog has not yet seroconverted, or (iii) for treatment monitoring