Following a request from EFSA, the Panel on Plant Protection Products and their Residues (PPR) developed an opinion on the state of the art of Toxicokinetic/Toxicodynamic (TKTD) models and their use in prospective environmental risk assessment (ERA) for pesticides and aquatic organisms. TKTD models are species-and compound-specific and can be used to predict (sub)lethal effects of pesticides under untested (time-variable) exposure conditions. Three different types of TKTD models are described, viz., (i) the 'General Unified Threshold models of Survival' (GUTS), (ii) those based on the Dynamic Energy Budget theory (DEBtox models), and (iii) models for primary producers. All these TKTD models follow the principle that the processes influencing internal exposure of an organism, (TK), are separated from the processes that lead to damage and effects/mortality (TD). GUTS models can be used to predict survival rate under untested exposure conditions. DEBtox models explore the effects on growth and reproduction of toxicants over time, even over the entire life cycle. TKTD model for primary producers and pesticides have been developed for algae, Lemna and Myriophyllum. For all TKTD model calibration, both toxicity data on standard test species and/or additional species can be used. For validation, substance and species-specific data sets from independent refined-exposure experiments are required. Based on the current state of the art (e.g. lack of documented and evaluated examples), the DEBtox modelling approach is currently limited to research applications. However, its great potential for future use in prospective ERA for pesticides is recognised. The GUTS model and the Lemna model are considered ready to be used in risk assessment. This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made.The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union. As a third deliverable of this mandate, the PPR Panel is asked to develop a Scientific Opinion describing the state of the art of Toxicokinetic/Toxicodynamic (TKTD) models for aquatic organisms and prospective environmental risk assessment (ERA) for pesticides with the main focus on: (i) regulatory questions that can be addressed by TKTD modelling, (ii) available TKTD models for aquatic organisms, (iii) model parameters that need to be included and checked in evaluating the acceptability of regulatory relevant TKTD models, and (iv) selection of the species to be modelled.Chapter 2 presents the underlying concepts, terminology, application domains and complexity levels of three different classes of TKTD models intended to be used in risk assessment, viz., (i) the 'General Unified Threshold models of Survival' (GUTS), (ii) toxicity models derived from the Dynamic Energy Budget theory (DEBtox models), and (iii) models for primary producers. All ...

Cultured myocytes from severely obese women express perturbations in FA metabolism and insulin signaling reminiscent of those observed in vivo. The obesity phenotype can be recapitulated in muscle cells from lean subjects via exposure to excess lipid, but not by overexpressing the FAT/CD36 FA transporter.

After RYGB, fasting insulin decreases to levels like those of lean control subjects and diabetes is reversed (fasting blood glucose < 125 mg/dl). This leads us to propose that 1) exclusion of food from the foregut corrects hyperinsulinemia and 2) fasting insulin is dissociated from the influence of fasting glucose, insulin resistance, and BMI. The mechanisms for reversal of diabetes in the face of reduced insulin remain a paradox.

Insulin sensitivity and glucose transport are greater in the postsurgery patients than predicted from the weight-matched group, suggesting that improved insulin sensitivity after bypass is due to something other than, or in addition to, weight loss. Improved insulin sensitivity is related to reduced inhibitor of kappaB kinase beta activity and enhanced insulin signaling in muscle.

The molecular mechanisms of obesity-associated insulin resistance are becoming increasingly clear, and the effects of various lipid molecules, such as diacylglycerol and ceramide, on the insulin signal are being actively explored. To better understand the divergent response to lipid exposure between lean and obese, we incubated primary human muscle cells from lean [body mass index (BMI) <25 kg/m(2)] and morbidly obese (BMI >40 kg/m(2)) subjects with the saturated fatty acid palmitate. Additionally, given that AMPK-activating drugs are widely prescribed for their insulin-sensitizing effects, we sought to determine whether 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR)-stimulated AMPK activation could prevent or reverse the deleterious effects of lipid on insulin signaling. We found that a 1-h palmitate incubation in lean myotubes reduced (P < 0.05) insulin-stimulated phosphoprotein kinase B (Akt), Akt substrate 160 (AS160), and inhibitory factor kappaBalpha (IkappaBalpha) mass, all of which were prevented with AICAR inclusion. With a longer incubation, we observed that myotubes from morbidly obese individuals appear to be largely resistant to the detrimental effects of 16 h lipid exposure as was evident, in contrast to the lean, by the absence of a reduction in insulin-stimulated insulin receptor substrate (IRS)-1 Tyr phosphorylation, phospho-Akt, and phospho-AS160 (P < 0.05). Furthermore, 16 h lipid exposure significantly reduced IkappaBalpha levels and increased phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and IRS1-Ser(312) in lean myotubes only (P < 0.05). Despite a divergent response to lipid between lean and obese myotubes, AICAR inclusion improved insulin signaling in all myotubes. These findings suggest an important role for regular exercise in addition to offering a potential mechanism of action for oral AMPK-activating agents, such as thiazolidinediones and metformin.

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The purpose of this study was to investigate the influence of exercise training on intramyocellular lipid (IMCL) content and test the hypothesis that the effect of endurance-oriented exercise training on IMCL is dependent on characteristics of the population studied. Lean (N = 11, body mass index (BMI) = 22.2 ± 0.7 kg·m−2), obese (N = 14, BMI = 38.8 ± 1.7 kg·m−2), and type 2 diabetic (N = 9, BMI = 35.5 ± 2.5 kg·m−2) participants were examined before and after 10 consecutive days of endurance-oriented (60 min·day−1 at ~70% V̇ O2peak) exercise training. IMCL and muscle glycogen were measured by Oil-Red-O and periodic acid – Schiff staining, respectively. The results indicated that IMCL was elevated (p < 0.05) in the obese and diabetic groups compared with the lean subjects prior to training. After training, IMCL content decreased (−35%) in the participants with type 2 diabetes; there were no changes in IMCL in the lean or obese groups. Muscle glycogen content was lower in the diabetic subjects than in the lean subjects both before and after training. These data indicate that changes in IMCL with exercise training do not exhibit a universal response but rather depend on the metabolic status of the population studied.

Objective To determine the overall effectiveness of instrument-assisted soft tissue mobilization (IASTM) in improving range of motion (ROM), pain, strength, and patient-reported function in order to provide recommendations for use. We also sought to examine the influence of IASTM on injured and healthy participants, body part treated, and product used. Data Sources We searched the Academic Search Premier, Alt Healthwatch, CINAHL Complete, Cochrane Library, MEDLINE with full text, NLM PubMed, Physical Education Index, Physiotherapy Evidence Database (PEDro), SPORTDiscus with full text, and Web of Science databases for articles published from 1997 through 2016. The Boolean string advantEDGE OR astym OR graston OR iastm OR “instrument assist* soft tissue mobil*” OR “augment* soft tissue mobil*” OR “myofascial release” OR “instrument assist* massage” OR “augment* massage” OR “instrument assist* cross fiber massage” was used. Study Selection Included articles were randomized controlled trials that measured ROM, pain, strength, or patient-reported function and compared IASTM treatment with at least 1 other group. Data Extraction Thirteen articles met the inclusion criteria. Four independent reviewers assessed study quality using the PEDro and Centre for Evidence-Based Medicine scales. Twelve articles were included in the effect-size analysis. Data Synthesis The average PEDro score for studies of uninjured participants was 5.83 (range = 5 to 7) and that for studies of injured participants was 5.86 (range = 3 to 7). Large effect sizes were found in outcomes for ROM (uninjured participants), pain (injured participants), and patient-reported function (injured participants). The different IASTM tools used in these studies revealed similar effect sizes in the various outcomes. Conclusions The current literature provides support for IASTM in improving ROM in uninjured individuals as well as pain and patient-reported function (or both) in injured patients. More high-quality research involving a larger variety of patients and products is needed to further substantiate and allow for generalization of these findings.