The interplay of fatigue dynamics and task achievement using optimal control predictive simulation.

Predictive simulation of human motion could provide insight into optimal techniques. In repetitive or long-duration tasks, these simulations must predict fatigue-induced adaptation. However, most studies minimize cost function terms related to actuator activations, assuming it minimizes fatigue. An additional modeling layer is needed to consider the previous use of muscles to reveal adaptive strategies to the decreased force production capability. Here, we propose interfacing Xia's three-compartment fatigue dynamics model with rigid-body dynamics. A stabilization invariant was added to Xia's model. We simulated the maximum repetition of dumbbell biceps curls as an optimal control problem (OCP) using direct multiple shooting. We explored three cost functions (minimizing torque, fatigue, or both) and two OCP formulations (full-horizon and sliding-horizon approaches). We adapted Xia's model by adding a stabilization invariant coefficients S=105 for direct multiple shooting. Sliding-horizon OCPs achieved 20 to 21 repetitions. The kinematic strategy slowly deviated from a plausible dumbbell lifting task to a swinging strategy as fatigue onset increasingly compromised the humerus to remain vertical. In full-horizon OCPs, the latter kinematic strategy was used over the whole motion, resulting in 32 repetitions. We showed that sliding-horizon OCPs revealed a reactive strategy to fatigue when only torque was included in the cost function, whereas an anticipatory strategy was revealed when the fatigue term was included in the cost function. Overall, the proposed approach has the potential to be a valuable tool in optimizing performance and helping reduce fatigue-related injuries in a variety of fields.

Is an ellipsoid surface suitable to model the scapulothoracic sliding plane?

Closed loop kinematic chain approaches are commonly used to assess scapular kinematics but with heterogeneous ellipsoid calibration procedures. This study aimed to assess whether an ellipsoid surface can model the scapulothoracic sliding plane and determine the optimal number of static poses to calibrate the ellipsoid parameters. An intracortical pin with a rigid cluster of four reflective markers was inserted into the left scapular spine of two healthy males (P1 and P2). They performed arm elevations, internal rotations, ball throwing, hockey shooting, and eating movements. Ellipsoid radii and center location were functionally calibrated for each participant and each movement, either based on all frames of a movement or based on a reduced number of frames (from 3 to 200 equally position-distributed frames). Across both participants and all movements, ellipsoid radii varied up to 10.2 cm, 3.9 cm, and 18.4 cm in the antero-posterior, medio-lateral, and cranio-caudal directions, respectively. When all frames of a movement were considered for calibration, the median scapula-to-ellipsoid distance was, on average, 0.52 mm and 0.38 mm for P1 and P2, respectively. When only five frames were considered for ellipsoid calibration, the scapula-to-ellipsoid median distance slightly increased with 0.57 mm and 0.47 mm for P1 and P2, respectively. To conclude, this study highlights that an ellipsoid surface may effectively be appropriate to model the scapulothoracic sliding plane, especially when the calibration is functional, participant- and movement-specific. Furthermore, the number of poses required for the ellipsoid calibration can be reduced to five, minimizing the experimental cost.

HMGB1 acts as an agent of host defense at the gut mucosal barrier.

Mucosal barriers provide the first line of defense between internal body surfaces and microbial threats from the outside world. 1 In the colon, the barrier consists of two layers of mucus and a single layer of tightly interconnected epithelial cells supported by connective tissue and immune cells. 2 Microbes colonize the loose, outer layer of colonic mucus, but are essentially excluded from the tight, epithelial-associated layer by host defenses. 3 The amount and composition of the mucus is calibrated based on microbial signals and loss of even a single component of this mixture can destabilize microbial biogeography and increase the risk of disease. 4-7 However, the specific components of mucus, their molecular microbial targets, and how they work to contain the gut microbiota are still largely unknown. Here we show that high mobility group box 1 (HMGB1), the prototypical damage-associated molecular pattern molecule (DAMP), acts as an agent of host mucosal defense in the colon. HMGB1 in colonic mucus targets an evolutionarily conserved amino acid sequence found in bacterial adhesins, including the well-characterized Enterobacteriaceae adhesin FimH. HMGB1 aggregates bacteria and blocks adhesin-carbohydrate interactions, inhibiting invasion through colonic mucus and adhesion to host cells. Exposure to HMGB1 also suppresses bacterial expression of FimH. In ulcerative colitis, HMGB1 mucosal defense is compromised, leading to tissue-adherent bacteria expressing FimH. Our results demonstrate a new, physiologic role for extracellular HMGB1 that refines its functions as a DAMP to include direct, virulence limiting effects on bacteria. The amino acid sequence targeted by HMGB1 appears to be broadly utilized by bacterial adhesins, critical for virulence, and differentially expressed by bacteria in commensal versus pathogenic states. These characteristics suggest that this amino acid sequence is a novel microbial virulence determinant and could be used to develop new approaches to diagnosis and treatment of bacterial disease that precisely identify and target virulent microbes.

Sensitivity of Shoulder Musculoskeletal Model Predictions to Muscle-Tendon Properties.

OBJECTIVE: While the sensitivity of estimated muscle forces to muscle-tendon properties is well documented for the lower limbs, little is known about the shoulder and upper limbs. The purpose of this study was to assess the sensitivity of estimated shoulder muscle forces and scapulohumeral joint force to muscle-tendon properties. METHODS: One healthy male participant performed arm flexions and simulated throwing maneuvers. Kinematics were recorded using intra-cortical pins. Muscle forces were estimated using static optimization with the generic delft shoulder and elbow in OpenSim, and scapulohumeral joint forces were calculated from the estimated forces. Then, variations from -25% to +25% of the nominal values of the tendon slack length, the optimal fiber length, the maximal isometric force, and the pennation angle were applied to the musculoskeletal model to compute affected muscle forces and scapulohumeral joint force. RESULTS: The variations in muscle-tendon properties led to changes up to 9.6 N or 174% in the muscle nominal forces. The more sensitive muscles were those that produced the greatest force: the rotator cuff muscles and the prime movers specific to the task. Among the four muscle-tendon properties, the maximal isometric force and the optimal fiber length had the greatest influence on the muscle force variability. Glenohumeral force was slightly influenced by muscle-tendon properties (<8%). CONCLUSION: Generic models (i.e., those without personalization of muscle-tendon properties) can lead to misinterpretations of muscle force. Efforts should focus on the maximal isometric force and the optimal fiber length of the rotator cuff muscles and prime movers.

Blood mixtures: impact of puncture site on blood parameters.

Various puncture routes, veins, arteries, heart, are used to take blood in animals. For anatomical reasons, differences in blood composition are expected among puncture sites. However, this issue has been rarely assessed and contrasted results have been reported: strong effects of puncture site versus a lack of effect. We captured free-ranging freshwater turtles from different locations to compare the mean concentrations of 12 blood parameters (metabolites, hormone, ions, and enzyme) among three puncture sites: (1) a lateral branch of the jugular vein, (2) a dorsal subcarapacial cervical plexus (sometimes incorrectly referred as the 'cervical sinus' in the literature), and (3) a caudal plexus site (sometimes incorrectly referred as the 'caudal sinus'). Because we used very small syringes (27-30G), we were able to separate lymph, blood, or blood-lymph mixtures. Our results show very strong effects of puncture site and of mixture level (mean maximal difference between sites was 250 %). We also found strong sex and geographical effects. Typically, there were differences in concentrations of blood solutes sampled from the lateral jugular vein and subcarapacial plexus, mainly due to sampling a mixture of blood and lymph from the 'blood' at the subcarapacial site and pure blood from the lateral jugular site, and likewise, samples from the caudal site were highly variable due to often sampling a mixture of blood and lymph. These results have technical and fundamental implications, especially when performing comparative analyses. Further, by selecting precise puncture sites, physiological differences between lymph and blood compartments could be investigated.

Determining in vivo sternoclavicular, acromioclavicular and glenohumeral joint centre locations from skin markers, CT-scans and intracortical pins: A comparison study.

To describe shoulder motion the sternoclavicular, acromioclavicular and glenohumeral joint centres must be accurately located. Within the literature various methods to estimate joint centres of rotation location are proposed, with no agreement of the method best suited to the shoulder. The objective of this study was to determine the most reliable non-invasive method for locating joint centre locations of the shoulder complex. Functional methods using pin mounted markers were compared to anatomical methods, functional methods using skin mounted markers, imaging-based methods using CT-scan data, and regression equations. Three participants took part in the study, that involved insertion of intracortical pins into the clavicle, scapula and humerus, a CT-scan of the shoulder, and finally data collection using a motion analysis system. The various methods to estimate joint centre location did not all agree, however suggestions about the most reliable non-invasive methods could be made. For the sternoclavicular joint, the authors suggest the anatomical method using the most ventral landmark on the sternoclavicular joint, as recommended by the International Society of Biomechanics. For the acromioclavicular joint, the authors suggest the anatomical method using the landmark defined as the most dorsal point on the acromioclavicular joint, as proposed by van der Helm. For the glenohumeral joint, the simple regression equation of Rab is recommended.

Casein-specific IL-4- and IL-13-secreting T cells: a tool to implement diagnosis of cow's milk allergy.

BACKGROUND: Cow's milk allergy (CMA) is a frequent food allergy in young children. The oral food challenge is the gold standard for diagnosis, and there is currently no reliable biological test. Our aim was to evaluate the diagnostic potential of a functional assay quantifying allergen-specific Th2 cells in CMA children. METHODS: A total of 29 children aged 2.8-10.5 years underwent a double-blind, placebo-controlled food challenge (DBPCFC) to cow's milk. Blood was collected before performing the DBPCFC, and peripheral mononuclear cells were cultured in an 18-h ELISpot assay with casein, α-lactalbumin, or ß-lactoglobulin. Numbers of antigen-specific IL-4- and IL-13-secreting lymphocytes and serum-specific IgE, IgG4, and total IgE levels were assessed. Receiver operating characteristic (ROC) curves were generated. RESULTS: A total of 17 (59%) children reacted to cow's milk and were therefore considered as allergic to cow's milk (CMA). The mean number of casein-specific IL-4- and IL-13-secreting T cells was higher in CMA than in non-CMA children (P = 0.009, 0.004, respectively). Moreover, it was inversely correlated with the cumulative dose of cow's milk tolerated (P = 0.003, 0.0009, respectively). ROC curve of combined IL-4 and IL-13 analysis showed an area under the curve of 0.98 (95% CI 0.90-1.06). For a cutoff of 10 IL-4- and 12 IL-13-secreting T cells, sensitivity and negative predictive value were 100%. CONCLUSIONS: Enumeration of casein-specific IL-4- and IL-13-secreting T cells appears a promising tool to improve diagnosis and, if confirmed in larger studies, could permit less frequent use of the oral food challenge.

Quantification of circulating house dust mite-specific IL-4- and IL-13-secreting T cells correlates with rhinitis severity in asthmatic children and varies with the seasons.

BACKGROUND: Defining suitable markers to diagnose and monitor allergy and its severity is essential to correctly assign patients for specific immunotherapy. Circulating levels of specific IgE are good markers of sensitization, but not of clinically symptomatic allergy. OBJECTIVE: To quantify circulating interleukin (IL)-4- and IL-13-secreting T cells specific for house dust mite (HDM) in children presenting HDM-allergic asthma associated or not with rhinitis and correlate results with clinical symptoms. METHODS: We analysed 26 children with HDM respiratory disease (allergic rhinitis and asthma) together with six children with non-allergic asthma. Peripheral blood mononuclear cells were stimulated with HDM extract in a 24-h ELISpot assay to quantify the number of HDM-specific IL-4- and IL-13-secreting T cells. Asthma severity and control, and rhinitis severity were scored according to the Global Initiative for Asthma (GINA) and the Allergic Rhinitis and its Impact on Asthma (ARIA) Guidelines. RESULTS: The number of HDM-specific IL-4- and IL-13-secreting T cells was higher in patients with allergic asthma as compared to patients with non-allergic asthma. It varied with the season of blood sampling with two peaks in the fall and early spring. Independently of the season, the number of HDM-specific IL-4-secreting T cells correlated with rhinitis severity (OR = 2; 95% IC:1.1-3.8; P = 0.04). CONCLUSIONS AND CLINICAL RELEVANCE: Allergen-specific IL-4- and IL-13-producing T cells were only detected in HDM-allergic asthmatic children (not in patients with non-allergic asthma). Their numbers correlated with clinical severity of allergic rhinitis.

Improvements in measuring shoulder joint kinematics.

For many clinical applications it is necessary to non-invasively determine shoulder motion during dynamic movements, and in such cases skin markers are favoured. However, as skin markers may not accurately track the underlying bone motion the methods currently used must be refined. Furthermore, to determine the motion of the shoulder a model is required to relate the obtained marker trajectories to the shoulder kinematics. In Wu et al. (2005) the International Society of Biomechanics (ISB) proposed a shoulder model based on the position of bony landmarks. A limitation of the ISB recommendations is that the reference positions of the shoulder joints are not standardized. The aims of this research project were to develop a method to accurately determine shoulder kinematics using skin markers, and to investigate the effect of introduction of a standardized reference configuration. Fifteen subjects, free from shoulder pathology, performed arm elevations while skin marker trajectories were tracked. Shoulder kinematics were reconstructed using a chain model and extended Kalman filter. The results revealed significant differences between the kinematics obtained with and without introduction of the reference configuration. The curves of joint angle tended towards 0° for 0° of humerus elevation when the reference configuration was introduced. In conclusion, the shoulder kinematics obtained with introduction of the reference configuration were found to be easier to interpret than those obtained without introduction of the reference configuration.

99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: immune therapies of type 1 diabetes: new opportunities based on the hygiene hypothesis.

Insulin-dependent (type 1) diabetes is a prototypic organ-specific autoimmune disease resulting from the selective destruction of insulin-secreting beta cells within pancreatic islets of Langerhans by an immune-mediated inflammation involving autoreactive CD4(+) and CD8(+) T lymphocytes which infiltrate pancreatic islets. Current treatment is substitutive, i.e. chronic use of exogenous insulin which, in spite of significant advances, is still associated with major constraints (multiple daily injections, risks of hypoglycaemia) and lack of effectiveness over the long term in preventing severe degenerative complications. Finding a cure for autoimmune diabetes by establishing effective immune-based therapies is a real medical health challenge, as the disease incidence increases steadily in industrialized countries. As the disease affects mainly children and young adults, any candidate immune therapy must therefore be safe and avoid a sustained depression of immune responses with the attendant problems of recurrent infection and drug toxicity. Thus, inducing or restoring immune tolerance to target autoantigens, controlling the pathogenic response while preserving the host reactivity to exogenous/unrelated antigens, appears to be the ideal approach. Our objective is to review the major progress accomplished over the last 20 years towards that aim. In addition, we would like to present another interesting possibility to access new preventive strategies based on the 'hygiene hypothesis', which proposes a causal link between the increasing incidence of autoimmune diseases, including diabetes, and the decrease of the infectious burden. The underlying rationale is to identify microbial-derived compounds mediating the protective activity of infections which could be developed therapeutically.

[Enteral nutrition: bolus versus continuous feeding]. / Modes de gavage, gavage à la mode.

Published evidence has not yielded clear guidelines about the best method of how to feed the preterm baby. Enteral feeding involves many potentially confounding interventions. Variations in nutritional practices are in part explained by difficulties in measuring outcome. Development and implementation of evidence-based nutrition practices led to improved nutrition outcomes.

Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice.

Interleukin-1 (IL-1) mediates symptoms of sickness during the host response to infection. IL-1 exerts its effects via several subtypes of receptors. To assess the role of IL-1 receptor type I (IL-1RI) in the sickness-inducing effects of IL-1, IL-1beta and the cytokine inducer lipopolysaccharide were administered to IL-1RI-deficient mice (IL-1RI-/-). Sickness was assessed by depression of social exploration, anorexia, immobility and body weight loss. IL-1RI-/- mice were resistant to the sickness-inducing effects of IL-1beta administered intraperitoneally (2 microg/mouse) and intracerebroventricularly (2 ng/mouse), but still fully responsive to lipopolysaccharide administered intraperitoneally (2.5 microg/mouse) and intracerebroventricularly (3 ng/mouse). The sensitivity of IL-1RI-/- mice to lipopolysaccharide was not due to a higher brain expression of proinflammatory cytokines other than IL-1, since lipopolysaccharide-induced expression of brain IL-1 beta, tumour necrosis factor-alpha (TNF-alpha) and IL-6 transcripts were identical in IL-1RI-/- and control mice when measured by semiquantitative reverse-transcriptase polymerase chain reaction 1 h after treatment. Blockade of TNF-alpha action in the brain by intracerebroventricular administration of a fragment of the soluble TNF receptor, TNF binding protein (3.6 microg/mouse), attenuated the depressive effects of intraperitoneal injection of lipopolysaccharide (1 microg/mouse) on behaviour in IL-1RI-/- but not in control mice. Since IL-1RI-/- mice were not more sensitive to intracerebroventricularly TNF-alpha (50 ng) than control mice, these results indicate that IL-1RI mediates the sickness effect of IL-1 and that TNF-alpha simply replaces IL-1 when this last cytokine is deficient.

Role of IL-6 in cytokine-induced sickness behavior: a study with IL-6 deficient mice.

Interleukin-6 (IL-6) is synthesized and released in response to the cytokine inducer lipopolysaccharide (LPS) and IL-1, and acts as an endogenous pyrogen. Systemic administration of LPS and IL-1 to mice induces signs of sickness, including reduction of social exploration, immobility and body weight loss. To assess the role of IL-6 in the induction of sickness behavior, male IL-6-deficient mice (IL-6 -/-, Balb/cAn genetic background) were used and compared to IL-6 +/+ littermates. The depressing effects of intraperitoneal LPS (2.5 microg/mouse) and IL-1beta (1.0 microg/mouse) on behavior and change in body weight were more marked in IL-6 +/+ than in IL-6 -/- mice. The same difference was observed when mice were injected with LPS (5 ng/mouse) and IL-1beta (1 ng/mouse) into the lateral ventricle of the brain (i.c.v.). These results show that IL-6 released at the periphery and /or in the central nervous system plays a role in the behavioral response to LPS and IL-1.

Increased sensitivity of prediabetic nonobese diabetic mouse to the behavioral effects of IL-1.

The nonobese diabetic (NOD) mouse is a model of spontaneous insulin-dependent diabetes mellitus (IDDM) or type I diabetes. In humans, and in animal models of IDDM, the progression of the disease is modulated by various environmental factors, particularly infectious agents. Interleukin-1 (IL-1) plays a pivotal role in the development of IDDM, and modulation of its synthesis may be a mechanism by which environmental modulation of disease progression occurs. Since various alterations at the level of the gene, number, and sensitivity of IL-1 receptors have been described in different animal models of autoimmune disease, we investigated, in the prediabetic NOD mouse, the presence of IL-1 receptors and their functional behavioral characteristics. Here we present evidence that prediabetic NOD mice exhibit a normal distribution and density of functional brain IL-1 receptors, but are more sensitive to the behavioral effects of IL-1 than the control ICR strain.

Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats.

Peripheral (i.p.) and central (i.c.v.) injections of lipopolysaccharide (LPS) have been shown to induce brain expression of proinflammatory cytokines and to depress social behaviour in rats, increase duration of immobility and induce body weight loss. To determine if the anti-inflammatory cytokine, interleukin-10 (IL-10) is able to modulate these effects, recombinant rat IL-10 was injected in the lateral ventricle of the brain (30, 100, 300 ng/rat) prior to i.p. or i.c.v. injection of LPS (250 micrograms/kg or 60 ng/rat, respectively). Social exploration was depressed for 6 h after i.p. LPS injection. This effect was attenuated by IL-10 (30 and 100 ng) 2 h after injection, whereas the highest dose of IL-10 blocked the depression of social interaction for 6 h after LPS injection. IL-10 produced the same effects on the increase of immobility although the results did not reach significance. Social exploration was depressed 3 h after i.c.v. LPS injection, and this was accompanied by increased immobility. These effects were totally blocked by i.c.v. IL-10 (300 ng/rat). Rats lost body weight after i.c.v. LPS, and this effect was attenuated by i.c.v. IL-10. These results indicate that IL-10 is able to modulate the production and/or action of central proinflammatory cytokines.

Biological activity and brain actions of recombinant rat interleukin-1alpha and interleukin-1beta.

IL-1alpha and IL-1beta have potent effects on the central nervous system resulting in fever, activation of the hypothalamic-pituitary-adrenal axis and behavioural depression. These effects have mainly been studied in rats, using recombinant human and mouse IL-1. Because IL-1alpha and IL-1beta show some species specificity in the potency of their biological activities, the objective of the present work was to directly compare the effects of recombinant rat IL-1alpha and IL-1beta in the rat system as a first step to dissect out the mechanisms that are involved in these effects. In vitro, recombinant rat IL-1alpha and IL-1beta bound with the same affinity as human IL-1 to the rat insulinoma Rin m5F cell line that mainly expresses type I IL-1 receptors. This binding activated IL-1 receptors, as shown by induction of the synthesis of TNF-alpha mRNA. In vivo, recombinant rat IL-1alpha and IL-1beta enhanced body temperature, increased plasma levels of corticosterone and ACTH, and depressed social behaviour. All these effects were obtained at doses 100-1,000 fold lower when IL-1 was injected centrally than when it was administered peripherally, indicating that they are centrally mediated. The relative potencies of recombinant rat IL-1alpha and IL-1beta were not the same depending on the endpoint and the route of injection, indicating that different mechanisms are likely to be involved in the various effects of IL-1 on the brain.

Interleukin-1-induced sickness behavior depends on behavioral lateralization in mice.

Inter-individual differences in brain-immune interactions have been demonstrated previously in mice using lateralization as a behavioral trait of population heterogeneity. Lipopolysaccharide (LPS), which is known to induce neurochemical, neuroendocrine, and immune responses depending on lateralization, is also able to induce sickness behavior, via the production of interleukin-1 (IL-1). The objective of this study was to determine whether lateralization can influence the behavioral response to LPS and to IL-1. To test this hypothesis, adult female C3H mice, previously selected for paw preference in a food reaching task, were injected intraperitoneally (i.p.) with 0.75 microg LPS or 0.75 microg recombinant IL-1beta. Sickness induced by these molecules was measured by depressed social behavior, increased immobility, loss of body weight, and reduced food intake during the 6 h following injection. LPS-induced sickness was similar in right- and left-pawed mice. In contrast, IL-1-induced sickness behavior was dependent on behavioral lateralization. IL-1-induced depression of social investigation was more pronounced in right-pawed mice than in left-pawed animals. Likewise, IL-1-induced immobility was more important in right-pawed mice. There was a similar trend for food intake to be lower and loss of body weight to be higher in right-pawed mice than in left-pawed animals. These results demonstrate that right-pawed mice are more sensitive to IL-1-induced sickness than left-pawed animals. They extend our previous data showing a greater susceptibility to stress of right-pawed animals. The existence of inter-individual differences in the reactivity to stress or immune activation may be useful to study the mechanisms of the various strategies used by an individual in response to environmental aggressions.

Cholecystokinin receptors do not mediate the behavioral effects of lipopolysaccharide in mice.

To test the possible role of cholecystokinin (CCK) in the decrease of social exploration induced by intraperitoneal (IP) injection of lipopolysaccharide (LPS, 100 microg/kg), mice were pretreated with IP or intracerebroventricular (ICV) injection of the CCKA receptor antagonist L-364,718 (3 mg/kg and 10 microg/kg, respectively) and the CCKB receptor antagonist L-365,260 (1 mg/kg and 10 microg/kg, respectively). L-364,718 and L-365,260 did not alter LPS-induced decrease in social investigation, whatever the route of administration, suggesting that endogenous cholecystokinin does not mediate the effect of proinflammatory cytokines on social exploration in mice.