A re-innervated in vitro skin model of non-histaminergic itch and skin neurogenic inflammation: PAR2-, TRPV1- and TRPA1-agonist induced functionality.

Background: Skin, and epidermis, is innervated by sensory nerve fibres. Interactions between them and signal transduction are only partially elucidated in physiological/pathological conditions, especially in pruritus. Objectives: To study the mechanisms involved in pruritus in vitro, we developed a skin explant model re-innervated by sensory neurons. Methods: This model is based on the co-culture of human skin explants and sensory neurons from dorsal root ganglia of rats. Innervation and the expression of protease activated receptor 2 (PAR2), transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin one (TRPA1) was analysed by immunostaining. The response of the model to TRPV1, PAR2 and TRPA1 agonists was analysed by patch-clamp, qPCR and enzyme-linked immunosorbent assay. Results: After 5 days of re-innervating nerve fibres was evidenced in the epidermis. Re-innervation was correlated with decrease of epidermal thickness and the number of apoptotic cells in the tissue. The major actors of non-histaminergic itch (PAR-2, thymic stromal lymphopoietin [TSLP], TSLP-R, TRPA1 and TRPV1) were expressed in neurons and/or epidermal cells of skin explants. After topical exposure of TRPV1-(Capsaicin), TRPA1-(Polygodial) and PAR2-agonist (SLIGKV-NH2) activation of reinnervating neurons could be shown in patch-clamp analysis. The release of TSLP was increased with capsaicin or SLIGKV but decreased with polygodial. Release of CGRP was increased by capsaicin and polygodial but decreased with SLIGKV. Activation by SLIGKV showed a decrease of VEGF; polygodial induced an increase of TSLP, Tumour necrosis factor (TNF) and nerve growth factor and capsaicin lead to a decrease of sema3 and TNF expression. Conclusion: The present model is suitable for studying itch and neurogenic inflammation pathways in vitro. We observed that activation of TRPV1, TRPA1 and PAR-2 leads to different response profiles in re-innervated skin explants.

Itch processing in the brain.

Itch is a sensation defined as the urge to scratch. The central mechanisms of itch are being increasingly studied. These studies are usually based on experimental itch induction methods, which can be classified into the following categories: histamine-induced, induction by other non-histamine chemicals (e.g. cowhage), physically induced (e.g. electrical) and mentally induced (e.g. audio-visual). Because pain has been more extensively studied, some extrapolations to itch can be proposed and verified by experiments. Recent studies suggest that the itch-processing network in the brain could be disrupted in certain diseases. This disruption could be related to the implication of new regions or the exclusion of already engaged brain regions from itch-processing network in the brain.

7 W mid-infrared supercontinuum generation up to 4.7 µm in an indium-fluoride optical fiber pumped by a high-peak power thulium-doped fiber single-oscillator.

In this letter, a high-power supercontinuum (SC) generation is achieved in an InF3 fiber with a maximum all bands output power of 7 W and spectrum extension up to 4.7 µm. An actively Q-switched mode-locked (QML) Tm3+-doped fiber single-oscillator has been used to pump the fluoride fiber. At the average power level of 15 W, the most energetic QML pulse provided by the fiber laser had an energy of 88 µJ and an estimated peak power of 60 kW. To the best of our knowledge, this is the first experimental demonstration of a Watt-level range supercontinuum generation in an InF3 fiber pumped by a single-oscillator laser system.

Functional and anatomical brain connectivity in psoriasis patients and healthy controls: a pilot brain imaging study after exposure to mentally induced itch.

BACKGROUND: Despite the prevalence of psoriasis, the processing of itch in psoriasis and its impact on the central nervous system (CNS) remain unclear. OBJECTIVE: We studied the influence of psoriasis on the CNS using magnetic resonance imaging techniques (fMRI and DTI, respectively) to investigate whether mentally induced itch can modify the functional connectivity or the white matter microstructure of the brain. METHODS: Fourteen patients with chronic psoriasis and 15 healthy controls were recruited. Itch was mentally induced in subjects by videos showing others scratching themselves. RESULTS: The observation of functional connectivity during the viewing the video revealed an interconnected network of brain regions that are more strongly coupled in psoriasis patients than in healthy controls. This network links the cerebellum, the thalami, the anteroposterior cingulum, the inferior parietal lobules, the middle temporal poles and the parahippocampal, hippocampal, lingual and supramarginal gyri. We also found connections with the right precuneus and both left insula and superior temporal gyrus. The DTI analysis showed that chronic itch affects the microstructure of white matter, including the anterior thalamic radiations, the superior and inferior longitudinal fasciculi, the corticospinal tracts, the cingulum, the external capsules, the inferior frontal-occipital fasciculi and both minor and major forceps. CONCLUSION: Our results indicate that there could exist a network which is more interconnected in psoriasis patients. Among two building blocks of this network, the subnetwork encoding the perception and control of itch sensation is more affected than the subnetwork representing mentalizing and empathy. With an approach consisting of measuring microstructural changes at a local level in the brain, we also contradict the findings obtained with global measures which stated that chronic psoriasis cannot alter the anatomy of the brain. This confirms that itchy pathophysiological conditions have similar effects on functional and structural connectivity as those observed in chronic pain.

Is testosterone linked to human aggression? A meta-analytic examination of the relationship between baseline, dynamic, and manipulated testosterone on human aggression.

Testosterone is often considered a critical regulator of aggressive behaviour. There is castration/replacement evidence that testosterone indeed drives aggression in some species, but causal evidence in humans is generally lacking and/or-for the few studies that have pharmacologically manipulated testosterone concentrations-inconsistent. More often researchers have examined differences in baseline testosterone concentrations between groups known to differ in aggressiveness (e.g., violent vs non-violent criminals) or within a given sample using a correlational approach. Nevertheless, testosterone is not static but instead fluctuates in response to cues of challenge in the environment, and these challenge-induced fluctuations may more strongly regulate situation-specific aggressive behaviour. Here, we quantitatively summarize literature from all three approaches (baseline, change, and manipulation), providing the most comprehensive meta-analysis of these testosterone-aggression associations/effects in humans to date. Baseline testosterone shared a weak but significant association with aggression (r = 0.054, 95% CIs [0.028, 0.080]), an effect that was stronger and significant in men (r = 0.071, 95% CIs [0.041, 0.101]), but not women (r = 0.002, 95% CIs [-0.041, 0.044]). Changes in T were positively correlated with aggression (r = 0.108, 95% CIs [0.041, 0.174]), an effect that was also stronger and significant in men (r = 0.162, 95% CIs [0.076, 0.246]), but not women (r = 0.010, 95% CIs [-0.090, 0.109]). The causal effects of testosterone on human aggression were weaker yet, and not statistically significant (r = 0.046, 95% CIs [-0.015, 0.108]). We discuss the multiple moderators identified here (e.g., offender status of samples, sex) and elsewhere that may explain these generally weak effects. We also offer suggestions regarding methodology and sample sizes to best capture these associations in future work.

Exercise testing-based algorithms to diagnose McArdle disease and MAD defects.

OBJECTIVE: As exercise intolerance and exercise-induced myalgia are commonly encountered in metabolic myopathies, functional screening tests are commonly used during the diagnostic work-up. Our objective was to evaluate the accuracy of isometric handgrip test (IHT) and progressive cycle ergometer test (PCET) to identify McArdle disease and myoadenylate deaminase (MAD) deficiency and to propose diagnostic algorithms using exercise-induced lactate and ammonia variations. METHODS: A prospective sample of 46 patients underwent an IHT and a PCET as part of their exercise-induced myalgia and intolerance evaluation. The two diagnostics tests were compared against the results of muscle biopsy and/or the presence of mutations in PYGM. A total of 6 patients had McArdle disease, 5 a complete MAD deficiency (MAD absent), 12 a partial MAD deficiency, and 23 patients had normal muscle biopsy and acylcarnitine profile (disease control). RESULTS: The two functional tests could diagnose all McArdle patients with statistical significance, combining a low lactate variation (IHT: <1 mmol/L, AUC = 0.963, P < .0001; PCET: <1 mmol/L, AUC = 0.990, P < .0001) and a large ammonia variation (IHT: >100 µmol/L, AUC = 0.944, P = .0005; PCET: >20 µmol/L, AUC = 1). PCET was superior to IHT for MAD absent diagnosis, combining very low ammonia variation (<10 µmol/L, AUC = 0.910, P < .0001) and moderate lactate variation (>1 mmol/L). CONCLUSIONS: PCET-based decision tree was more accurate than IHT, with respective generalized squared correlations of 0.796 vs 0.668. IHT and PCET are both interesting diagnostic tools to identify McArdle disease, whereas cycle ergometer exercise is more efficient to diagnose complete MAD deficiency.

COMT Val(158) Met genotype is associated with reward learning: a replication study and meta-analysis.

Identifying mechanisms through which individual differences in reward learning emerge offers an opportunity to understand both a fundamental form of adaptive responding as well as etiological pathways through which aberrant reward learning may contribute to maladaptive behaviors and psychopathology. One candidate mechanism through which individual differences in reward learning may emerge is variability in dopaminergic reinforcement signaling. A common functional polymorphism within the catechol-O-methyl transferase gene (COMT; rs4680, Val(158) Met) has been linked to reward learning, where homozygosity for the Met allele (linked to heightened prefrontal dopamine function and decreased dopamine synthesis in the midbrain) has been associated with relatively increased reward learning. Here, we used a probabilistic reward learning task to asses response bias, a behavioral form of reward learning, across three separate samples that were combined for analyses (age: 21.80 ± 3.95; n = 392; 268 female; European-American: n = 208). We replicate prior reports that COMT rs4680 Met allele homozygosity is associated with increased reward learning in European-American participants (ß = 0.20, t = 2.75, P < 0.01; ΔR(2) = 0.04). Moreover, a meta-analysis of 4 studies, including the current one, confirmed the association between COMT rs4680 genotype and reward learning (95% CI -0.11 to -0.03; z = 3.2; P < 0.01). These results suggest that variability in dopamine signaling associated with COMT rs4680 influences individual differences in reward which may potentially contribute to psychopathology characterized by reward dysfunction.

Social neuroendocrinology of human aggression: examining the role of competition-induced testosterone dynamics.

A large body of evidence indicates that individual differences in baseline concentrations of testosterone (T) are only weakly correlated with human aggression. Importantly, T concentrations are not static, but rather fluctuate rapidly in the context of competitive interactions, suggesting that acute fluctuations in T may be more relevant for our understanding of the neuroendocrine mechanisms underlying variability in human aggression. In this paper, we provide an overview of the literature on T and human competition, with a primary focus on the role of competition-induced T dynamics in the modulation of human aggression. In addition, we discuss potential neural mechanisms underlying the effect of T dynamics on human aggression. Finally, we highlight several challenges for the field of social neuroendocrinology and discuss areas of research that may enhance our understanding of the complex bi-directional relationship between T and human social behavior.

Component reductions in oxygen delivery generate variable haemodynamic and stress hormone responses.

BACKGROUND: In clinical practice, global oxygen delivery (DO2) is often considered as a whole; however pathological and adaptive responses after a decrease in individual constituents of the DO2 equation (cardiac output, haemoglobin, oxyhaemoglobin saturation) are likely to be diverse. We hypothesized that an equivalent decrease in DO2 after reductions in each separate component of the equation would result in different haemodynamic, tissue oxygenation, and stress hormonal responses. METHODS: Anaesthetized, fluid-resuscitated male Wistar rats were subjected to circulatory, anaemic, or hypoxic hypoxia (by haemorrhage, isovolaemic haemodilution, and breathing a hypoxic gas mix, respectively), produced either rapidly over 5 min or graded over 30 min, to a targeted 50% decrease in global oxygen delivery. Sham-operated animals acted as controls. Measurements were made of haemodynamics, skeletal muscle tissue oxygen tension, blood gas analysis, and circulating stress hormone levels. RESULTS: Whereas haemorrhage generated the largest decrease in cardiac output, and the greatest stress hormone response, haemodilution had the most marked effect on arterial pressure. In contrast, rapid hypoxaemia produced a minor impact on global haemodynamics yet induced the greatest decrease in regional oxygenation. A greater degree of hyperlactataemia was observed with graded insults compared with those administered rapidly. CONCLUSIONS: Decreasing global oxygen delivery, achieved by targeted reductions in its separate components, induces varying circulatory, tissue oxygen tension, and stress hormone responses. We conclude that not all oxygen delivery is the same; this disparity should be emphasized in classical teaching and re-evaluated in patient management.

Influence of sensory neuropeptides on human cutaneous wound healing process.

BACKGROUND: Close interactions exist between primary sensory neurons of the peripheral nervous system (PNS) and skin cells. The PNS may be implicated in the modulation of different skin functions as wound healing. OBJECTIVE: Study the influence of sensory neurons in human cutaneous wound healing. METHODS: We incubated injured human skin explants either with rat primary sensory neurons from dorsal root ganglia (DRG) or different neuropeptides (vasoactive intestinal peptide or VIP, calcitonin gene-related peptide or CGRP, substance P or SP) at various concentrations. Then we evaluated their effects on the proliferative and extracellular matrix (ECM) remodeling phases, dermal fibroblasts adhesion and differentiation into myofibroblasts. RESULTS: Thus, DRG and all studied neuromediators increased fibroblasts and keratinocytes proliferation and act on the expression ratio between collagen type I and type III in favor of collagen I, particularly between the 3rd and 7th day of culture. Furthermore, the enzymatic activities of matrix metalloprotesases (MMP-2 and MMP-9) were increased in the first days of wound healing process. Finally, the adhesion of human dermal fibroblasts and their differentiation into myofibroblasts were promoted after incubation with neuromediators. Interestingly, the most potent concentrations for each tested molecules, were the lowest concentrations, corresponding to physiological concentrations. CONCLUSION: Sensory neurons and their derived-neuropeptides are able to promote skin wound healing.

[Classification of urinary calculi in a pediatric population from Brittany]. / Proposition de "profils types" des calculs urinaires dans une population pédiatrique bretonne.

INTRODUCTION: Urinary lithiasis in children is relatively seldom in France as in industrialized countries. The determination of their etiology based on their composition may lead to a better treatment. METHOD: One hundred and eight urinary calculi from 6 months through 18-year-old children were analyzed by using spectrophotometry, in order to specify their structure. Six groups were evidenced through a multidimensional analysis based on the presence of components weighing at least 5% of the total. RESULTS: The youngest children affected were mostly boys, and the sex ratio switched after 12.5 years. Above 14 years of age, the number of calculi significantly raised. Their composition varied with the gender, and their localization with the age. Finally a correlation between infection and composition of the calculus was shown in our study. CONCLUSION: The classification of calculi among six groups according to their composition, along with clinical informations and morphologic studies, has proven its value in determining the etiology of the lithiasis. These data help to better understand the kind of lithiasis that may be observed and the physiopathology of the mechanism explaining it from the gender and age.

Body mass index, a major confounder to insulin resistance association with unprovoked venous thromboembolism. Results from the EDITH case-control study.

Shared risk factors help explain the association between venous thromboembolism (VTE) and atherothrombosis. The potential association between insulin resistance and VTE has been poorly evaluated. Thus, we aimed to assess the association between insulin resistance and VTE in the EDITH hospital-based case-control study. Between May 2000 and December 2004, 677 patients with unprovoked VTE and their age- and sex-matched controls were included. Fasting glycaemia and insulinaemia were measured and insulin resistance was estimated with the homeostasis model assessment of insulin resistance (HOMA-IR) equation. The association between HOMA-IR and VTE was determined in non-diabetic patients in a quintile-based analysis. A total of 590 non-diabetic cases (median age 73.0 years, 255 men) and 581 non-diabetic controls (median age 72.0 years, 247 men) were analysed. There was a trend for a higher median level of HOMA-IR index in cases than in controls (1.21 [interquartile range 0.84-2.10] vs1.19 [interquartile range 0.72-2.02], p=0.08). The unadjusted analysis showed an increased risk of unprovoked VTE associated with increasing HOMA-IR (odds ratio [OR] 1.53; 95% confidence interval [CI] 1.00-2.34 for the highest quintile of HOMA-IR compared with the first quintile). Adjustment for lipid lowering drugs and antiplatelet agents use slightly modified the association (OR 1.51; 95% CI 0.97-2.34). When body mass index was added in the adjusted model, HOMA-IR was no longer associated with VTE (OR 1.08; 95% CI 0.67-1.73). Our results highlight the role of body mass index in the association between cardiovascular risk factors and VTE.

Study of the VOC emissions from a municipal solid waste storage pilot-scale cell: comparison with biogases from municipal waste landfill site.

The emission of volatile organic compounds (VOCs) from municipal solid waste stored in a pilot-scale cell containing 6.4 tonnes of waste (storage facility which is left open during the first period (40 days) and then closed with recirculation of leachates during a second period (100 days)) was followed by dynamic sampling on activated carbon and analysed by GC-MS after solvent extraction. This was done in order to know the VOC emissions before the installation of a methanogenesis process for the entire waste mass. The results, expressed in reference to toluene, were exploited during the whole study on all the analyzable VOCs: alcohols, ketones and esters, alkanes, benzenic and cyclic compounds, chlorinated compounds, terpene, and organic sulphides. The results of this study on the pilot-scale cell are then compared with those concerning three biogases from a municipal waste landfill: biogas (1) coming from waste cells being filled or recently closed, biogas (2) from all the waste storage cells on site, and biogas (3) which is a residual gas from old storage cells without aspiration of the gas. The analysis of the results obtained revealed: (i) a high emission of VOCs, principally alcohols, ketones and esters during the acidogenesis; (ii) a decrease in the alkane content and an increase in the terpene content were observed in the VOCs emitted during the production of methane; (iii) the production of heavier alkanes and an increase in the average number of carbon atoms per molecule of alkane with the progression of the stabilisation/maturation process were also observed. Previous studies have concentrated almost on the analysis of biogases from landfills. Our research aimed at gaining a more complete understanding of the decomposition/degradation of municipal solid waste by measuring the VOCs emitted from the very start of the landfill process i.e. during the acidogenesis and acetogenesis phases.

Interaction of purified alternative oxidase from thermogenic Arum maculatum with pyruvate.

Plant alternative oxidase (AOX) activity in isolated mitochondria is regulated by carboxylic acids, but reaction and regulatory mechanisms remain unclear. We show that activity of AOX protein purified from thermogenic Arum maculatum spadices is sensitive to pyruvate and glyoxylate but not succinate. Rapid, irreversible AOX inactivation occurs in the absence of pyruvate, whether or not duroquinol oxidation has been initiated, and is insensitive to duroquinone. Our data indicate that pyruvate stabilises an active conformation of AOX, increasing the population of active protein in a manner independent of reducing substrate and product, and are thus consistent with an exclusive effect of pyruvate on the enzyme's apparent V(max).

[Computer-assisted management of depots for blood products in health establishments]. / Gestion informatique d'un dépôt de produits sanguins labiles d'un établissement de santé.

To manage the filing of blood components at the hospital of the city of Bayeux, the laboratory uses Cursus, a dedicated software for haemovigilance. Benefits for using this software at different steps of the blood bank management are: simplification, security and harmonization of practices during receipt and issurance of blood components, securing recordings with the use of bar codes for patient identification and blood components listing, implementation of a computerized tracking system for transfusion, traceability, limitation of written documents and availability of statistics on the management of the depot.

[Adaptation of free and total plasma carnitine determination on the Dimension HM, X-Pand model (Dade Behring)]. / Adaptation des dosages plasmatiques de carnitine libre et totale sur automate Dimension HM, modèle X-Pand (Dade Behring).

L-carnitine is a quaternary ammonium compound that facilitates long-chain fatty acids crossing through the mitochondrial membrane allowing their beta-oxidation. Human pathologies relatives to carnitine are mainly deficiencies, with myopathy and lipids metabolism disorders. The aim of this study was to validate the free and total carnitine plasmatic level measurement using the Dimension HM, X-Pand model analyzer (Dade Behring). Free carnitine was directly determined on plasma samples, deproteinized by using ultrafiltration, whereas total carnitine was measured after alkaline hydrolysis. Within-day and between-day imprecision were < 4,00 and 9,00 % respectively. The method is linear through 250,00 micromol/L and the limit of quantification is 3,00 micromol/L. Our method was correlated to tandem mass spectrometry (r = 0,956 for free and total carnitine). Recovery of free and total carnitine from spiked plasmas was > 99 %. On board stability of cartridge (5 days) and of calibration (at least 30 days) are in agreement with a method easily adaptable in routine laboratories.

Soil clean up by venting: comparison between modelling and experimental VOC removal results.

Many investigations into specific or accidental pollution relate to hydrocarbons of oil origin: fuels (gasoline or gas oil), fuel oil and lubricants. Pollution by petroleum products is a source of volatile organic compounds in soil. Therefore, laboratory column venting experiments were completed in order to investigate the removal of a pure compound (toluene) and a mixture of two (toluene and n-heptane) and five (toluene, n-heptane, ethylbenzene, m-xylene and p-xylene) compounds. The choice of the compounds, as well as their proportion in the mixture was made on the basis of the real fuel composition. The objective of this study is a comparison between the experimental volatile organic compounds removal results and the predicted values of a simple classical analytical mathematical model that enables the modelling of the venting process. The proposed model for the contaminants transport describes the removal of organic compounds from soil, the contaminants being distributed among four phases: vapour, nonaqueous liquid phase, aqueous and "solid" phase; local phases equilibrium and ideal behaviour of all four phases were found to be accurate enough to describe the interphase mass transfer. The testing of the mathematical model accuracy has been done by using the following performance criteria: dynamic absolute error, average error, model accuracy and correlation coefficient. The reasonable agreement between the predicted and the experimental results as well as the values of the performance criteria prove that the mathematical model is suitable to describe the removal of volatile organic compounds pollutants by venting in the range of experimental conditions used in the pilot plant.