[Adipocytes, adipokines and metabolic alterations in pulmonary fibrosis]. / Adipocytes, adipokines et altérations métaboliques dans la fibrose pulmonaire.

Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by severe remodeling of the lung parenchyma, with an accumulation of activated myofibroblasts and extracellular matrix, along with aberrant cellular differentiation. Within the subpleural fibrous zones, ectopic adipocyte deposits often appear. In addition, alterations in lipid homeostasis have been associated with IPF pathophysiology. In this mini-review, we will discuss the potential involvement of the adipocyte secretome and its paracrine or endocrine-based contribution to the pathophysiology of IPF, via protein or lipid mediators in particular.

Advances on the early cellular events occurring upon exposure of human macrophages to aluminum oxyhydroxide adjuvant.

Aluminum compounds are the most widely used adjuvants in veterinary and human vaccines. Despite almost a century of use and substantial advances made in recent decades about their fate and biological effects, the exact mechanism of their action has been continuously debated, from the initial "depot-theory" to the direct immune system stimulation, and remains elusive. Here we investigated the early in vitro response of primary human PBMCs obtained from healthy individuals to aluminum oxyhydroxide (the most commonly used adjuvant) and a whole vaccine, in terms of internalization, conventional and non-conventional autophagy pathways, inflammation, ROS production, and mitochondrial metabolism. During the first four hours of contact, aluminum oxyhydroxide particles, with or without adsorbed vaccine antigen, (1) were quickly recognized and internalized by immune cells; (2) increased and balanced two cellular clearance mechanisms, i.e. canonical autophagy and LC3-associated phagocytosis; (3) induced an inflammatory response with TNF-α production as an early event; (4) and altered mitochondrial metabolism as assessed by both decreased maximal oxygen consumption and reduced mitochondrial reserve, thus potentially limiting further adaptation to other energetic requests. Further studies should consider a multisystemic approach of the cellular adjuvant mechanism involving interconnections between clearance mechanism, inflammatory response and mitochondrial respiration.

Clearance, biodistribution, and neuromodulatory effects of aluminum-based adjuvants. Systematic review and meta-analysis: what do we learn from animal studies?

Aluminum (Al) salts are commonly used as adjuvants in human and veterinary vaccines for almost a century. Despite this long history of use and the very large number of exposed individuals, data in the literature concerning the fate of these molecules after injection and their potential effects on the nervous system is limited. In the context of (i) an increase of exposure to Al salts through vaccination; (ii) the absence of safety values determined by health regulators; (iii) the lack of robustness of the studies used as references to officially claim Al adjuvant innocuity; (iv) the publication of several animal studies investigating Al salts clearance/biopersistence and neurotoxicity; we have examined in this review all published studies performed on animals and assessing Al adjuvants kinetics, biodistribution, and neuromodulation since the first work of A. Glenny in the 1920s. The diversity of methodological approaches, results, and potential weaknesses of the 31 collected studies are exposed. A large range of protocols has been used, including a variety of exposure schedule and analyses methods, making comparisons between studies uneasy. Nevertheless, published data highlight that when biopersistence, translocation, or neuromodulation were assessed, they were documented whatever the different in vivo models and methods used. Moreover, the studies pointed out the crucial importance of the different Al adjuvant physicochemical properties and host genetic background on their kinetics, biodistribution, and neuromodulatory effects. Regarding the state of the art on this key public health topic, further studies are clearly needed to determine the exact safety level of Al salts.

A retrospective study of ketamine administration and the development of acute or post-traumatic stress disorder in 274 war-wounded soldiers.

The objective of this study was to explore whether ketamine prevents or exacerbates acute or post-traumatic stress disorders in military trauma patients. We conducted a retrospective study of a database from the French Military Health Service, including all soldiers surviving a war injury in Afghanistan (2010-2012). The diagnosis of post-traumatic stress disorder was made by a psychiatrist and patients were analysed according to the presence or absence of this condition. Analysis included the following covariables: age; sex; acute stress disorder; blast injury; associated fatality; brain injury; traumatic amputation; Glasgow coma scale; injury severity score; administered drugs; number of surgical procedures; physical, neurosensory or aesthetic sequelae; and the development chronic pain. Covariables related to post-traumatic and acute stress disorders with a p ≤ 0.10 were included in a multivariable logistic regression model. The data from 450 soldiers were identified; 399 survived, of which 274 were analysed. Among these, 98 (36%) suffered from post-traumatic stress disorder and 89 (32%) had received ketamine. Fifty-four patients (55%) in the post-traumatic stress disorder group received ketamine vs. 35 (20%) in the no PTSD group (p < 0.001). The 89 injured soldiers who received ketamine had a median (IQR [range]) injury severity score of 5 (3-13 [1-26]) vs. 3 (2-4 [1-6] in the 185 patients who did not (p < 0.001). At multivariable analysis, only acute stress disorder and total number of surgical procedures were independently associated with the development of post-traumatic stress disorder. In this retrospective study, ketamine administration was not a risk factor for the development of post-traumatic stress disorder in the military trauma setting.

[Critical analysis of reference studies on aluminium-based adjuvants toxicokinetics]. / Adjuvants aluminiques des vaccins : analyse critique des études toxicocinétiques de référence.

We reviewed the three reference toxicokinetic studies commonly used to suggest innocuity of aluminum (Al)-based adjuvants. A single experimental study was carried out using isotopic 26Al (Flarend et al., 1997). This study ignored adjuvant cell capture. It was conducted over a short period of time (28 days) and used only two rabbits per adjuvant. At the endpoint, Al retention was 78% for aluminum phosphate and 94% for aluminum hydroxide, both results being incompatible with quick elimination of vaccine-derived Al in urines. Tissue distribution analysis omitted three important retention sites: the injected muscle, the draining lymph node and bone. Two theoretical studies have evaluated the potential risk of vaccine Al in infants, by reference to the oral Minimal Risk Level (MRL) extrapolated from animal studies. Keith et al., 2002 used a too high MRL (2mg/kg/d), an erroneous model of 100% immediate absorption of vaccine Al, and did not consider renal and blood-brain barrier immaturity. Mitkus et al. (2011) only considered absorbed Al, with erroneous calculations of absorption duration. They ignored particulate Al captured by immune cells, which play a role in systemic diffusion and the neuro-inflammatory potential of the adjuvant. MRL they used was both inappropriate (oral Al vs injected adjuvant) and far too high (1mg/kg/d) with regard to experimental studies of Al-induced memory and behavioral changes. Both paucity and serious weaknesses of these studies strongly suggest that novel experimental studies of Al adjuvants toxicokinetics should be performed on the long-term, including post-natal and adult exposures, to ensure innocuity and restore population confidence in Al-containing vaccines.

Effects of complex life cycles on genetic diversity: cyclical parthenogenesis.

Neutral patterns of population genetic diversity in species with complex life cycles are difficult to anticipate. Cyclical parthenogenesis (CP), in which organisms undergo several rounds of clonal reproduction followed by a sexual event, is one such life cycle. Many species, including crop pests (aphids), human parasites (trematodes) or models used in evolutionary science (Daphnia), are cyclical parthenogens. It is therefore crucial to understand the impact of such a life cycle on neutral genetic diversity. In this paper, we describe distributions of genetic diversity under conditions of CP with various clonal phase lengths. Using a Markov chain model of CP for a single locus and individual-based simulations for two loci, our analysis first demonstrates that strong departures from full sexuality are observed after only a few generations of clonality. The convergence towards predictions made under conditions of full clonality during the clonal phase depends on the balance between mutations and genetic drift. Second, the sexual event of CP usually resets the genetic diversity at a single locus towards predictions made under full sexuality. However, this single recombination event is insufficient to reshuffle gametic phases towards full-sexuality predictions. Finally, for similar levels of clonality, CP and acyclic partial clonality (wherein a fixed proportion of individuals are clonally produced within each generation) differentially affect the distribution of genetic diversity. Overall, this work provides solid predictions of neutral genetic diversity that may serve as a null model in detecting the action of common evolutionary or demographic processes in cyclical parthenogens (for example, selection or bottlenecks).

[Affective mentalizing in Addictive Borderline Personality: A literature review]. / La mentalisation affective de la personnalité limite addictive : une revue de la littérature.

This literature review concerns affective mentalizing in borderline addictive personality. This concept postulates the group between addictions and borderline personalities may correspond to Personality Disorders (PDs). First, we will present conceptualizations and evaluations of affective mentalizing. The latter refers to one dimension of mentalization, a process by which an individual interprets his/her mental states and those of others. Lecours and Bouchard proposed a hierarchic model: the Élaboration verbale de l'affect (EVA). They also developed an empiric methodology: the Grille de l'élaboration verbale de l'affect (GEVA). The methodological approach of Lecours fulfils the requirements made by Cho-Kain, Gunderson and Luyten, involving a narrower operationalization of the mentalization concept through the evaluation of its dimensions. Conceptualizations and evaluations enabled focus on mentalization psychopathology. Fonagy and Bateman studied this latter in the subjects with PDs, particularly in Borderline Personality Disorders (BPD). We describe mentalization failure, its etiology and consequences in the BPD. Several forms of mentalization psychopathology are identified. Its etiology is largely environmental. Fonagy and Bateman developed the optimum developmental model of mentalization and referred to it to explain etiology of mentalization failure in BPD. Consequences of mentalization failure explicate its functioning. Mentalization may be considered as essential in their comprehension and their care. Research about mentalization of PDs does not integrate addiction as one comorbidity factor. However, Allen, Fonagy and Bateman describe a bidirectional interaction between mentalization failure and addiction. We propose to examine the mentalization of Borderline Addictive Personality. This concept groups addictions and borderline personalities in just one clinical entity other than their links of co-morbidities.

Naked-eye nanobiosensor for therapeutic drug monitoring of methotrexate.

Sensing of methotrexate at clinically-relevant concentrations was achieved with a plasmon-coupling assay. In this assay, free methotrexate and folic acid Au nanoparticles competed for human dihydrofolate reductase (hDHFR)-functionalized Au nanoparticles (Au NP). The hDHFR-functionalized Au NPs were immobilized on a small glass sensor inserted in a portable 4-channel LSPR reader. This allowed rapid (minutes) and sensitive (nanomolar range) measurement of methotrexate concentration by means of total internal reflection plasmonic spectroscopy. The large bathochromic shifts of the plasmon-coupling assay led to striking colour changes visible to the naked eye for methotrexate at clinically-relevant concentrations. The results demonstrate the potential for therapeutic drug monitoring of a widely used chemotherapy agent, as assessed with the naked eye.

Single chip SPR and fluorescent ELISA assay of prostate specific antigen.

A multi-channel system combining fluidics and micropatterned plasmonic materials with wavelength interrogation surface plasmon resonance (SPR) and fluorescence detection was integrated from the combination of a small and motorized fluorescence microscope mounted on a portable 4-channel SPR instrument. The SPR and fluorescent measurements were performed based on the same detection area in a multi-channel fluidic, with a sensing scheme for prostate-specific antigen (PSA) consisting of a sandwich assay with a capture anti-PSA immobilized onto the SPR sensor and a detection anti-PSA modified with horseradish peroxidase (HRP). In this dual-detection instrument, fluorescence was measured from the solution side of the micropatterned gold film, while the interface between the glass prism and the gold film served to interrogate the SPR response. The SPR sensors were comprised of microhole arrays fabricated by photolithography to enhance the instrumental response for PSA detection by approximately a factor of 2 to 3 and they were coated with a self-assembled monolayer of a peptide (3-MPA-HHHDD-OH) to minimize nonspecific adsorption. PSA was successfully detected at clinical concentrations from 10 pM to 50 nM with this integrated system in a single assay lasting 12 minutes, almost centering on the desired range for PSA diagnostic tests (>4 ng mL(-1) or >150 pM). The combination of two robust techniques in a single chip and instrument has led to a simple and effective assay that can be carried out on a small and portable instrument providing rapid biodetection of an important cancer biomarker with a dynamic range of nearly 4 orders of magnitude in the clinical range.

Plasmonic sensors for the competitive detection of testosterone.

The ability to detect small molecules in a rapid and sensitive manner is of great importance in the field of clinical chemistry, and the advancement of novel biosensors is key to realising point-of-care analysis for essential targets. Testosterone is an example of such a small molecule, the detection of which is important in both clinical analysis, and in the sporting industry to prevent doping. As such, a portable, rapid and sensitive test for testosterone would be of great use across a variety of analytical fields. Here we report on a novel method of testosterone analysis, based on a competitive inhibition assay utilising functionalized gold nanoparticles. Two sensing platforms are directly compared for the detection of testosterone based on both classical SPR and LSPR. We provide an in-depth discussion on the optimum surface chemistries needed to create a stable detection conjugate before successfully detecting testosterone using our newly developed portable 4-channel SPR instrument. We provide the first detailed study into the comparison of SPR and LSPR for the analysis of a small molecule, and provide a simple and effective method of testosterone detection that could potentially be extended to a variety of different analytes.

Altered nociception in mice with genetically induced hypoglutamatergic tone.

Extensive pharmacological evidence supports the idea that glutamate plays a key role in both acute and chronic pain. In the present study, we investigated the implication of the excitatory amino acid in physiological nociception by using mutant mice deficient in phosphate-activated glutaminase type 1 (GLS1), the enzyme that synthesizes glutamate in central glutamatergic neurons. Because homozygous GLS1-/- mutants die shortly after birth, assays for assessing mechanical, thermal and chemical (formalin) nociception were performed on heterozygous GLS1+/- mutants, which present a clear-cut decrease in glutamate synthesis in central neurons. As compared to paired wild-type mice, adult male GLS1+/- mutants showed decreased responsiveness to mechanical (von Frey filament and tail-pressure, but not tail-clip, tests) and thermal (Hargreaves' plantar, tail-immersion and hot-plate tests) nociceptive stimuli. Genotype-related differences were also found in the formalin test for which GLS1+/- mice exhibited marked decreases in the nociceptive responses (hindlimb lift, lick and flinch) during both phase 1 (0-5 min) and phase 2 (16-45 min) after formalin injection. On the other hand, acute treatment with memantine (1mg/kg i.p.), an uncompetitive antagonist at NMDA glutamate receptors, reduced nociception responses in wild-type but not GLS1+/- mice. Conversely, antinociceptive response to acute administration of a low dose (1mg/kg s.c.) of morphine was significantly larger in GLS1+/- mutants versus wild-type mice. Our findings indicate that genetically driven hypoactivity of central glutamatergic neurotransmission renders mice hyposensitive to nociceptive stimulations, and promotes morphine antinociception, further emphasizing the critical role of glutamate in physiological nociception and its opioid-mediated control.

Detection, characterization and biological activities of [bisphospho-thr3,9]ODN, an endogenous molecular form of ODN released by astrocytes.

Astrocytes synthesize and release endozepines, a family of regulatory neuropeptides, including diazepam-binding inhibitor (DBI) and its processing fragments such as the octadecaneuropeptide (ODN). At the molecular level, ODN interacts with two types of receptors, i.e. it acts as an inverse agonist of the central-type benzodiazepine receptor (CBR), and as an agonist of a G protein-coupled receptor (GPCR). ODN exerts a wide range of biological effects mediated through these two receptors and, in particular, it regulates astrocyte activity through an autocrine/paracrine mechanism involving the metabotropic receptor. More recently, it has been shown that Müller glial cells secrete phosphorylated DBI and that bisphosphorylated ODN ([bisphospho-Thr(3,9)]ODN, bpODN) has a stronger affinity for CBR than ODN. The aim of the present study was thus to investigate whether bpODN is released by mouse cortical astrocytes and to compare its potency to ODN. Using a radioimmunoassay and mass spectrometry analysis we have shown that bpODN as well as ODN were released in cultured astrocyte supernatants. Both bpODN and ODN increased astrocyte calcium event frequency but in a very different range of concentration. Indeed, ODN stimulatory effect decreased at concentrations over 10(-10)M whereas bpODN increased the calcium event frequency at similar doses. In vivo effects of bpODN and ODN were analyzed in two behavioral paradigms involving either the metabotropic receptor (anorexia) or the CBR (anxiety). As previously described, ODN (100ng, icv) induced a significant reduction of food intake. Similar effect was achieved with bpODN but at a 10 times higher dose (1000 ng, icv). Similarly, and contrasting with our hypothesis, bpODN was also 10 times less potent than ODN to induce anxiety-related behavior in the elevated zero maze test. Thus, the present data do not support that phosphorylation of ODN is involved in receptor selectivity but indicate that it rather weakens ODN activity.

Metal-enhanced fluorescence and FRET on nanohole arrays excited at angled incidence.

The influence of experimental parameters on the performance of plasmonic sensors is of great importance in analytical sciences. The plasmon coupling conditions (angle of incidence, metal composition, laser frequency and excitation/emission properties of fluorophores) were thus investigated for surface plasmon-enhanced fluorescence on metallic nanohole arrays. Optimal fluorescence enhancements were achieved when the plasmon resonance, the excitation laser and the fluorophore's excitation wavelengths were matched. The enhancement of the acceptor emission of a rhodamine 6G(Rh6G)-Quasar670™ FRET pair was achieved on the nanohole arrays by tuning the plasmon wavelength with the maximal overlap of the donor's emission and acceptor excitation. Silver nanohole arrays achieved larger fluorescence enhancement than gold nanohole arrays at 532 nm, while gold nanohole arrays led to larger fluorescence enhancement at 635 nm. These results demonstrate the importance of tuning the plasmon coupling conditions for surface plasmon-enhanced fluorescence sensing.

[Non-tuberculous mycobacterial infection of a totally implanted perfusion device]. / Infection à mycobactérie non tuberculeuse d'une chambre implantable pour perfusion.

INTRODUCTION: Catheter-related infection by non-tuberculous mycobacteria is rare but difficult to diagnose and the treatment is not standardized. CASE REPORT: A 64-year-old woman treated for lung cancer with intravenous chemotherapy developed an infection of her totally implanted perfusion device with Mycobacterium chelonae. The infection was cured after surgical removal of the device and treatment with oral clarithromycin. CONCLUSION: Mycobacteria may infect vascular access devices. Rapid diagnosis of such infections allows early treatment.

Zonal shear and super-rotation in a magnetized spherical Couette-flow experiment.

We present measurements performed in a spherical shell filled with liquid sodium, where a 74-mm-radius inner sphere is rotated while a 210-mm-radius outer sphere is at rest. The inner sphere holds a dipolar magnetic field and acts as a magnetic propeller when rotated. In this experimental setup called "Derviche Tourneur Sodium" (DTS), direct measurements of the velocity are performed by ultrasonic Doppler velocimetry. Differences in electric potential and the induced magnetic field are also measured to characterize the magnetohydrodynamic flow. Rotation frequencies of the inner sphere are varied between -30 Hz and +30 Hz, the magnetic Reynolds number based on measured sodium velocities and on the shell radius reaching to about 33. We have investigated the mean axisymmetric part of the flow, which consists of differential rotation. Strong super-rotation of the fluid with respect to the rotating inner sphere is directly measured. It is found that the organization of the mean flow does not change much throughout the entire range of parameters covered by our experiment. The direct measurements of zonal velocity give a nice illustration of Ferraro's law of isorotation in the vicinity of the inner sphere, where magnetic forces dominate inertial ones. The transition from a Ferraro regime in the interior to a geostrophic regime, where inertial forces predominate, in the outer regions has been well documented. It takes place where the local Elsasser number is about 1. A quantitative agreement with nonlinear numerical simulations is obtained when keeping the same Elsasser number. The experiments also reveal a region that violates Ferraro's law just above the inner sphere.

Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular ejection fraction.

BACKGROUND: Patients with severe aortic stenosis and reduced left ventricular ejection fraction (LVEF) have a poor prognosis with conservative therapy but a high operative mortality when treated surgically. Recently, transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement (SAVR) for patients considered at high or prohibitive operative risk. The objective of this study was to compare TAVI and SAVR with respect to postoperative recovery of LVEF in patients with severe aortic stenosis and reduced LV systolic function. METHODS AND RESULTS: Echocardiographic data were prospectively collected before and after the procedure in 200 patients undergoing SAVR and 83 patients undergoing TAVI for severe aortic stenosis (aortic valve area ≤1 cm(2)) with reduced LV systolic function (LVEF ≤50%). TAVI patients were significantly older (81±8 versus 70±10 years; P<0.0001) and had more comorbidities compared with SAVR patients. Despite similar baseline LVEF (34±11% versus 34±10%), TAVI patients had better recovery of LVEF compared with SAVR patients (ΔLVEF, 14±15% versus 7±11%; P=0.005). At the 1-year follow-up, 58% of TAVI patients had a normalization of LVEF (>50%) as opposed to 20% in the SAVR group. On multivariable analysis, female gender (P=0.004), lower LVEF at baseline (P=0.005), absence of atrial fibrillation (P=0.01), TAVI (P=0.007), and larger increase in aortic valve area after the procedure (P=0.01) were independently associated with better recovery of LVEF. CONCLUSION: In patients with severe aortic stenosis and depressed LV systolic function, TAVI is associated with better LVEF recovery compared with SAVR. TAVI may provide an interesting alternative to SAVR in patients with depressed LV systolic function considered at high surgical risk.

Adaptation and validation of the Tower of London test of planning and problem solving in people with intellectual disabilities.

BACKGROUND: There is a need for validated, standardised tools for the assessment of executive functions in adults with intellectual disabilities (ID). This study examines the validity of a test of planning and problem solving (Tower of London) with adults with ID. METHOD: Participants completed an adapted version of the Tower of London (ToL) while day-centre staff completed adaptive function (Adaptive Behaviour Scale - Residential and Community: Second Edition, modified version) and dysexecutive function (DEX-Independent Rater) questionnaires for each participant. Correlation analyses of test and questionnaire variables were undertaken. RESULTS: The adapted ToL has a robust structure and shows significant associations with independent living skills, challenging behaviour and behaviours related to dysexecutive function. CONCLUSIONS: The adapted ToL is a valid test for use with people with ID. However, there is also a need to develop other ecologically valid tools based on everyday planning tasks undertaken by people with ID.

Repulsion and metabolic switches in the collective behavior of bacterial colonies.

Bacteria inoculated on surfaces create colonies that spread out, forming patterns shaped by their mutual interactions. Here, by a combination of experiments and modeling, we address two striking phenomena observed when colonies spread out circularly, without dendritic instabilities. First, the velocity of spreading is generically found to decrease as levels of nutrients initially deposited on the surface increase. We demonstrate that the slowdown is due to phenomena of differentiation, leading to the coexistence of bacteria in different states of motility and we model their dynamics. Second, colonies spreading out from different inocula on the same surface are observed to merge or repel (halting at a finite distance), depending on experimental conditions. We identify the parameters that determine the fate of merging versus repulsion, and predict the profile of arrest in the cases of repulsion.