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The use of Space has drastically evolved these last ten years. Tomorrow will see easier and cheaper access to Space, satellite servicing, in-orbit manufacturing, human private spaceflights to ever increasing number of Orbital Stations, road to the Moon, Asteroids, Mars … It seems fundamental to make sure we can rely on robust, reliable, frequent and affordable access to and from LEO with both automatic systems and human missions; such systems are the bricks with which all the future operations in Space will be built. Independent human access to space from Europe for our astronauts is a key to any future in Space. It has been studied in depth since the 80's with Hermes Spaceplane, then through numerous studies, pre-development activities, and demonstrations such as ARD, X38-CRV or IXV, which now allow Europe to reconsider such an endeavor with a much higher confidence. We have worked during one year on every aspect of a European Human spaceflight system aimed at being launched from Guiana Space Center. It would be a logical addition to new orbital infrastructures in LEO which, following the ISS retirement, are already under deployment by governments and commercial entities in the US, Russia, China, India. We found out that Europe could play a very specific role, deploying a “universal” vehicle capable to visit any future LEO architecture; following its historical tradition, Europe would be in a position to cooperate potentially with everyone in LEO! We traded the various types of potential vehicles dealing with the recovery techniques for both nominal and abort cases. The launch with Ariane 6 has been looked at in detail and a particular effort has been devoted to the adaptation of the Guiana Space Center. A cautious examination of the required technologies shows that European industry is fully ready, and that most of these technologies are available. In particular, we have shown the readiness of Human-Rating systems, based on the ATV, Orion ESM and ISS pressurized modules. Even if the capability requires a significant budget, the question is to know if Europe can be left aside in the future? Such a program would release a very strong positive sign for the young generations cradled with the feats of our astronauts; it would give motivating STEM objectives to the next generation of students. As a major space power it is clearly strategic for Europe to develop independent human access to LEO in the current multipolar world.

In this work we have collected a set of 30 trypanosomicidal naphthoquinones and developed pharmacophoric and 3D-QSAR models as tools for the design of new potential anti-Chagasic compounds. Firstly, qualitative information was obtained from SAR and pharmacophoric models identifying some fragments around the 2-aryloxynaphthoquinone scaffold important for the antiparasitic activity. Then, 3D-QSAR CoMFA and CoMSIA models were developed. The models showed adequate statistical parameters where the steric, electrostatic, and hydrophobic features explain the trypanosomicidal effect. Therefore, to validate our models, we carried out the design, synthesis, and biological evaluation on

Lower respiratory tract infections (LRTIs) produced by viruses are the most frequent cause of morbidity and mortality in children younger than 5 years of age. The immune response triggered by viral infection can induce a strong inflammation in the airways and cytokines could be considered as biomarkers for disease severity as these molecules modulate the inflammatory response that defines the outcome of patients. Aiming to predict the severity of disease during respiratory tract infections, we conducted a 1-year follow-up observational study in infants who presented upper or lower respiratory tract infections caused by seasonal respiratory viruses. At the time of enrollment, nasopharyngeal swabs (NPS) were obtained from infants to measure mRNA expression and protein levels of IL-3, IL-8, IL-33, and thymic stromal lymphopoietin. While all cytokines significantly increased their protein levels in infants with upper and lower respiratory tract infections as compared to control infants, IL-33 and IL-8 showed a significant increase in respiratory syncytial virus (RSV)-infected patients with LRTI as compared to patients with upper respiratory tract infection. We also found higher viral loads of RSV-positive samples with a greater IL-8 response at the beginning of the symptoms. Data obtained in this study suggest that both IL-8 and IL-33 could be used as biomarkers for clinical severity for infants suffering from LRTIs caused by the RSV.

This study examines the effects of diets supplemented with various lipids selected to induce divergent milk fat content responses (including a milk fat depression) between dairy cows and goats on plasma lipid composition. The objective was to better understand the mechanisms behind the regulation of milk fat secretion in these two ruminant species. Twelve Holstein cows and 12 Alpine goats were fed a basal diet not supplemented (CTL) or supplemented with corn oil plus wheat starch (COS, 5% DM intake (DMI)), marine algae powder of Schizochytrium sp. (MAP, 1.5% DMI), or hydrogenated palm oil (HPO, 3% DMI), in a replicated 4 × 4 Latin square design, during 28 days. On day 27, blood samples were collected for lipid analysis. Plasma lipid classes were quantified by high-performance thin-layer chromatography, with triacylglycerol (TAG) and free fatty acid (FFA) fractions analysed for FA composition by GLC. Plasma molecular species of TAG and ceramides were determined by HPLC-high-resolution MS and by liquid chromatography-triple quadrupole, respectively. Irrespective of diet, plasma total lipid content was higher in cows than goats (+61%), and TAG concentration was higher in goats than cows (+157%). In cows, conversely to goats, COS increased the trans-10 C18:1 proportion in the free FA (+248%) and the TAG (+195%) fractions. In cows and goats, MAP induced increases in cholesterol esters, cholesterol and phospholipids compared to CTL and changes in the plasma free FA and FA of TAG profiles. In both ruminant species, the concentrations of the lipid fractions were unchanged by HPO compared to CTL. Our results point to species specificities and different diet effects in plasma concentrations and compositions of lipid fractions in cows and goats. These new data highlight how diets, that induce large variations in milk fat secretions, affect the plasma lipid classes available for milk fat synthesis.

In this work we have collected a set of 30 trypanosomicidal naphthoquinones and developed pharmacophoric and 3D-QSAR models as tools for the design of new potential anti-Chagasic compounds. Firstly, qualitative information was obtained from SAR and pharmacophoric models identifying some fragments around the 2-aryloxynaphthoquinone scaffold important for the antiparasitic activity. Then, 3D-QSAR CoMFA and CoMSIA models were developed. The models showed adequate statistical parameters where the steric, electrostatic, and hydrophobic features explain the trypanosomicidal effect. Therefore, to validate our models, we carried out the design, synthesis, and biological evaluation on T. cruzi epimastigotes of five new compounds (33a-e). According to CoMFA model, three out of five compounds showed pIC50 values within one logarithmic unit of deviation. The two compounds that did not fit the predictions were those with high lipophilicity, which agreed with the SAR and pharmacophore models. Docking and molecular dynamic studies were performed on T. cruzi trypanothione reductase, in a proposed binding site for this type of naphthoquinone. Interestingly, 33a-e showed the same interaction pattern as a naphthoquinone inhibitor (2). Finally, predicted drug-likeness properties indicated that 33a-e have optimal oral bioavailability. Thus, this study provides new in silico models for obtaining novel trypanosomicidal compounds.

Motivational deficits (e.g., apathy) and dysregulation (e.g., addiction) in HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for motivational alterations, however, has yet to be systematically evaluated. Thus, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed and drug-seeking behavior. First, at the genotypic level, motivational deficits in HIV-1 Tg rats treated with vehicle were characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose. Motivational dysregulation was evidenced by enhanced drug-seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated both motivational deficits and dysregulation in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited lower levels of dendritic branching and a shift towards longer dendritic spines with decreased head diameter. Treatment with SE, however, led to long-term enhancements in dendritic spine morphology in HIV-1 Tg animals supporting a potential underlying basis by which SE exerts its therapeutic effects. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.

The percentage of college students receiving unproductive grades in introductory mathematics courses is a concern for post-secondary institutions across the country. Many factors can be targeted as...

BackgroundEvidence shows that dysfunctional SSc keratinocytes contribute to fibrosis by altering dermal homeostasis (1, 2). Whether interleukin-25 (IL-25), an IL-17 family member regulating many epidermal functions (3), takes part in skin fibrosis is unknown.ObjectivesTo investigate the role of IL-25 in skin fibrosis.MethodsThe expression of IL-25 was evaluated by immunofluorescence and in situ hybridization in 10 SSc and 7 healthy donors (HD) skin biopsies. Epidermal equivalents (EE) reconstituted by primary HD keratinocytes were used as a model to study transcriptomic changes induced by IL-25 in the epidermis. RNA expression profile in EE was characterized by RNAseq. The conditioned medium (CM) from primary SSc and HD keratinocytes primed with IL-25 was used to stimulate fibroblasts. IL-6, IL-8, MMP-1, type-I collagen (col-I), and fibronectin production by fibroblasts was assessed by ELISA.ResultsSSc epidermis expressed lower levels of IL-25 compared to HD. In EE, IL-25 regulated several molecular pathways related to wound healing and extracellular matrix (ECM) remodeling. Compared to control CM, the CM from IL-25-primed keratinocytes enhanced the fibroblast production of MMP-1, IL-6, IL-8, but not of Col-I nor fibronectin. However, IL-25 significantly reduced the production of Col-I when applied directly to fibroblasts and partially inhibit α-smooth muscle actin (α-SMA) expression promoted by TGFβ. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators.ConclusionThese results show that IL-25 participates to skin homeostasis and its decreased expression in SSc may contribute to skin fibrosis by favoring ECM deposition over degradation.References[1]Russo B, Brembilla NC, Chizzolini C. Interplay between Keratinocytes and Fibroblasts: A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders. Frontiers in immunology. 2020; 11:648.[2]Russo B, Borowczyk J, Boehncke WH, Truchetet ME, Modarressi A, Brembilla NC, et al. Dysfunctional keratinocytes increase dermal inflammation in systemic sclerosis. Results from tissue-engineered scleroderma epidermis. Arthritis & rheumatology. 2021.[3]Borowczyk J, Shutova M, Brembilla NC, Boehncke WH. IL-25 (IL-17E) in epithelial immunology and pathophysiology. J Allergy Clin Immunol. 2021.AcknowledgementsWe thank Natacha Civic and Mylène Docquier (Genomics Platform) for performing the RNA sequencing; Nicolas Laudet (Bioimaging Core Facility) for quantification of immune-histology, François Prodon and Olivier Brun for microscope imaging (Bioimaging Core Facility), Marie Ebrahim Malek and Laura de Luca (Histology Core Facility) for contribution to tissue preparation (all at University Medical Center, Geneva, Switzerland).Disclosure of InterestsBarbara Russo: None declared, Julia Borowczyk: None declared, Pietro Cacialli: None declared, Philippe Moguelet: None declared, Marie-Elise Truchetet Speakers bureau: Abbvie, Lilly, SOBI and Boehringer Ingelheim, Ali Modaressi: None declared, Nicolò Brembilla: None declared, Julian Bertrand: None declared, Wolf-Henning Boehncke Speakers bureau: Abbvie, Almirall, BMS, Celgene, Leo, Lilly, Novartis, and UCB, Carlo Chizzolini Speakers bureau: GSK, Roche, Boehringer Ingelheim

The persistence of motivational alterations, including apathy, in older HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for apathy, however, has yet to be systematically evaluated. Thus, beginning at approximately seven to nine months of age, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed behavior. First, at the genotypic level, apathetic behavior in older HIV-1 Tg rats treated with vehicle was characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose and enhanced drug seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated alterations in goal-directed behaviors and reduced drug seeking behavior in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited prominent decreases in dendritic branching and a shift towards longer dendritic spines with decreased head diameter; synaptic dysfunction that was partially restored by SE treatment. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.

An environmental barrier-coated Sylramic-iBN/pyrolytic carbon/chemical vapor infiltration silicon carbide ceramic matrix composite was characterized in a harsh combustion environment under two conditions; (i) with a coating surface temperature of 1480℃, and (ii) with a combustion flame distance of 120 mm (constant flux). Three coating systems were evaluated; Coating “A” (ytterbium silicate using hafnium–silicate bond), Coating “B” (ytterbium silicate using alumina bond), and Coating “C” (ytterbium–silica compounds using alumina bond). All three coatings survived with essentially no mass loss up to 25 h when tested at 1480℃. At a flame distance of 120 mm coatings “A” and “B” experienced extensive degradation and strength loss while coating “C” had practically no degradation in retained strength. Coating “C” outperformed the other two coatings exposed to the harsh combustion environment. It performed best in terms of material loss, thermal barrier capability, and residual tensile strength.

Background Blood pressure (BP) readings taken in clinics are often higher than BP readings taken in a research setting. Recent guidelines and clinical trials have highlighted the necessity of using automated office blood pressure (AOBP) devices and standardizing measurement procedures. The goal of the present study was to compare AOBP vs manual BP measurement in both research and clinical environments in which operators and devices were the same and measurement procedures were standardized and optimal. Methods Clinical manual BP and AOBP measurement estimates were gathered from a retrospective cohort of patients followed in a hypertension clinic. Research AOBP and manual BP measurement data were obtained from past research studies. Descriptive statistics and agreement analyses with Cohen kappa coefficients were developed. The AOBP/manual BP measurement gap between clinical and research follow-up was compared using an unpaired t test. Results Two hundred eighty-eight patients were included in the clinical cohort, and 195 patients contributed to research-grade BP data. All patients had hypertension. AOBP averages were lower than manual measurement averages in both clinical (−3.6 ± 14.9 mm Hg / −3.0 ± 8.8 mm Hg) and research (−2.7 ± 10.0 / −2.4 ± 6.3 mm Hg) environments. The gap between measurement methods did not differ between research and clinical data. Cohen kappa coefficient was lower in the clinical context because of greater variability and more time between BP measurements (5.5 ± 2.9 months). Conclusions Manual BP readings were slightly higher than AOBP estimates. The difference was not influenced by the real-world context of clinical practice. Office nonautomated BP measurements may still be valuable if measurement procedures are well standardized and performed by trained nurses.

We report on the design and testing of a new minimally invasive device for crossing chronic total occlusions in the coronary and peripheral vasculature. The device is based on a novel shock wave generator that exploits inverse dispersion in solid waveguides to amplify the signal of broadband piezoelectric ultrasound transducers. Results of tests assessing the safety, efficacy, and mechanism of action of the device on a variety of surrogates, ex vivo arteries, and live animals are presented.

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Morbidity and mortality in post-CA patients are due largely to the cerebral dysfunction that accompanies prolonged whole-body ischemia called as post-CA syndrome (PCAS). PCAS involves strong inflammatory responses including neuroinflammation. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches which can target neuroinflammation and lead to good neurological outcome post-CA. Moreover, delivering drugs across the blood-brain barrier to the target injured cells for treating diffuse brain injury is a major challenge. We hypothesize that dendrimer-based N-acetyl-L-cysteine (D-NAC) therapy ameliorates Neuroinflammation by specifically targeting activated glial cells and leads to a marked improvement in post-CA neurological outcome. we used an asphyxial CA rat model to determine the effects of D-NAC treatment. D-NAC was administered 30-minute post return of spontaneous circulation after cardiopulmonary resuscitation (ROSC). The behavioral neurologic deficit score (NDS score) was evaluated at 4, 24 and 48 hrs post-CA. CA resulted in a 50% decrease in survival and a dramatic decrease in NDS score acutely. D-NAC improved survival to 75% and led to a more rapid improvement in NDS scores when compared to the saline group in the short term while free NAC was not effective. We also tested long term (7 days) behavioral outcomes (novel object and fear conditioning) post-CA. Administration of D-NAC significantly improved novel object recognition and decreases freezing behavior in a novel context suggesting an improvement in cognitive deficits following CA in this model. In summary, acute administration of D-NAC following CA results in physiological and behavioral improvements both acutely and long term.

Resume Introduction L’incidence de la lithiase urinaire est en augmentation dans les pays industrialises. Cette modification peut s’expliquer entre autres par des modifications alimentaires. De plus en plus de jeunes patients presentent des lithiases urinaires. L’objectif de cette etude etait d’analyser et de mettre a jour l’epidemiologie des calculs dans le Sud de la France selon l’âge et le sexe. Materiel et methodes Une etude monocentrique retrospective de 2009 a juin 2015 a inclus tous les calculs urinaires analyses par spectrophotometrie infrarouge. Des groupes ont ete composes selon la teneur en mineraux (oxalocalciques avec sous-type whewellite, weddellite, calculs phosphocalciques, acide urique…). Resultats Un total de 749 calculs ont ete analyses. Le sex-ratio etait de 1,96 tout âge confondu. Les calculs les plus frequents etaient oxalocalciques (51,3 %), puis mixtes (21,2 %) et phosphocalciques (11,9 %). Les calculs oxalocalciques sont majoritairement composes de whewellite (42 %) et les calculs phosphocalciques de carbapatite (18,6 %). Les calculs de whewellite etaient plus frequents chez les hommes ( p = 0,0009), de meme que les calculs d’acide urique ( p = 0,01) et les calculs mixtes chez les femmes ( p = 0,00003), de meme que les phosphocalciques ( p = 0,0005). Conclusions L’epidemiologie de la lithiase urinaire a change avec une augmentation de l’incidence chez les femmes, avec des patients plus âges. Un changement dans le type de calcul a ete observe avec une augmentation de la proportion des calculs mixtes, surtout chez les femmes. Des etudes nutritionnelles et metaboliques sont necessaires pour determiner les etiologies de ce changement de composition. Niveau de preuve 4.

Motivational alterations, such as apathy, in HIV-1+ individuals are associated with decreased performance on tasks involving frontal-subcortical circuitry. We used the HIV-1 transgenic (Tg) rat to assess effect of long-term HIV-1 protein exposure on motivated behavior using sucrose (1–30%, w/v) and cocaine (0.01–1.0 mg/kg/infusion) maintained responding with fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. For sucrose-reinforced responding, HIV-1 Tg rats displayed no change in EC50 relative to controls, suggesting no change in sucrose reinforcement but had a downward shifted concentration-response curves, suggesting a decrease in response vigor. Cocaine-maintained responding was attenuated in HIV-1 Tg rats (FR1 0.33 mg/kg/infusion and PR 1.0 mg/kg/infusion). Dose-response tests (PR) revealed that HIV-1 Tg animals responded significantly less than F344 control rats and failed to earn significantly more infusions of cocaine as the unit dose increased. When choosing between cocaine and sucrose, control rats initially chose sucrose but with time shifted to a cocaine preference. In contrast, HIV-1 disrupted choice behaviors. DAT function was altered in the striatum of HIV-1 Tg rats; however, prior cocaine self-administration produced a unique effect on dopamine homeostasis in the HIV-1 Tg striatum. These findings of altered goal directed behaviors may determine neurobiological mechanisms of apathy in HIV-1+ patients.

Context Paper home blood pressure (HBP) charts are commonly brought to physicians at office visits. The precision and accuracy of mental calculations of blood pressure (BP) means are not known. Methods A total of 109 hypertensive patients were instructed to measure and record their HBP for 1 week and to bring their paper charts to their office visit. Study section 1: HBP means were calculated electronically and compared to corresponding in-office BP estimates made by physicians. Study section 2: 100 randomly ordered HBP charts were re-examined repetitively by 11 evaluators. Each evaluator estimated BP means four times in 5, 15, 30, and 60 s (random order) allocated for the task. BP means and diagnostic performance (determination of therapeutic systolic and diastolic BP goals attained or not) were compared between physician estimates and electronically calculated results. Results Overall, electronically and mentally calculated BP means were not different. Individual analysis showed that 83% of in-office physician estimates were within a 5-mmHg systolic BP range. There was diagnostic disagreement in 15% of cases. Performance improved consistently when the time allocated for BP estimation was increased from 5 to 15 s and from 15 to 30 s, but not when it exceeded 30 s. Conclusion Mentally calculating HBP means from paper charts can cause a number of diagnostic errors. Chart evaluation exceeding 30 s does not significantly improve accuracy. BP-measuring devices with modern analytical capacities could be useful to physicians.

Fatigue behavior of Sylramic-iBN/BN/CVI SiC CMC was investigated under tension–tension fatigue using a test facility which simulated simultaneously both loading and combustion conditions of hot-section components of gas turbine engines. Combustion environment was created using a high-velocity oxygen fuel gun to impinge combustion flame on one side of specimen subjected to fatigue to simulate the real situation. The flame-impinged surface of specimen was heated to average temperature of 1250, 1350, or 1480 °C. Ultimate tensile strength of CMC was about 270 MPa at 1480 °C under combustion environment. Fatigue life diagram was established at stress ratio of 0.1 and frequency of 1 Hz. The CMC survived up to 25 h at 46 and 33 % of ultimate tensile strength under combustion at 1250 and 1350 °C, respectively. However, it could not survive 25 h at 1480 °C under combustion fatigue environment even with no stress on the specimen due to degradation/erosion of the material. Microscopic analysis of fracture surface showed oxidation of BN interface, which was more on flame side than other side. Fracture surfaces showed oxide formation over matrix, fibers, and/or fiber/matrix interphase causing embrittlement and thereafter failure of CMC.

Automated office blood pressure (AOBP) measuring devices are increasingly recommended as preferred blood pressure (BP) diagnostic tools, but it is unclear how they compare and how clinical environments impact their performance.This prospective randomized factorial parallel 4-group study compared BP estimates by BpTRU (VSM MedTech, Vancouver, BC, Canada) and Omron HEM 907 (Omron Healthcare, Kyoto, Japan) devices in closed vs open areas. Patients diagnosed with hypertension were recruited during office visits. After baseline open-room AOBP measurement with the BpTRU, patients had a second BP measurement with either the BpTRU or HEM 907 in either open or closed areas. Absolute BP levels and differences between the first and second measurements were compared. Diagnostic performance was also assessed.Two hundred fifty-eight patients were studied. Their mean age was 66.2 ± 12.0 years, and 62% were men. The mean of first AOBP estimates was 127.4/73.3 mm Hg. Analyses of subsequent measurements revealed no influence of open or closed areas on BP means and diagnostic performance. Conversely, the Omron HEM 907 exceeded BpTRU systolic BP measurements by 4.6 mm Hg (0.01) in closed areas and by 3.9 mm Hg (0.01) in open areas. The discrepancy between devices was amplified at lower BP levels.Although different areas did not influence BP estimates, the Omron HEM 907 significantly exceeded BpTRU measurements on average and especially at lower BP levels. These differences should be considered when interchanging devices and could have clinical decision impacts in a population of patients treated for hypertension. Our results support the constant use of only 1 device type in a given clinic.

Purposes: This work consists of studying the interseed and tissue composition effects for two model iodine seeds: the IBt Interseed‐125 and the 6711 model seed. Materials & Methods: Three seeds were modeled with the MCNP MC code in a water sphere to evaluate the interseed effect. The dose calculated at different distances from the centre was compared to the dose summed when the seeds were simulated separately. The tissue composition effect was studied calculating the radial dose function for different tissues. Before carrying out post‐implant studies, the absolute dose calculated by MC was compared to experiment results: with LiF TLDs in an acrylic breast phantom and with an EBT Gafchromic film placed in a water tank. Afterwards, the TG‐43 approximation effects were studied for a prostate and breast post‐implant. Results and Discussion: The interseed effect study shows that this effect is more important for model 6711 (15%) than for IBt (10%) due to the silver rod in 6711. For both seed models the variations of the radial dose function as a function of the tissue composition are quasi similar. The absolute dose comparisons between MC calculations and experiments give good agreement (inferior to 3% in general). For the prostate and breast post‐implant studies, a 10% difference between MC calculations and the TG‐43 is found for both models of seeds. Conclusion: This study shows that the differences in dose distributions between TG43 and MC are quite similar for the two models of seeds and are about 10% for the studied post‐implant treatments.

Background and Purpose The most common mutation in cystic fibrosis (CF), F508del, causes defects in trafficking, channel gating and endocytosis of the CF transmembrane conductance regulator (CFTR) protein. Because CF is an orphan disease, therapeutic strategies aimed at improving mutant CFTR functions are needed to target the root cause of CF. Experimental Approach Human CF airway epithelial cells were treated with roscovitine 100 μM for 2 h before CFTR maturation, expression and activity were examined. The mechanism of action of roscovitine was explored by recording the effect of depleting endoplasmic reticulum (ER) Ca2+ on the F508del-CFTR/calnexin interaction and by measuring proteasome activity. Key Results Of the cyclin-dependent kinase (CDK) inhibitors investigated, roscovitine was found to restore the cell surface expression and defective channel function of F508del-CFTR in human CF airway epithelial cells. Neither olomoucine nor (S)-CR8, two very efficient CDK inhibitors, corrected F508del-CFTR trafficking demonstrating that the correcting effect of roscovitine was independent of CDK inhibition. Competition studies with inhibitors of the ER quality control (ERQC) indicated that roscovitine acts on the calnexin pathway and on the degradation machinery. Roscovitine was shown (i) to partially inhibit the interaction between F508del-CFTR and calnexin by depleting ER Ca2+ and (ii) to directly inhibit the proteasome activity in a Ca2+-independent manner. Conclusions and Implications Roscovitine is able to correct the defective function of F508del-CFTR by preventing the ability of the ERQC to interact with and degrade F508del-CFTR via two synergistic but CDK-independent mechanisms. Roscovitine has potential as a pharmacological therapy for CF.

Plaque rupture in atherosclerosis is the primary cause of potentially deadly coronary events, yet about 40% of ruptures occur away from the plaque cap shoulders and cannot be fully explained with the current biomechanical theories. Here, cap buckling is considered as a potential destabilizing factor which increases the propensity of the atherosclerotic plaque to rupture and which may also explain plaque failure away from the cap shoulders. To investigate this phenomenon, quasistatic 2D finite element simulations are performed, considering the salient geometrical and nonlinear material properties of diverse atherosclerotic plaques over the range of physiological loads. The numerical results indicate that buckling may displace the location of the peak von Mises stresses in the deflected caps. Plaque buckling, together with its deleterious effects is further observed experimentally in plaque caps using a physical model of deformable mock coronary arteries with fibroatheroma. Moreover, an analytical approach combining quasistatic equilibrium equations with the Navier-Bresse formulas is used to demonstrate the buckling potential of a simplified arched slender cap under intraluminal pressure and supported by foundations. This analysis shows that plaque caps - calcified, fibrotic or cellular - may buckle in specific undulated shapes once submitted to critical loads. Finally, a preliminary analysis of intravascular ultrasonography recordings of patients with atherosclerotic coronary arteries corroborates the numerical, experimental and theoretical findings and shows that various plaque caps buckle in vivo. By displacing the sites of high stresses in the plaque cap, buckling may explain the atherosclerotic plaque cap rupture at various locations, including cap shoulders.

Resume Introduction Le cancer du rein est un cancer frequent en augmentation. Les metastases pancreatiques des cancers du rein sont rares. L’objectif de cette etude etait d’evaluer la survie globale chez des patients operes de metastases pancreatiques de cancer du rein au sein de l’institut du cancer de Montpellier (ICM). Patients et methodes De 2000 a 2012 au sein de l’ICM, nous avons etudie retrospectivement les patients ayant eu une chirurgie curative de metastases pancreatiques et leur suivi avec la mise ou non sous therapie ciblee. Resultats Trente-huit patients ont ete pris en charge dans notre centre pour des metastases pancreatiques de cancer du rein. Douze patients ont subi une resection pancreatique pour des metastases metachrones. Quatre patients (33,3 %) etaient en vie apres avoir ete operes de leurs metastases pancreatiques, tous sans traitement medicamenteux adjuvant et en remission. Sur ces 12 patients, 6 ont eu des therapies ciblees (50 %) du fait d’une progression metastatique, 5 sont decedes et le 6 e etait en progression sous therapie ciblee par TKI. Le delai moyen entre l’apparition des metastases et le deces etait de 89,9 mois, quand une chirurgie curative pancreatique etait realisee. Si les patients n’etaient pas operes, le delai moyen entre apparition des metastases et le deces etait de 33,1 mois ( p = 0,004). Conclusion Le traitement chirurgical des metastases pancreatiques quand il est possible permettrait d’augmenter l’esperance de vie des patients, voire d’amener des patients en remission. D’autres etudes sont necessaires pour evaluer l’impact des therapies ciblees dans cette indication. Niveau de preuve 5.

To compare postoperative complications in patients with or without preoperative immunonutrition before cystectomy.A prospective, multicenter, pilot, case-control study was conducted during 6 months. Patients with 7-day preoperative immunonutrition were prospectively included and compared with a retrospective, matched control group without immunonutrition. Early complication rates and the length of hospital stay were analyzed. The bilateral type I error was0.05; the power was 90%. Thirty patients in each group were required.Thirty patients were included in each group, on a comparable basis. In the immunonutrition group, fewer postoperative complications (40 vs. 76.7%; p = 0.008), less paralytic ileus at D7 (6.6 vs. 33.3%; p = 0.02), fewer infections (23.3 vs. 60%; p = 0.008), and in particular less pyelonephritis (16.7 vs. 46.7%; p = 0.03) occurred. Clavien's grades for complications were higher in the control group (p = 0.04). Mortality, pulmonary embolism, anastomotic fistulae, and wound dehiscence were similar between two groups. The length of stay was reduced by 3 days in the immunonutrition group.In this pilot case-control study, immunonutrition is associated with a decrease in postoperative complications, urinary tract infections, Clavien's grade for complications, and paralytic ileus in patients undergoing cystectomy for bladder cancer. Prospective randomized placebo control studies are needed to confirm these promising results.

HIV-1 enters the central nervous system early in infection; although HIV-1 does not directly infect neurons, HIV-1 may cause a variety of neurological disorders. Neuronal loss has been found in HIV-1, but synaptodendritic injury is more closely associated with the neurocognitive disorders of HIV-1. The HIV-1 transactivator of transcription (Tat) protein causes direct and indirect damage to neurons. The cysteine rich domain (residues 22–37) of Tat is important for producing neuronal death; however, little is known about the effects of the Tat protein functional domains on the dendritic network. The ability of HIV-1 Tat 1–101 Clades B and C, Tat 1–86 and Tat 1–72 proteins, as well as novel peptides (truncated 47–57, 1–72δ31–61, and 1–86 with a mutation at Cys22) to produce early synaptodendritic injury (24 h), relative to later cell death (48 h), was examined using cell culture. Treatment of primary hippocampal neurons with Tat proteins 1–72, 1–86 and 1–101B produced a significant early reduction in F-actin labeled puncta, implicating that these peptides play a role in synaptodendritic injury. Variants with a mutation, deletion, or lack of a cysteine rich region (1–86[Cys22], 1–101C, 1–72δ31–61, or 47–57) did not cause a significant reduction in F-actin rich puncta. Tat 1–72, 1–86, and 1–101B proteins did not significantly differ from one another, indicating that the second exon (73–86 or 73–101) does not play a significant role in the reduction of F-actin puncta. Conversely, peptides with a mutation, deletion, or lack of the cysteine rich domain (22–37) failed to produce a loss of F-actin puncta, indicating that the cysteine rich domain plays a key role in synaptodendritic injury. Collectively, these results suggest that for Tat proteins, 1) synaptodendritic injury occurs early, relative to cell death, and 2) the cysteine rich domain of the first exon is key for synaptic loss. Preventing such early synaptic loss may attenuate HIV-1 associated neurocognitive disorders.

International audience; Cystic fibrosis is caused by a mutation in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. N-butyl 1-deoxynojirimycin (N-Bu DNJ), a clinical candidate for the treatment of cystic fibrosis, is able to act as a CFTR corrector by overcoming the processing defect of the mutant protein. To explore the potential of multivalency on CFTR correction activity, a library of twelve DNJ click clusters with valencies ranging from 3 to 14 were synthesized. Significantly, the trivalent analogues were found to be up to 225-fold more potent than N-Bu DNJ and up to 1000-fold more potent than the corresponding monovalent models. These results provide the first description of a multivalent effect for correcting protein folding defects in cells and should have application for the treatment of a number of protein folding disorders. Preliminary mechanistic studies indicated that CFTR correction activity enhancement was not due to a multivalent effect in ER-glucosidase inhibition or to a different mode of action of the multivalent iminosugars.

Introduction L’obesite est un probleme epidemiologique majeur de nos societes actuelles. La Sleeve gastrectomie est une des techniques chirurgicales restrictives de l’obesite morbide, avec un risque de fistule de 2,4 % dans la litterature. Aucun parametre clinique ou biologique ne permet a l’heure actuelle de predire la survenue d’une fistule. La procalcitonine est un marqueur preditif de la survenue d’infection post operatoire.

Resume Objectifs Evaluer la faisabilite et les resultats de la realisation en consultation d’une videocystoscopie souple en lumiere bleue precedee d’une instillation d’Hexvix® (GE Healthcare) pour le diagnostic initial ou la surveillance des tumeurs vesicales (TV). L’objectif de cette etude etait de comparer le nombre de lesions vues en lumiere blanche et en lumiere bleue, et d’evaluer dans quel pourcentage de cas l’utilisation de l’Hexvix® en consultation modifiait la prise en charge. Patients et methodes Trente patients (26 hommes et quatre femmes) consecutifs ont ete evalues prospectivement par videofibroscopie vesicale en lumiere bleue (videocystoscope Wolf PDD®) realisee une heure apres une instillation endovesicale Hexvix®. Tous les examens ont ete realises en consultation externe sous anesthesie locale par gel de xylocaine : 23 (76,6 %) patients dans le cadre d’une surveillance de TV et sept (23,4 %) pour le diagnostic d’une hematurie a echographie normale. Lorsqu’une lesion suspecte ou une TV etait decouverte, les patients ont beneficie d’une resection endoscopique sous anesthesie avec nouvelle cystoscopie en lumiere bleue. Resultats Des lesions suspectes ont ete mises en evidence chez dix patients sur 30, cinq en lumiere blanche et bleue, cinq en lumiere bleue uniquement. Parmi les cinq lesions uniquement visibles en lumiere bleue, trois etaient des tumeurs urotheliales (toutes pTa de bas grade, moins de 5 mm) et deux des lesions non specifiques. Aucune lesion de CIS n’a ete mise en evidence lors de cette etude. La fibroscopie en lumiere bleue a permis de diagnostiquer des lesions invisibles en lumiere blanche chez trois patients (10 %) et a modifie la prise en charge de cinq patients (16,7 %). La duree de la cystoscopie etait en moyenne de 9,5 minutes. La tolerance de l’examen a ete bonne et aucune complication n’est survenue. Conclusion L’utilisation de la videocystoscopie souple en lumiere bleue +Hexvix® a permis d’ameliorer le taux de detection des TV. En dehors des lesions de CIS, cette amelioration a ete liee au diagnostic de TV de petite taille peu agressives. Les indications doivent etre precisees par des etudes de plus grande envergure et une evaluation medico-economique.

Journal de Gynecologie Obstetrique et Biologie de la Reproduction - Vol. 40 - N° 6 - p. 549-556

In order to generate new data for vitamin D content for the Canadian Nutrient File, a method for the quantification of vitamin D3 and 25(OH)D3 in foodstuffs has been modified and improved. Vitamin D3 was quantified using reverse phase liquid chromatography (LC) with UV-diode array detector (UV-DAD), while 25(OH)D3 was measured by triple quadrupole mass spectrometry (APCI MS/MS). Quantification was by internal standards (IS) using vitamin D2 and 25(OH)D2. A Certified Reference Material (CRM-421 containing vitamin D3) and a control sample (internally generated reference material of ground pork containing both vitamin D3 and 25(OH)D3) were used as validation and quality control tools. Limit of detection for both compounds was 0.04 μg/100 g. Accuracy for vitamin D in the CRM-421 was 99% (0.142 mg/kg for a target of 0.143, n = 10). Recovery of vitamin D3 in ground pork was 97% (88% absolute recovery). For 25(OH)D3, a recovery of 94% (73% absolute recovery) was obtained. Using this method, data for vitamin D3 and 25(OH)D3 content in a variety of foods (pork, beef, eggs, poultry, fish, and dinners) have been generated.

The goals of this study were to (1) estimate the prevalence of HIV infection among women accessing services at a women's health center in rural Haiti and (2) to identify economic risk factors for HIV infection in this population.Women who accessed healthcare services at this center between June 1999 and December 2002 were recruited to participate. The analysis was based on data from a case-control study of sexually transmitted diseases (STDs) in rural Haiti. HIV prevalence in the study population was 4%.In multivariate analyses, partner occupation was associated with HIV infection in women, with mechanic (OR 9.0, 95% CI 1.8-45) and market vendor (OR 4.2, 95% CI 1.6-11) reflecting the strongest partner occupational risk factors. Partner's occupation as a farmer reduced the risk of infection in women by 60% (95% CI 0.14-1.1). Factors indicating low socioeconomic status (SES), such as food insecurity (OR 2.0, 95% CI 0.75-5.6) and using charcoal for cooking (OR 1.7, 95% CI 0.72-3.8) suggested an association with HIV infection.Given pervasive gender inequality in Haiti, women's economic security often relies on their partners' income earning activities. Our findings show that although factors reflecting poverty are associated with HIV-positive status, stronger associations are observed for women whose partners indicated a more secure occupation (e.g., mechanic or market vendor). Policies and programs that expand access to education and economic opportunities for women and girls may have long-term implications for HIV prevention in Haiti and other resource-poor settings.

La chirurgia dell’otosclerosi, nata negli anni Sessanta, e una chirurgia funzionale, che da dei buoni risultati. Un miglioramento dell’udito e ottenuto in piu del 95% dei pazienti. L’indicazione chirurgica deve essere posta con attenzione e si basa sull’analisi di fattori uditivi, ma anche generali. La presenza di una sordita, di natura trasmissiva e fonte di limitazione sociale, e una condizione indispensabile. La realizzazione di un esame TC, al fine di evidenziare il focolaio otosclerotico, e raccomandata dalla Societe francaise d’oto-rhino-laryngologie et de chirurgie de la face et du cou. Possono essere realizzate diverse tecniche: platinectomia parziale o totale e platinotomia, con o senza laser. Non vi sono attualmente meta-analisi che sintetizzino i risultati della chirurgia dell’otosclerosi. Nessuno studio di questo tipo permette attualmente di affermare che una tecnica operatoria sia inferiore o superiore a un’altra. Lo studio delle grandi casistiche storiche e piu recenti della letteratura mostra una stabilita dei risultati da molti anni. Il rischio di complicanze postoperatorie e da prendere in considerazione e deve essere spiegato al paziente, in particolare quello di cofosi postoperatoria, che e stimato tra lo 0,5% e l’1% degli interventi. Le altre complicanze sono dominate da una disgeusia spesso reversibile, da vertigini e da una perforazione della membrana timpanica. Queste complicanze possono essere fonte di conflitto con i pazienti quando non sono state spiegate prima dell’intervento e quando le alternative terapeutiche non sono state illustrate e commentate. Questa comprensione e l’accettazione da parte del paziente dei rischi operatori sono punti importanti. L’informazione del paziente deve essere piu chiara e completa possibile, basandosi sui dati della letteratura medica. E indispensabile la raccolta di un consenso informato, di cui un esempio e stato pubblicato on line dal portale ORL France sotto l’egida del College francais d’otorhino- laryngologie (ORL) et de chirurgie cervico-faciale e della Societe francaise d’oto-rhino-laryngologie et de chirurgie de la face et du cou.

La cirugia de la otospongiosis, cuyo origen se remonta a la decada de 1960, es una cirugia funcional que proporciona buenos resultados. En mas del 95% de los pacientes se logra mejorar la audicion. La indicacion quirurgica debe plantearse con cuidado y se basa en el analisis de factores tanto auditivos como generales. La presencia de una hipoacusia de transmision y que cause problemas sociales es una condicion indispensable. La Societe Francaise d'Oto-rhino-laryngologie et de Chirurgie de la Face et du Cou recomienda la realizacion de una exploracion mediante tomografia computerizada (TC), para poner de manifiesto el foco de otospongiosis. Pueden utilizarse varias tecnicas: platinectomia parcial o total y platinotomia con o sin laser. Hasta el momento, ningun metaanalisis ha sintetizado los resultados de la cirugia de la otospongiosis. Ningun estudio de este tipo permite en la actualidad afirmar que una tecnica quirurgica sea inferior o superior a las demas. El estudio de las grandes series historicas y mas recientes de la literatura muestra una estabilidad de los resultados desde hace muchos anos. El riesgo de complicaciones postoperatorias debe tenerse en cuenta y hay que explicarlo al paciente, sobre todo el de cofosis postoperatoria, que se estima en un 0,5-1% de las intervenciones. Las otras complicaciones estan dominadas por la disgeusia (a menudo reversible), el vertigo y la perforacion de la membrana timpanica. Estas complicaciones pueden provocar conflictos con los pacientes cuando no se han explicado antes de la intervencion y si no se han presentado y comentado las alternativas terapeuticas. La comprension y aceptacion por parte del paciente de los riesgos quirurgicos son aspectos esenciales. La informacion ofrecida al paciente debe ser lo mas clara y completa posible, basandose en los datos de la literatura medica. Es indispensable cumplimentar un consentimiento informado, del que existen varios modelos que pueden consultarse en linea en las distintas paginas de Internet de las sociedades de otorrinolaringologia (ORL) de los diversos paises.

Defining the impact on health of exposure to a low-dose pesticide mixture via food intake is a topical question since epidemiological studies suggest that this may increase the risk of pathologies and particularly haematopoietic malignancies. Here we investigated on the haematopoietic system of mice, the effect of a mixture of six pesticides frequently ingested through the intake of fruits and vegetables produced in France (alachlor, captan, diazinon, endosulfan, maneb, mancozeb). The mixture was administered repeatedly by gavage to mice for 4 weeks at levels derived from the human Acceptable Daily Intake (ADI) level adapted to the mean weight of mice. Using a NMR-based metabonomic approach, we show that this treatment led to specific gender-linked variations in the level of hepatic metabolites involved in oxidative stress and in the regulation of glucose metabolism, indicating a metabolic signature for this repeated administration. Interestingly, exposure to the low-dose pesticide mixture induced significant changes in the blood cell counts with modifications in the clonogenic and differentiating capacities of haematopoietic progenitors showing abnormalities in the granulocytic and monocytic lineages in female and male mice, respectively. From a molecular point of view, the changes induced by the pesticide treatment correlated with modifications of the PI 3-kinase/Akt signalling pathway, the tyrosine kinase Pyk2 and the c-Myc transcription factor, which are involved in the balance between self-renewal and differentiation of haematopoietic stem cells. Our results point to a significant effect of a very low dose of a mixture of commonly used pesticides on mice metabolism and haematopoietic system with major differences between males and females.

A Monte Carlo (MC) study was carried out to evaluate the effects of the interseed attenuation and the tissue composition for two models of 125I low dose rate (LDR) brachytherapy seeds (Medi-Physics 6711, IBt InterSource) in a permanent breast implant. The effect of the tissue composition was investigated because the breast localization presents heterogeneities such as glandular and adipose tissue surrounded by air, lungs, and ribs. The absolute MC dose calculations were benchmarked by comparison to the absolute dose obtained from experimental results. Before modeling a clinical case of an implant in heterogeneous breast, the effects of the tissue composition and the interseed attenuation were studied in homogeneous phantoms. To investigate the tissue composition effect, the dose along the transverse axis of the two seed models were calculated and compared in different materials. For each seed model, three seeds sharing the same transverse axis were simulated to evaluate the interseed effect in water as a function of the distance from the seed. A clinical study of a permanent breast 125I implant for a single patient was carried out using four dose calculation techniques: (1) A TG-43 based calculation, (2) a full MC simulation with realistic tissues and seed models, (3) a MC simulation in water and modeled seeds, and (4) a MC simulation without modeling the seed geometry but with realistic tissues. In the latter, a phase space file corresponding to the particles emitted from the external surface of the seed is used at each seed location. The results were compared by calculating the relevant clinical metrics V85, V100, and V200 for this kind of treatment in the target. D90 and D50 were also determined to evaluate the differences in dose and compare the results to the studies published for permanent prostate seed implants in literature. The experimental results are in agreement with the MC absolute doses (within 5% for EBT Gafchromic film and within 7% for TLD-100). Important differences between the dose along the transverse axis of the seed in water and in adipose tissue are obtained (10% at 3.5 cm). The comparisons between the full MC and the TG-43 calculations show that there are no significant differences for V85 and V100. For V200, 8.4% difference is found coming mainly from the tissue composition effect. Larger differences (about 10.5% for the model 6711 seed and about 13% for the InterSource125) are determined for D90 and D50. These differences depend on the composition of the breast tissue modeled in the simulation. A variation in percentage by mass of the mammary gland and adipose tissue can cause important differences in the clinical dose metrics V200, D90, and D50. Even if the authors can conclude that clinically, the differences in V85, V100, and V200 are acceptable in comparison to the large variation in dose in the treated volume, this work demonstrates that the development of a MC treatment planning system for LDR brachytherapy will improve the dose determination in the treated region and consequently the dose-outcome relationship, especially for the skin toxicity.

Different processing approaches were adopted to obtain the best combination of strength and toughness. The approach that yielded superior properties was examined in detail to study the mechanical response of nanoscale calcium carbonate-reinforced high density polyethylene in conjunction with unreinforced high density polyethylene. The reinforcement of high density polyethylene with nanoscale calcium carbonate increases impact strength and is not accompanied by decrease in yield strength. The addition of nanoscale calcium carbonate to high density polyethylene alters the micromechanism of deformation from crazing-tearing in high density polyethylene to fibrillation in high density polyethylene-calcium carbonate nano-composite.

A new type of injector has been developed for gas chromatographic analysis. The injector has high volume and band compression (HVBC) capabilities useful for the analysis of complex samples. The injector consists essentially of a packed liner operated at room temperature while a narrow heated zone is used to axially scan the liner selectively desorbing the compounds of interest. The scanning speed, distance and temperature of the zone are precisely controlled. The liner is connected to an interface which can vent the solvent or any undesirable compounds, and transfer the analytes to an analytical column for separation and quantification. The injector is designed to be compatible with injection volumes from 1 to more than 250microL. At a low sample volume of 1microL, the injector has competitive performances compared to those of the "on-column" and "split/splitless" injectors for the fatty acid methyl esters and toxaphene compounds tested. For higher volumes, the system produces a linear response according to the injected volume. In this explorative study, the maximum volume injected seems to be limited by the saturation of the chromatographic system instead of being defined by the design of the injector. The HVBC injector can also be used to conduct "in situ" pretreatment of the sample before its transfer to the analytical column. For instance, a toxaphene sample was successively fractionated, using the HVBC injector, in six sub-fractions characterized by simpler chromatograms than the chromatogram of the original mixture. Finally, the ability of the HVBC injector to "freeze" the separation in time allowing the analyst to complete the analysis at a later time is also discussed.

Celiac disease (CD), which occurs in Europe with varying frequency, is known to be associated with HLA-B8 and even more strongly with HLA-Dw3 because of the high linkage disequilibrium between these two antigens. After typing for HLA-A, -B and -DR antigens in adult patients with CD, we can confirm the high prevalence of B8 (72.7%) and of DRw3 (63.7%). However we find that DRw7 is also significantly increased (54.5%); DRw3 and DRw7, taken together, represent 86% of our 22 patients.