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Resume Introduction L’atteinte respiratoire liee a la maladie associee aux IgG4, proteiforme et d’intensite variable, peut etre grave. Nous rapportons un cas de maladie associee aux IgG4 revelee par une pneumopathie infiltrante diffuse d’aggravation rapidement progressive. Observation Il s’agit d’un homme âge de 69 ans, ancien fumeur, hospitalise initialement pour enquete etiologique d’une pneumopathie interstitielle diffuse revelee par une toux, une dyspnee febrile et une alteration de l’etat general evoluant depuis 3 mois. L’aggravation rapide de l’hypoxemie imposait un transfert en soins intensifs respiratoires pour instauration d’une ventilation non invasive (VNI) et d’une oxygenotherapie a haut debit. Le scanner thoracique revelait des condensations lobaires inferieure droite et moyenne, des plages de verre depoli diffuses, un epaississement des septa inter-lobulaires ainsi que des adenomegalies mediastinales et une pleuresie bilaterale de faible abondance. Une maladie associee aux IgG4 etait suspectee devant une augmentation des IgG4 seriques. La confirmation diagnostique fut obtenue par une biopsie renale montrant une glomerulonephrite aigue avec une infiltration lympho-plasmocytaire, une fibrose d’aspect storiforme et plus de 60 plasmocytes IgG4+ par champ a fort grossissement. L’evolution etait rapidement favorable sous corticotherapie systemique. Conclusion Habituellement au second plan, l’atteinte respiratoire de la maladie associee aux IgG4 peut egalement se reveler par une insuffisance respiratoire severe avec ou sans atteinte extra-thoracique.

Resume Introduction Les anticorps anti programmed death-1 (PD-1) et programmed death-ligand 1 (PD-L1) sont des immunotherapies utilisees dans le traitement de nombreuses tumeurs solides. Des cas de pneumopathies interstitielles induites par les anti PD-1 ont largement ete decrits, mais les donnees sont moins nombreuses avec les anti PD-L1. L’avelumab est une nouvelle immunotherapie de la classe des anti PD-L1. Observation Il s’agit d’une femme de 66 ans, tabagique sevree, traitee par avelumab et axitinib depuis le 15 novembre 2016 pour un cancer renal a cellules claires. Elle presente une pneumopathie interstitielle decouverte fortuitement 4 mois apres le debut du traitement avec des lesions scannographiques de verre depoli, des reticulations intra-lobulaires et une adenopathie de la zone 4R. Le bilan exhaustif ne met pas en evidence de retentissement fonctionnel respiratoire, ni d’etiologie infectieuse ou immunologique. Les anomalies radiologiques regressent spontanement apres l’arret du traitement, permettant de retenir le diagnostic de pneumopathie medicamenteuse. Conclusion L’avelumab peut induire une pneumopathie interstitielle. Son mecanisme incertain necessite des etudes complementaires. Une surveillance des explorations fonctionnelles respiratoire et du scanner thoracique est necessaire pour une prise en charge precoce.

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension. Heritable and sporadic forms have been distinguished. Hypoxemia, profound reduction in the diffusion of carbon monoxide and haemodynamic confirmation of pre-capillary pulmonary hypertension are the major diagnostic criteria. Thoracic CT scanning and a response to pharmaceutical therapy provide additional information to confirm the diagnosis. A 52-year-old patient, three of whose siblings had pulmonary hypertension, was admitted with dyspnoea, malaise and palpitations. Right heart catheterisation confirmed pre-capillary pulmonary hypertension. A search for an EIF2AK4 mutation was carried out, and this showed a composite biallelic heterozygous mutation compatible with the diagnosis of familial PVOD, identical to that showed in one of his brothers. Given the signs of severity of the disease and the diagnosis of PVOD, whose response to pharmaceutical therapy is often poor, the patient was placed on a waiting list for lung transplantation. Despite a similar diagnosis in 3 brothers and follow-up proposed 11 years before the diagnosis, pulmonary hypertension appeared within a few weeks and led immediately to a severe clinical situation. Annual clinical and echocardiographic monitoring had been strongly advised to the patient, but had not allowed diagnosis at a mild or moderate stage of the disease. This clinical case shows that the identification of factors predicting the development of heritable PVOD at a pre-symptomatic stage is an important issue for clinical research.

Resume Introduction Les pneumopathies a eosinophiles sont caracterisees par une alveolite a polynucleaires eosinophiles. Elles peuvent etre idiopathiques ou relever de differentes causes. L’origine medicamenteuse doit etre toujours evoquee. Observation Nous rapportons le cas d’une femme de 57 ans, fumeuse, atteinte d’un trouble bipolaire, traitee par divalproate de sodium depuis plus de 2 ans, qui presentait une dyspnee non febrile depuis 5 mois. Les explorations realisees montraient une hypoxemie severe, un trouble ventilatoire obstructif severe, de multiples images en verre depoli avec un aspect de crazy paving au scanner thoracique, une hypereosinophilie sanguine et une alveolite a eosinophiles au lavage broncho-alveolaire. Le diagnostic de pneumopathie a eosinophiles au divalproate de sodium etait retenu apres un bilan etiologique exhaustif, et l’amelioration radio-clinique etait rapide apres l’arret du medicament, sans recours a la corticotherapie systemique. Conclusion Le divalproate de sodium peut induire une pneumopathie a eosinophiles plusieurs annees apres son introduction. Un diagnostic rapide et un arret du traitement ont permis une guerison complete dans le cas rapporte.

PURPOSE Prophylactic radiotherapy to prevent procedure-tracts metastases from malignant pleural mesothelioma remains controversial and clinical practice varies. The purpose was to assess the efficacy of local radiotherapy in a single fraction of 10Gy in preventing malignant seeding at intervention pleural site in patients with malignant pleural mesothelioma. MATERIAL AND METHODS This is a retrospective cohort study, including patients with histological confirmed malignant pleural mesothelioma treated by prophylactic irradiation to prevent interventional site metastases with a unique fraction of 10Gy with 6 to 18MeV, from January 1990 to December 2013 in the institut de cancerologie de Lorraine (Nancy, France). RESULTS Ninety-one patients were treated by irradiation in intervention site, involving 120 intervention pleural sites, 91 thoracoscopies, 17 thoracotomies with chest drain and 12 CT or ultrasound guided needle biopsies. The median follow-up was 7 months (interquartile between 3 and 15 months). The overall survival was 43.5% at 12 months. The local progression free survival was 43.7% at 12 month. The incidence of local recurrence was 8% at 12 months. The median interval from radiotherapy to local recurrence was 4 months (2; 32). No grade II or higher toxicity was observed. CONCLUSION Irradiation of pleural intervention sites with a single fraction of 10Gy is effective, well tolerated, simple, fast and cost effective.

The first reports of hepatic steatosis following pancreaticoduodenectomy (PD) were published several years ago; however, clear risk factors remain to be identified. Therefore, the aim of this study was to identify the risk factors for hepatic steatosis post-PD. We studied 90 patients who had undergone PD between September 2005 and January 2015. The inclusion criteria were as follows: available unenhanced CT within one month before PD and at least one unenhanced CT acquisition between PD and chemotherapy initiation. Using scanners, we studied the liver and spleen density as well as the surface areas of visceral (VF) and subcutaneous fat (SCF). These variables were previously identified by univariate and multivariate analyses. Hepatic steatosis occurred in 25.6% of patients at 45.2 days, on average, post-PD. Among the patients with hepatic steatosis, the average liver density was 52 HU before PD and 15.1 HU post-PD (p

Resume Introduction L’histoire naturelle des maladies pulmonaires orphelines est rarement connue. Nous presentons l’evolution a long terme d’une forme bronchectasiante de la maladie a depots de chaines legeres (MDCL) d’immunoglobulines non amyloides. Observation Il s’agit d’une femme fumeuse chez qui le diagnostic de dilatation des bronches d’etiologie indeterminee est porte a l’âge de 50 ans. Dix ans apres, l’hypothese d’une MDCL pulmonaire est evoquee devant l’aspect caracteristique des bronchectasies, l’apparition de kyste pulmonaires, l’augmentation du taux serique des chaines legeres Kappa. La confirmation diagnostique est obtenue par biopsie pulmonaire chirurgicale. Aucune hemopathie maligne n’est retrouvee. Durant les 12 ans de suivi, l’aggravation de la dyspnee d’effort est lente et concomitante a l’extension des bronchectasies et des kystes realisant un aspect de pneumopathie multikystique. Les EFR montrent une preservation des volumes pulmonaires et une diminution moderee de la capacite de diffusion du monoxyde de carbone (DLCO). Conclusion Nous decrivons l’evolution d’une presentation rare de la MDCL pulmonaire isolee sous la forme de bronchectasies kystiques diffuses, a parois fines, non secretantes, s’associant a une destruction kystique du parenchyme pulmonaire. L’hypothese d’une MDCL pulmonaire doit etre evoquee devant des bronchectasies atypiques d’etiologie indeterminee.

International audience; PURPOSE:To describe the multidetector row computed tomography (MDCT) imaging features of HCC that develops in patients who are free from underlying liver cirrhosis and to determine if the MDCT presentation of this specific tumor differs from that of the more common HCC that develops in patients with liver cirrhosis using a retrospective case-control study.PATIENTS AND METHODS:The MDCT examinations of 38 patients with HCC in non-cirrhotic liver (group 1) were quantitatively and qualitatively analyzed and compared to those obtained in 38 patients with HCC in cirrhotic liver (group 2) matched for age and gender. Quantitative and qualitative characteristics of HCC of both groups were compared using univariate analysis.RESULTS:HCCs were significantly larger in group 1 (81.5mm±55.5) than in group 2 (44.5mm±39.1 SD; P=0.0015). In group 1, HCCs were more frequently single tumors (87%) than in group 2 (37%) (P

Radioembolization (RE) is a selective internal radiotherapy technique in which yttrium-90 blended microspheres are infused through the hepatic arteries. It is based on the fact that primary and secondary hepatic tumors are vascularized mostly by arterial blood flow whereas healthy hepatocytes obtain their blood supply mostly from the portal network. This enables high radiation doses to be delivered, sparing the surrounding non-malignant liver parenchyma. Most of the complications are caused by unexpected particles passing into the gastrointestinal tract through branches originating from the main hepatic arterial supply. Knowledge of this hepatic arterial network and of its variations and the technical considerations this raises are required in preparation for treatment. This work describes the specific anatomical features and techniques for this anatomy through recent literature illustrated by cases from our own experience.

Nestorone® (NES) is a potent nonandrogenic progestin being developed for contraception. NES is a synthetic progestin that may possess neuroprotective and myelin regenerative potential as added health benefits. In receptor transactivation experiments, NES displayed greater potency than progesterone to transactivate the human progesterone receptor (PR). This was confirmed by docking experiments where NES adopts the same docking position within the PR ligand-binding domain (LBD) as progesterone and forms additional stabilizing contacts between 17α-acetoxy and 16-methylene groups and PR LBD, supporting its higher potency than progesterone. The analog 13-ethyl NES also establishes similar contacts as NES with Met909, leading to comparable potency as NES. In contrast, NES is not stabilized within the human androgen receptor LBD, leading to negligible androgen receptor transactivation. Because progesterone acts in the brain by both PR binding and indirectly via binding of the metabolite allopregnanolone to γ-aminobutyric acid type A receptor (GABAAR), we investigated if NES is metabolized to 3α, 5α-tetrahydronestorone (3α, 5α-THNES) in the brain and if this metabolite could interact with GABAAR. In female mice, low concentrations of reduced NES metabolites were identified by gas chromatography/mass spectrometry in both plasma and brain. Electrophysiological studies showed that 3α, 5α-THNES exhibited only limited activity to enhance GABAAR-evoked responses with WSS-1 cells and did not modulate synaptic GABAARs of mouse cortical neurons. Thus, the inability of reduced metabolite of NES (3α, 5α-THNES) to activate GABAAR suggests that the neuroprotective and myelin regenerative effects of NES are mediated via PR binding and not via its interaction with the GABAAR.

Many progestins have been developed for use in contraception, menopausal hormone therapy, and treatment of gynecological diseases. They are derived from either progesterone or testosterone, and they act by binding to the progesterone receptor (PR), a hormone-inducible transcription factor belonging to the nuclear receptor superfamily. Unlike mineralocorticoid, glucocorticoid, and androgen receptors, the steroid-receptor contacts that trigger the switch of the ligand-binding domain from an inactive to an active conformation have not yet been identified for the PR. With this aim, we solved the crystal structure of the ligand-binding domain of the human PR complexed with levonorgestrel, a potent testosterone-derived progestin characterized by a 13-ethyl substituent. Via mutagenesis analysis and functional studies, we identified Met909 of the helix 12 as the key residue for PR activation by both testosterone- and progesterone-derived progestins with a 13-methyl or a 13-ethyl substituent. We also showed that Asn719 contributes to PR activation by testosterone-derived progestins only, and that Met759 and Met909 are responsible for the high potency of 19-norprogestins and of 13-ethyl progestins, respectively. Our findings provide a structural guideline for the rational synthesis of potent PR agonist and antagonist ligands that could have therapeutic uses in women's health.

Polyethylene glycol (PEG), a high-molecular weight colloid, is added to preservation solutions in order to decrease cold- and ischemia-induced injuries of the grafted organ. We evaluated on LLC-PK1, a porcine proximal tubular epithelial cell line (1) the efficiency of several commercial preservation solutions (University of Wisconsin, Euro-Collins, Celsior, SCOT, IGL-1), and (2) whether adding PEG (400-35,000 Da) in a simple extracellular-type buffer modified cell integrity and mitogen-activated protein kinase (MAPK) signaling pathways. SCOT was the most efficient commercial solution. Moreover, only PEG 35,000 Da totally preserved cell viability, induced a decrease on reactive oxygen species production and a decrease on p38-MAPK activation. Furthermore PEG 35,000 Da stimulated c-Jun N-terminal kinase (JNK). However, the inhibition of JNK pathway, with the specific SP600125 inhibitor, in the presence of PEG 35,000 Da did not affect cell survival. We also confirmed on whole pig kidney the protective effect of PEG 35,000 Da on cold-induced tubular injuries. This study confirms PEG antioxidative properties, but we demonstrate that its effect on JNK signaling pathway had also a paradoxical effect on cell death. This sheds a new light on PEG effects during cell preservation, independently from the classical immuno-camouflaging hypothesis.

Local recurrences after breast-conserving surgery occur mostly in the quadrant harbouring primary carcinoma. The main objective of postoperative radiotherapy should be the sterilisation of residual cancer cells in the operative area while irradiation of the whole breast may be avoided. We have developed a new technique of intraoperative radiotherapy of a breast quadrant after the removal of the primary carcinoma (ELIOT). A mobile linear accelerator with a robotic arm is utilised delivering electron beams able to produce energies from 3 to 9 MeV. Different dose levels were tested from 10 to 21 Gy without important side effects. A randomized trial is currently ongoing in order to compare conventional irradiation and ELIOT. More than 400 patients have been enrolled. In addition a new approach for nipple and areola complex conservation, including ELIOT, is under investigation.

Objectif de l’etude Le recours a la radiotherapie prophylactique afin de prevenir les metastases des sites d’intervention pleurale dans le mesotheliome pleural malin demeure controverse et les pratiques cliniques variees. L’objectif etait d’evaluer l’efficacite de la radiotherapie externe en une seance unique de 10 Gy en prevention de l’ensemencement des sites d’intervention pleurale des patients atteints de mesotheliome pleural malin. Materiel et methode Il s’agit d’une etude epidemiologique descriptive retrospective de cohorte, incluant les patients atteints d’un mesotheliome pleural malin histologiquement prouve irradies en regard des sites d’intervention pleurale en une seance unique de 10 Gy par des electrons de 6 a 18 MeV, entre janvier 1990 et decembre 2013 a l’institut de cancerologie de Lorraine. Resultats Quatre-vingt-onze patients ont ete traites par irradiation prophylactique des sites d’intervention pleurale a l’institut de cancerologie de Lorraine, soit 120 sites d’intervention pleurale : 91 thoracoscopies, 17 thoracotomies avec drainage pleural, 12 ponctions–biopsies guidees par scanographie ou echographie. Le suivi median etait de 7 mois (intervalle interquartile entre 3 et 15 mois). La probabilite de survie globale etait de 43,5 % a 12 mois, celle de survie sans progression locale de 43,7 %. L’incidence de la progression locale etait de 8 % a 12 mois. Le temps median ecoule entre l’irradiation et la progression locale etait de 4 mois (extremes : 2–32 mois). Il n’y avait pas d’effet secondaire precoce ou tardif de grade superieur ou egal a deux. Conclusion L’irradiation des sites d’intervention pleurale en une seance unique de 10 Gy est efficace, bien toleree, simple, rapide et peu couteuse.

The human progesterone receptor (PR) plays a key role in reproductive function in women. PR antagonists have numerous applications in female health care including regular and emergency contraception, and treatment of hormone-related pathological conditions such as breast cancer, endometriosis, and leiomyoma. The main factor limiting their long-term administration is the fact that they cross-bind to other oxo-steroid receptors. Ulipristal acetate (UPA), a highly potent PR antagonist, has recently come onto the market and is much more selective for PR than the other oxo-steroid receptors (androgen, AR, glucocorticoid, GR, and mineralocorticoid, MR receptors) and, remarkably, it displays lower GR-inactivating potency than RU486. We adopted a structural approach to characterizing the binding of UPA to the oxo-steroid receptors at the molecular level. We solved the X-ray crystal structure of the ligand-binding domain (LBD) of the human PR complexed with UPA and a peptide from the transcriptional corepressor SMRT. We used the X-ray crystal structure of the GR in its antagonist conformation to dock UPA within its ligand-binding cavity. Finally, we generated three-dimensional models of the LBD of androgen and mineralocorticoid receptors (AR and MR) in an antagonist conformation and docked UPA within them. Comparing the structures revealed that the network of stabilizing contacts between the UPA C11 aryl group and the LBD is responsible for its high PR antagonist potency. It also showed that it is the inability of UPA to contact Gln642 in GR that explains why it has lower potency in inactivating GR than RU486. Finally, we found that the binding pockets of AR and MR are too small to accommodate UPA, and allowed us to propose that the extremely low sensitivity of MR to UPA is due to inappropriate interactions with the C11 substituent. All these findings open new avenues for designing new PR antagonist compounds displaying greater selectivity.

Streptococcus pneumoniae is the main causal agent of pathologies that are increasingly resistant to antibiotic treatment. Clinical resistance of S. pneumoniae to β-lactam antibiotics is linked to multiple mutations of high molecular mass penicillin-binding proteins (H-PBPs), essential enzymes involved in the final steps of bacterial cell wall synthesis. H-PBPs from resistant bacteria have a reduced affinity for β-lactam and a decreased hydrolytic activity on substrate analogues. In S. pneumoniae , the gene coding for one of these H-PBPs, PBP2x, is located in the cell division cluster (DCW). We present here structural evidence linking multiple β-lactam resistance to amino acid substitutions in PBP2x within a buried cavity near the catalytic site that contains a structural water molecule. Site-directed mutation of amino acids in contact with this water molecule in the “sensitive” form of PBP2x produces mutants similar, in terms of β-lactam affinity and substrate hydrolysis, to altered PBP2x produced in resistant clinical isolates. A reverse mutation in a PBP2x variant from a clinically important resistant clone increases the acylation efficiency for β-lactams and substrate analogues. Furthermore, amino acid residues in contact with the structural water molecule are conserved in the equivalent H-PBPs of pathogenic Gram-positive cocci. We suggest that, probably via a local structural modification, the partial or complete loss of this water molecule reduces the acylation efficiency of PBP2x substrates to a point at which cell wall synthesis still occurs, but the sensitivity to therapeutic concentrations of β-lactam antibiotics is lost.

The aim of our study was to determine the stability of ten antineoplastic drugs stored in their initial package, in conditions of temperature which may be encountered during transport to hospital pharmacy or storage. Stability was determined by high-performance liquid chromatography after storage at cold temperature (+ 4°C) and warm temperature ( + 33°C) for 6 or 12 months comparatively to room temperature ( + 21°/ + 23°C) as recommended by the manufacturers. No change in color was observed in any sample throughout the study except for a yellow hue in fluorouracil vials stored at + 33°C. With the exception of melphalan, all the drugs were stable when stored at both temperatures for 6 and 12 months. Melphalan concentration decreased to less than 90% of theoretical concentration from 6 months storage at + 4°C. In spite of the yellow hue which developed in the fluorouracil vials stored at + 33°C, this drug was found at greater than 90% of the theoretical concentration. Among the ten drugs assayed for stability at unusual temperatures, eight were found to be stable. Two displayed temperature sensitivity as shown by change of color or loss of drug. Temperature should be controlled during storage and transport of drugs, particularly for fluorouracil and melphalan.

SummaryWith certain concerns recently reported on metal-on-metal bearing couples in total hip arthroplasty, this study's objective is to review the current knowledge concerning release of metal ions and its potential consequences. Each metal-on-metal implant presents different tribological properties. The analytical techniques for metals are accurate and the Co ion rates seem acceptable up to 2μg/L. A delayed type IV hypersensitivity reaction (atypical lymphocytic vasculitis-associated lesion [ALVAL]) may be the source of arthroplasty failure. Idiosyncratic, it remains unpredictable even using cutaneous tests and apparently is rare (0.3%). Today, there are no scientific or epidemiologic data supporting a risk of carcinogenesis or teratogenesis related to the use of a metal-on-metal bearings couple. Solid pseudotumors nearly exclusively are observed with resurfacing procedures, carrying a high annual revision rate in women under 40 years of age, occurring particularly in cases of acetabular malposition and with use of cast molded Cr-Co alloys. Osteolysis manifests through complete and progressive radiolucent lines or through cavitary lesions stemming from ALVAL-type alterations or impingement problems or implant incompatibility. The formation of wear debris exceeding the biological tolerance is possible with implant malposition, subluxation, and jamming of the femoral head in cases of cup deformity. Moreover, each implant presents different metal ion production; assessment of their performance and safety is required before their clinical use. With the knowledge available today, metal-on-metal bearing couples are contraindicated in cases of metal allergies or end stage renal dysfunction and small size resurfacing should cautiously be used.

The diving response elicited by breath-holding (BH) and immersion mainly consists of bradycardia, decreased cardiac output, and peripheral vasoconstriction. These responses reduce oxygen consumption and thereby prolong the duration of the dive. They may also lead to cardiac arrhythmias or hypoxia, however, which in turn may play a role in the occurrence of syncope during BH. The aim of the present study was to analyze the cardiac responses to prolonged breath-holding in elite divers during a competition. Heart rate behaviour and the incidence of arrhythmia were recorded in 16 well-trained breath-hold divers (BHD) using a cardio-frequency meter (for 15 divers) and a Holter (for one diver) during maximal static breath-holding. Anthropometric, spirometric, and training characteristics such as percentage of body fat, pulmonary volumes and years of BH training were also determined. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV (1)) were higher than the predicted values (+7.7%, p

Temporally-asymmetric Hebbian learning is a class of algorithms motivated by data from recent neurophysiology experiments. While traditional Hebbian learning rules use mean bring rates to drive learning, this new form of learning involves precise bring times. Hence, such algorithms can capture temporal spike correlations. We present circuits and methods to implement temporally-asymmetric Hebbian learning in analog VLSI. We also describe a small feed-forward 2 layer network that learns spike trains correlations. A chip including a single neuron and a network of adaptive spiking neurons has been fabricated in a CMOS 0.6/spl mu/ process to validate the ideas presented.

alpha 1-Adrenergic receptors were identified, characterized, and localized in rat cervix on Day 6 of pregnancy by autoradiography. Autoradiographic study was performed in slide-mounted rat cervix sections using [3H]-prazosin ([3H]-PRAZ) as ligand. Binding was time dependent and specific. Pharmacological study indicated that specific [3H]-PRAZ binding was inhibited with high affinity by prazosin and phenylephrine and low affinity by yohimbine and clonidine. In cervix, the alpha 1-adrenergic receptors were localized mainly to the inner circular layer of the myometrium. Binding to the outer longitudinal layer of myometrium was moderate, and binding was absent in the endometrium. The regional distribution of alpha 1-adrenergic receptors strongly suggests that the circular layer of myometrium may function as an important modulator of contractile response of the cervix, probably involved in the retention of blastocysts at the utero-cervical end of the horn.