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Sarcoidosis is a systemic granulomatous disease characterized by pulmonary involvement in most patients and more rarely by extrapulmonary involvement such as ocular, skin, salivary, lymph nodes and joints damages. Neurological and cardiac involvements are uncommon but are associated with increased morbidity and mortality. Cardiac sarcoidosis affects 5 to 20% of patients depending on the studies and autopsy studies even report cardiac involvement in 25% of sarcoidosis patients. This review aims to summarise main data on the diagnostic value of the different imaging techniques in cardiac sarcoidosis and to also detail the management of these patients who require a multidisciplinary approach.

Defended species are often conspicuous and this is thought to be an honest signal of defences, i.e. more toxic prey are more conspicuous. Neotropical butterflies of the large Ithomiini tribe numerically dominate communities of chemically defended butterflies and may thus drive the evolution of mimetic warning patterns. Although many species are brightly coloured, most are transparent to some degree. The evolution of transparency from a warning-coloured ancestor is puzzling as it is generally assumed to be involved in concealment. Here, we show that transparent Ithomiini species are indeed less detectable by avian predators (i.e. concealment). Surprisingly, transparent species are not any less unpalatable, and may in fact be more unpalatable than opaque species, the latter spanning a larger range of unpalatability. We put forth various hypotheses to explain the evolution of weak aposematic signals in these butterflies and other cryptic defended prey. Our study is an important step in determining the selective pressures and constraints that regulate the interaction between conspicuousness and unpalatability.

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Ocular disease in Behçet's disease is frequent and may be associated with a poor functional prognosis. Uveitis is the most common ocular manifestation in Behçet's disease and represents a diagnostic criterion of the disease. The ocular involvement is inaugural of the disease in 20% of the cases or may develop 2 to 3 years after the beginning of the extraocular signs. The risk of blindness at 5 years is in the order of 15 to 25%, mainly due to macular involvement or retinal vasculitis. Uveitis may be anterior, intermediate, posterior or panuveitis. Anterior uveitis is rarely isolated and is frequently accompanied by posterior involvement. Anterior uveitis is always non granulomatous, sometimes associated with hypopion. Posterior involvement may include the presence of hyalitis, retinal vasculitis, mainly venous and often occlusive, macular edema, and/or foci of necrotizing retinitis. Behçet's disease is a chronic disorder, characterized by a relapsing and remitting course. Male patients with younger age at onset and severe lesions at presentation are at higher risk of severe visual loss over time. The main goals in the management of patients with Behçet's disease-associated uveitis are rapid suppression of intraocular inflammation, preservation of vision, and prevention of recurrences. The treatment is based on the use of systemic glucocorticosteroids and immunosuppressive agents. Posterior segment involvement requires the use of corticosteroids and immunosuppressants, primarily azathioprine. This treatment does not appear to be sufficient for severe uveitis with reduced visual acuity or retinal vasculitis that requires anti-TNF α or interferon α. Therapeutic strategies such as TNF-alpha blockers have dramatically improved the visual prognosis of patients with intraocular inflammation related to this chronic and potentially blinding condition.

Objectives Interferon-free direct-acting antiviral (DAA)-based therapy has proven to be very effective in patients with hepatitis C virus-cryoglobulinemia vasculitis (HCV-CV). However, their mechanisms of action and their effects on cellular immunity remain poorly defined. Methods 27 HCV-CV patients treated with DAA therapy, 12 healthy donors (HD) and 12 HCV were included. We investigated the effects of DAA-based therapy on cellular and cytokine abnormalities in HCV-CV patients by flow cytometry, cytokine Multiplex and enzyme-linked immunosorbent assay. Results Compared with HD and HCV, pre-DAA abnormalities in HCV-CV patients included a decreased percentage of CD4+CD25hiFoxP3+ regulatory T cells (P Conclusions Our results indicate that DAA-based therapy effectively normalizes many of the disturbances in peripheral B and T lymphocyte homeostasis of HCV-CV patients. Disclosure of Interest None declared

Zusammenfassung: Gegenstand und Ziel: Beschreibung von klinischem Erscheinungsbild, Diagnostik, Therapie sowie einer 27 Monate dauernden Verlaufsuntersuchung eines Plattenepithelkarzinoms des dritten Augenlids bei einem Pferd. Material und Methoden: Ein siebenjähriger Haflinger-Wallach wurde mit einer progressiv wachsenden Umfangsvermehrung im Bereich des rechten dritten Augenlids in der Klinik vorgestellt. Unter Allgemeinanästhesie erfolgte die chirurgische Exzision des rechten dritten Augenlids. Zwei Iridium- 192-Stäbe wurden subkutan im Bereich des rechten nasalen Augenwinkels in das Ober- und Unterlid eingebracht. Ergebnisse: Das Pferd zeigte keinerlei therapiebedingte Komplikationen. Innerhalb von 27 Monaten nach der Behandlung trat kein Rezidiv auf. Schlussfolgerungen: Das Plattenepithelkarzinom des dritten Augenlids kann bei rechtzeitiger Therapie erfolgreich mittels chirurgischer Exzision und interstitieller Brachytherapie behandelt werden. Klinische Relevanz: Die interstitielle Brachytherapie in Kombination mit einer chirurgischen Tumorexzision kann eine Therapieform des periokulären Plattenepithelkarzinoms mit Langzeiterfolg darstellen. Die Durchführung der interstitiellen Brachytherapie ist Spezialkliniken vorbehalten.

The arterial lesions affect about 10% of patients with Behçet's disease (BD). Aortic inflammatory involvement includes predominantly aortic aneurysmal lesions affecting most often the abdominal aorta. They account for the severity of the disease and are a leading cause of death when they hit the aorta or pulmonary arteries. Within the arterial lesions of BD, aortic involvement is, with femoral lesions, the most common site involved (18-28% of patients with vascular disease). Unlike other large vessels vasculitis (i.e. giant cell arteritis and Takayasu's arteritis) diffuse aortitis is observed in less than 5% of patients with BD. Aortic lesions of BD may be asymptomatic (systematic imaging or occasionally associated with other vascular event) or be revealed by the occurrence of abdominal, thoracic or lumbar pain, or an aortic valve insufficiency. Fever is frequently associated. Increase in acute phase reactants is common in these patients. Histological analysis may show infiltration by lymphocytes, neutrophils and plasma cells in the media and adventitia and a proliferation of the vasa vasorum in the media as well as a fibroblastic proliferation. In the later phase, a fibrous thickening of the media and adventitia is observed as well as a proliferation and thickening of the vasa vasorum. The therapeutic management should always include a medical treatment for the control of inflammation (corticosteroids, immunosuppressive drugs and/or biotherapy) and often an endovascular or surgical treatment if the aneurysm is threatening. The choice between endovascular or surgical treatment is considered case by case, depending on the experience of the team, anatomical conditions and of the clinical presentation. In this review, we provide a detailed and updated review of the literature to describe the aortic inflammatory damage associated with Behçet's disease.

Several studies argue for the presence of CCK2 receptors in the human pancreas but their physiological role in normal exocrine pancreas and their contribution to pancreatic pathologies is unknown. In order to allow an easy investigation of their pancreatic function, we created the ElasCCK2 transgenic mice expressing the human receptor in pancreatic exocrine cells. In this model, the CCK2 receptor is specifically expressed in the exocrine pancreas and has typical molecular and binding features. It is functional and mediates enzyme release but stimulating concentrations of agonists are not physiological. Results of phenotypic and long-term studies show that activation of CCK2 receptors stimulates growth of the pancreas in correlation with an increase of acinar tissue. This finding is also consistent with the demonstration of an efficient coupling of the transgenic receptor to protein synthesis. Alterations in pancreatic histology and development of preneoplastic lesions are apparent from postnatal day 50. Moreover, expression of this G-protein-coupled receptor leads to the development of tumours in older animals with an incidence of 15%. Although tumours have distinct phenotypes they all exhibit ductular strucures. Immunohistochemical analysis of these structures shows their acinar origin. These data, linking for the first time the development of pancreatic carcinogenesis in vivo to the expression of the CCK2 receptor, support a key role of the CCK2 receptor in the initiation of pancreatic cancer. Moreover, ElasCCK2 mice provide a model for carcinogenesis by transformation and dedifferentiation of acinar cells.

Neurons within the medullary subnucleus reticularis dorsalis (SRD) of the rat convey selectively nociceptive information from all parts of the body. We have sought to define the neuronal networks that convey information from widespread noxious stimuli to the diffuse thalamocortical system and also modulate spinal outflow. The experiments, which were performed in rats, were designed to determine whether efferents from the SRD issue collaterals to the thalamus and spinal cord. Injections of the tracers fluorogold and tetramethylrhodamine-labelled dextran were centred stereotaxically in two areas that receive dense projections from the SRD: the cervical spinal cord and the lateral ventromedial thalamus (VMl), respectively. In other experimental series, SRD neurons were characterized electrophysiologically and individually labelled in a Golgi-like manner following juxtacellular iontophoresis of biotin-dextran. More than half reticulothalamic neurons within the SRD provided monosynaptic connections to the spinal cord. SRD neurons that responded to Adelta- or Adelta- and C-fibre activation from any area of the body had axons that gave both ascending and descending collaterals. Because the SRD innervates several areas involved in motor processing and receives strong, direct influences from several cortical regions, it could provide a structural basis for the processing of nociceptive and motor activities.

La dysplasie fibromusculaire est definie comme une maladie de la paroi arterielle, segmentaire, non atheromateuse, entrainant des stenoses des arteres de petite et grande taille et plus rarement des anevrysmes et des dissections. L’atteinte de l’artere renale, la plus frequente (60 a 100 %), se manifeste par une stenose des arteres renales, asymptomatique ou compliquee d’hypertension arterielle ou d’une alteration de la fonction renale. Les atteintes des arteres carotides ou vertebrales sont moins frequentes (10 a 35 %). La prise en charge chirurgicale des dysplasies fibromusculaires est devenue beaucoup plus rare du fait du developpement des techniques d’angioplastie transluminale. Les criteres anatomopathologiques ne sont de fait plus des criteres pronostiques pertinents. La presentation clinique et le profil evolutif different en fonction de la presentation angiographique (atteinte unifocale ou multifocale), avec un taux de guerison de l’hypertension arterielle plus important au cours des atteintes unifocales. En presence d’une dysplasie fibromusculaire renale, ne sont revascularises que les patients symptomatiques (hypertension arterielle recente ou resistante au traitement) ou avec une asymetrie de taille renale ou une alteration de la fonction renale. L’angioplastie transluminale est proposee en premiere intention sauf en cas de lesions complexes ou de stenoses associees a un anevrysme.

Takayasu arteritis (TAK) is a large-vessel vasculitis that induces damage to the aorta and its branches. Glucocorticoids remain the gold standard of therapy for TAK. The nature of the T cells driving vascular inflammation and the effects of glucocorticoids on the systemic components of TAK are not understood. The aim of this study was to analyze T cell homeostasis and cytokine production in peripheral blood and inflammatory lesions of the aorta in patients with TAK.T cell homeostasis and cytokine production in peripheral blood and inflammatory lesions of the aorta were analyzed using Luminex analysis, flow cytometry, and immunohistochemical analysis. The study included 41 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK (17 patients with active TAK and 24 patients with disease in remission), 30 patients with giant cell arteritis and 39 patients with Behçet's disease (disease controls), and 20 age- and sex-matched healthy control subjects.We observed a marked increase in the expression of Th1 and Th17 cells, which correlated with TAK disease activity. The addition of serum from patients with active TAK to sorted CD4+ T cells from healthy donors in culture medium induced significant production of interferon-γ (IFNγ) and interleukin-17A (IL-17A). We demonstrated the presence of IFNγ-, IL-6-, and IL-17A-producing T cells in vascular inflammatory infiltrates in patients with TAK. Corticosteroid therapy was associated with decreased levels of circulating Th1 cytokines in corticosteroid-treated patients with TAK compared with steroid-free patients with TAK (for IL-2, mean ± SD 5,079 ± 5,300 versus 7,359 ± 3,197 pg/ml; for IFNγ, 2,592 ± 3,072 versus 8,393 ± 3,392 pg/ml; for tumor necrosis factor α, 847 ± 724 versus 1,491 ± 392 pg/ml). However, glucocorticoids had essentially no effect on the frequency of Th17 cytokines (IL-1 receptor, IL-17, and IL-23).The Th17 and Th1 pathways contribute to the systemic and vascular manifestations of TAK. Glucocorticoid treatment suppresses Th1 cytokines but spares Th17 cytokines in patients with TAK.

Fibromuscular dysplasia is a segmentary, non-atherosclerotic, non-inflammatory vascular disease that may result in stenosis, occlusion, aneurysms or dissection of medium arteries. Renal involvement is the most frequent location, described in 60-100% of patients. Renal stenosis can be asymptomatic or complicated with arterial hypertension or less frequently with renal insufficiency. Carotid and vertebral involvements are less frequent (10-35%). Surgical management of fibromuscular dysplasia is now less common because of the better efficacy of percutaneous transluminal angioplasty. Thus, histologic characteristics are no longer relevant prognostic criteria. Clinical features and outcome vary according to angiographic presentation (focal or multifocal disease), with an increased recovery rate of hypertension with focal lesions. In the presence of renal fibromuscular dysplasia, only symptomatic patients are revascularized (recent or resistant hypertension) or patients with asymmetric renal size or impaired renal function. Transluminal angioplasty is the first-line treatment except for patients with complex lesions or stenosis associated with aneurysm.

In order to determine which physiological functions can be regulated by the pancreatic CCKB/gastrin receptor, studies were carried out on pancreatic acini from mice expressing transgenic CCKB/gastrin receptors in the exocrine pancreas (ElasCCKB mice). Acini were stimulated by sulfated gastrin in the presence of SR 27897 (1.8 µm), blocking endogenous CCKA receptors. After 30 min incubation with gastrin, the secretion of chymotrypsinogen and amylase showed superimposable monophasic dose–response curves. Enzyme secretion was detectable and maximal at 100 pm and 1 nm of gastrin, respectively. No increase in chymotrypsinogen and amylase mRNAs was detected for doses of gastrin which specifically occupy the CCKB/gastrin receptor. In contrast, gastrin stimulated total protein synthesis in isolated acini from ElasCCKB mice. [35S]Methionine incorporation into total proteins was increased dose-dependently to a maximum for 30 pm gastrin and inhibited with higher doses (> 300 pm). Gastrin stimulated p70 S6 kinase activity for concentrations ranging from 10 pm to 1 nm. Gastrin-stimulated p70 S6 kinase activity and protein synthesis were blocked by rapamycin and wortmannin. Therefore, in ElasCCKB mice acinar cells, the CCKB/gastrin receptor mediates enzyme release and protein synthesis. However, a more efficient coupling of the CCKB/gastrin receptor to protein synthesis than to enzyme secretion was demonstrated. CCKB/gastrin receptor-stimulated protein synthesis likely results from an enhancement of mRNA translation and involves phosphatidyl inositol 3-kinase and p70 S6 kinase.

The distribution and organization of cortical projections to the subnucleus reticularis dorsalis (SRD), the neighboring cuneate nucleus (Cu), and trigeminal nucleus caudalis (Sp5C) were studied in the rat using microinjections of wheat germ agglutinin-apo horseradish peroxidase-gold and Biotin-Dextran. Cortical cells projecting to the caudal medulla were confined to the contralateral layer V with their descending axons crossing the midline at the level of pyramidal decussation. Cortical afferents to Sp5C originated from cells located mainly in the primary somatosensory cortex (S1) and the insular cortex, whereas cortical projections to the Cu originated mainly from the primary motor cortex (M1), the primary and secondary somatosensory cortex (S1 and S2). The SRD received dense cortical afferents from larger, widespread cortical areas: M1, M2, S1, S2, and the insular cortex. The existence of dense cortico-SRD connections supports the possibility of a pyramidal influence over SRD neurons, which might modify nociceptive information ascending to the cortex itself. This proposal is consistent with the fact that SRD efferents terminate densely in thalamic areas that influence sensorimotor cortical regions which in turn project to the SRD. Moreover, these corticofugal mechanisms could allow the cortex to select its own input by suppressing or augmenting transmission of signals through SRD-hindbrain/forebrain pathways or by coordinating activities in spino-SRD-spinal circuits and thus selecting the relevant information produced by the noxious stimulus.

La tronc cerebral presente un interet particulier dans la douleur car on a pu montrer tant chez l’animal que chez l’homme, que la tres grande majorite des fibres cheminant dans le quadrant ventrolateral de la moelle, qui contient les voies nociceptives, se termine dans la formation reticulee bulbaire. Des donnees recentes ont montre qu’une region denommee Subnucleus Reticularis Dorsalis (SRD) joue un role selectif dans le tranfert de l’information nociceptive vers des regions thalamiques responsables de l’activation du cortex frontal, tout en etant impliquee dans une boucle modulant le pasage des influx au niveau spinal. Ces etudes mettent au premier plan les anciennes hypotheses selon lesquelles certaines regions de la formtion reticulee bulbaire constituent un relais majeur des influx nociceptifs vers le thalamus. En plus des voies spino-thalamiques, ces voies spino-reticulo-thalamiques pourraient jouer un role clef dans le cheminement des signaux nociceptifs vers le cortex anterieur.

The distribution and organization of diencephalic projections from the subnucleus reticularis dorsalis (SRD) and the neighbouring cuneate nucleus (Cu) were studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin in SRD and Cu and wheat germ agglutinin-apo horseradish peroxidase-gold in some selected thalamic areas. As previously reported, the efferent projections from the Cu were essentially contralateral and terminated mainly in the ventroposterolateral thalamic nucleus. Less dense terminals from the Cu were also observed in the posterior thalamic group, the ventral aspect of the zona incerta and the caudal and dorsal portion of the reuniens area. Retrograde tracer injections in the medial ventroposterolateral thalamic nucleus labeled numerous cells in the contralateral Cu, with a smaller number in the gracile nucleus. From the SRD, terminals were observed in the lateral aspect of the ventromedial thalamic nucleus, the lateral parafascicular area and, to a lesser extent, in the ventral aspect of the zona incerta and the core of the reuniens area. Retrograde tracer injections in the lateral part of the ventromedial thalamic nucleus labeled cells in the caudal medulla, many of which were located in the dorsal-most aspect of the SRD throughout its caudo-rostral extent. The existence of SRD-thalamic connections reinforces the idea that the caudal reticular formation is an important nociceptive relay to the thalamus. Our data shed new light on old hypotheses suggesting that, in addition to spino-thalamic pathways, spino-reticulo-thalamic pathways may play an important role in distributing pain signals to the forebrain.

A specific method for pancreatic elastase II activity analysis was developed. True elastase II activity could be discriminated from that of elastase I and chymotrypsin. The postnatal development of four pancreatic proteases in the duodenal juice of children and in the pancreatic homogenates of calves and piglets was measured. The study was carried out on patients without (14 children) and with (5 children) pancreatic insufficiency. Calves and piglets were either milk-fed or weaned until slaughter at different ages. Profiles of enzyme development were globally similar in milk-fed piglets and calves, while in children without pancreatic insufficiency, no significant change was observed between 4 and 168 months. In children with pancreatic insufficiency, enzyme activity was low. In animals, elastase II and chymotrypsin activities were maximal at birth, decreased with age, and probably were associated with the digestion of milk protein. In contrast, elastase I and trypsin activities increased markedly after weaning in connection with the intake of solid food.

To bring to the fore the most important prognostic factors in Ewing's sarcoma (ES) with current protocols, we studied the classical prognostic factors, dose intensity (DI) of actual received drugs, age and histological response to induction therapy and their correlation in 39 patients with localized ES treated from 11/85 to 06/95 to identify eventual predictors of event-free survival (EFS). Inclusion criteria were age 35 yr or less, definitive local treatment by our team and chemotherapy including at least 4 drugs: vincristine (VCR), dactinomycin (DACT), doxorubicin (DOXO) cyclophosphamide (CPX). The endpoint was the absence of relapse. Parameters related to the status of patients were tested using the Chi square test or Fisher's exact test. The non parametric Kruskal-Wallis test was used for quantitative data. When necessary stratified analysis was done using the Mantel Cox test. With a median follow-up of 7 yr, overall survival (OS) and EFS were both 67% at 7 yr. According to univariate analysis, the significant predictors of survival were the DI of VCR and DACT, the histological response to preoperative chemotherapy (CT), the patient's age (18 yr DFS: 84%;18 yr DFS: 38%). The risk of metastases was almost tenfold higher in patients with low received DI of VCR (DFS 40% versus 95%) and of DACT (DFS 48% versus 94%). The prognostic value of primary tumor characteristics (tumoral volume or location) was erased by the comprehensive treatment. Following multivariate analysis, the actual received DI of VCR (p0.02) and DACT (p0.03) and the histological response to preoperative CT (p0.05) were retained as the only significant independent predictors of EFS. Taking into account the actual received DI of VCR and DACT, the prognostic value of age disappears. In conclusion, this study points out the main role of the drug DI in ES (particularly VCR and DACT) and of histological response to preoperative CT.

Vascular involvement is a common complication of Behçet's disease (BD) and affects up to 40% of BD patients. These complications worsen the prognosis of BD. The concept of vasculo-Behçet has been adopted for cases in which vascular complications dominate the clinical features. Vascular manifestations affect particularly young men, during the first years following onset of the disease. Venous complications are the most frequent vascular complications, affecting 14 to 40% of BD patients. Superficial and deep lower limb thrombosis is the most frequent venous complications but one third of venous thrombosis concern large vessels (such as cerebral venous thrombosis, pulmonary embolism, and inferior or superior vena cava, etc.). Budd-Chiari syndrome is the worst prognostic factor increasing mortality by 9 times. Arterial complications (2 to 17% of BD patients) include aneurysms and occlusions/stenosis. Main locations of arterial lesions are aortic (abdominal and thoracic), femoral, pulmonary and iliac arteries. Aneurysms are the most severe arterial complications, particularly pulmonary aneurysms associated with a high risk of massive bleeding. Cardiac complications (up to 6% of BD patients) include pericarditis, endocardial lesions (aortic regurgitation and less often mitral insufficiency), myocardial lesions (myocardial infarction, myocarditis and endomyocardial fibrosis) and intracardiac thrombosis (right ventricle and atrium). Coronary lesions complicated to myocardial infarction are the most severe cardiac complications. Treatment is based on corticosteroids and immunosuppressive drugs. The use of anticoagulation in venous thrombosis is still controversial.

Five of the six families with the Berardinelli-Seip syndrome in Norway cluster in six adjacent rural municipalities of south-western Norway. The six patients from this area were born between 1951 and 1973, none between 1974 and 1995. The absence of new cases may be explained by a decrease in the intraregion marriage rate and inbreeding. Genealogical investigations show that the mutation must have occurred at least 400 years ago. The sixth family was clinically different and geographically sporadic from a Finnish-descent rural East Norwegian population. A genetic linkage study of all six families revealed fresh crossovers versus the disease allele in nine DNA marker systems and the absence of recombination in three (maximum Lod score + 1.3). None of the Inst showed allelic association. These families are included in an international effort to map the CLBS locus. The patients have been included in the homozygosity testing of totally 28 patients in an international collaborative study. The three patients, assumed identical in descent from both parents, were jointly homozygous in none of the 250 dinucleotide markers tested. A. heterochromatic 9qh + segregated from one parent in two families.

Le carcinome hepatocellulaire (CHC) est une tumeur du foie de mauvais pronostic constituant un enjeu de sante publique. Les maladies chroniques du foie sont des facteurs de risque et sont frequemment associees a une insulinoresistance. L’obesite, le diabete de type 2 et le syndrome metabolique sont egalement des facteurs de risque. Des etudes epidemiologiques suggerent que l’hyperinsulinemie, qui est compensatrice a l’insulinoresistance, participe au developpement et/ou a la progression du CHC (Liver Int, 2015). Le recepteur de l’insuline est une tyrosine kinase exprimee sous deux isoformes, IR-A et IR-B, resultant d’un epissage alternatif et different de 12 acides amines dans le domaine extracellulaire. L’epissage est regule au cours du developpement : IR-A est principalement exprimee dans le foie fœtal ; les hepatocytes adultes expriment IR-B qui relaie les effets anaboliques de l’hormone. Nous avons recemment decrit des anomalies d’expression du recepteur de l’insuline dans une collection de tumeurs de CHC (Cancer Res, 2013) : l’expression de IR-B est diminuee, tandis que l’expression de IR-A est induite par un mecanisme impliquant une deregulation de l’epissage alternatif sous controle de l’activation de la voie EGFR. Cette deregulation contribue a augmenter le ratio d’expression IR-A/IR-B. Nous montrons que le ratio IR-A/IR-B est plus eleve dans les tumeurs exprimant des marqueurs de mauvais pronostic et qu’un ratio eleve est associe a une diminution de la survie des patients operes. Nos travaux en cours se concentrent sur les mecanismes sous-jacents en nous focalisant sur l’impact de IR-A sur la differenciation cellulaire, la reprogrammation metabolique et le phenotype souche/progeniteur.

Neurons within the medullary subnucleus reticularis dorsalis (SRD) of the rat convey selectively nociceptive information from all parts of the body. We have sought to define the neuronal networks that convey information from widespread noxious stimuli to the diffuse thalamocortical system and also modulate spinal outflow. The experiments, which were performed in rats, were designed to determine whether efferents from the SRD issue collaterals to the thalamus and spinal cord. Injections of the tracers fluorogold and tetramethylrhodamine-labelled dextran were centred stereotaxically in two areas that receive dense projections from the SRD: the cervical spinal cord and the lateral ventromedial thalamus (VMl), respectively. In other experimental series, SRD neurons were characterized electrophysiologically and individually labelled in a Golgi-like manner following juxtacellular iontophoresis of biotin-dextran. More than half reticulothalamic neurons within the SRD provided monosynaptic connections to the spinal cord. SRD neurons that responded to Adelta- or Adelta- and C-fibre activation from any area of the body had axons that gave both ascending and descending collaterals. Because the SRD innervates several areas involved in motor processing and receives strong, direct influences from several cortical regions, it could provide a structural basis for the processing of nociceptive and motor activities.

We have used several anatomical tracing techniques to study the organization of the lateral ventromedial thalamic nucleus in the rat, a region that is selectively activated by cutaneous nociceptive inputs from any part of the body. The lateral ventromedial thalamic projections are organized as a widespread dense band covering mainly layer I of the dorsolateral anterior-most aspect of the cortex. This band diminishes progressively as one moves caudally, disappearing completely at 1mm caudal to bregma level. These widespread projections contrast with the circumscribed projections to the deep layers of the primary somatosensory and insular cortices from the adjacent ventral posteromedial and ventroposterior parvicellular thalamic regions, respectively. Injections into the lateral part of the ventromedial thalamic nucleus of an anterograde/retrograde tracer showed that the cortical layer I areas showing the densest projections from this thalamic region also contain the greatest number of retrogradely labeled cells in cortical layers V and VI. The same injections retrogradely labeled numerous cells which were confined to the dorsal subnucleus reticularis dorsalis in an area that contains a concentration of neurons with widespread nociceptive convergence. Finally, the lateral part of the ventromedial thalamic nucleus was also differentially labeled following a topical application of tetramethylrhodamine-labeled dextran on the dorsolateral anterior cortex. These findings suggest that lateral ventromedial thalamic neurons could be part of a spino-reticulo-thalamo-cortical network that allows signals of pain from any part of the body surface to spread across widespread cortical areas.

In addition to spinal pathways carrying nociceptive information directly to the diencephalon, some such information is relayed within the caudal brainstem. Indeed, it has been known for a long time that the majority of ascending axons located in the anterolateral quadrant of the spinal white matter, which contains the pain pathways in mammals, terminate within the medullary reticular formation [1–3]. Interestingly, the notion of a receptive centre (centrum receptorium or sensorium)within the reticular formation was introduced by Kohnstamm and Quensel [4] for bulbar reticular areas receiving spinal afferents. In a study of retrograde cellular reactions in the bulbar reticular formation to high mesencephalic lesions, the same authors demonstrated ascending pathways connecting the centrum receptorium with higher levels of the brain. They postulated that reticulo-thalamic projections might be part of a polysynaptic path responsible for the conduction of pain and temperature to higher brain levels [5].

In order to determine which physiological functions can be regulated by the pancreatic CCKB/gastrin receptor, studies were carried out on pancreatic acini from mice expressing transgenic CCKB/gastrin receptors in the exocrine pancreas (ElasCCKB mice). Acini were stimulated by sulfated gastrin in the presence of SR 27897 (1.8 microM), blocking endogenous CCKA receptors. After 30 min incubation with gastrin, the secretion of chymotrypsinogen and amylase showed superimposable monophasic dose-response curves. Enzyme secretion was detectable and maximal at 100 pM and 1 nM of gastrin, respectively. No increase in chymotrypsinogen and amylase mRNAs was detected for doses of gastrin which specifically occupy the CCKB/gastrin receptor. In contrast, gastrin stimulated total protein synthesis in isolated acini from ElasCCKB mice. [35S]Methionine incorporation into total proteins was increased dose-dependently to a maximum for 30 pM gastrin and inhibited with higher doses (300 pM). Gastrin stimulated p70 S6 kinase activity for concentrations ranging from 10 pM to 1 nM. Gastrin-stimulated p70 S6 kinase activity and protein synthesis were blocked by rapamycin and wortmannin. Therefore, in ElasCCKB mice acinar cells, the CCKB/gastrin receptor mediates enzyme release and protein synthesis. However, a more efficient coupling of the CCKB/gastrin receptor to protein synthesis than to enzyme secretion was demonstrated. CCKB/gastrin receptor-stimulated protein synthesis likely results from an enhancement of mRNA translation and involves phosphatidyl inositol 3-kinase and p70 S6 kinase.

We report here that antiinsulin receptor (anti-IR) autoantibodies (AIRs) from a newly diagnosed patient with type B syndrome of insulin resistance induced cellular resistance not only to insulin but also to insulin-like growth factor I (IGF-I) for the stimulation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase activities and of glycogen and DNA syntheses. The molecular mechanisms of this dual resistance were investigated. Patient AIRs bound the IR at the insulin-binding site and caused insulin resistance at the IR level by inducing a 50% decrease in cell surface IRs and a severe defect in the tyrosine kinase activity of the residual IRs, manifested by a loss of insulin-stimulated IR autophosphorylation and IR substrate-1 (IRS-1)/IRS-2 phosphorylation. In contrast, cell resistance to IGF-I occurred at a step distal to IGF-I receptors (IGF-IRs), as AIRs altered neither IGF-I binding nor IGF-I-induced IGF-IR autophosphorylation, but inhibited the ability of IGF-IRs to mediate tyrosine phosphorylation of IRS-1 and IRS-2 in response to IGF-I. Coimmunoprecipitation assays showed that in AIR-treated cells, IRs, but not IGF-IRs, were constitutively associated with IRS-1 and IRS-2, strongly suggesting that AIR-desensitized IRs impeded IGF-I action by sequestering IRS-1 and IRS-2. Accordingly, AIRs had no effect on the stimulation of mitogen-activated protein kinase activity or DNA synthesis by vanadyl sulfate, FCS, epidermal growth factor, or platelet-derived growth factor, all of which activate signaling pathways independent of IRS-1/IRS-2. Thus, AIRs induced cell resistance to both insulin and IGF-I through a novel mechanism involving a constitutive and stable association of IRS-1 and IRS-2 with the IR.

A predominance of the pancreatic cholecystokinin (CCK) receptor of the B/gastrin subtype (CCK-B/G) was reported in calves older than 1 month. Specific CCK-A and CCK-B/G receptor antagonists (SR 27897 and PD 135158, respectively) were used to identify the CCK receptor subtype involved in exogenous CCK- and gastrin-induced exocrine pancreatic responses. Conscious calves (2 months old) with catheterized pancreas, jugular vein and duodenum were used; the pancreatic juice was continuously reinfused. CCK (30 pmol kg–1 min–1, 40 min) evoked an increase in pancreatic juice flow and enzyme secretion, while the same dose of gastrin increased enzyme secretion alone. CCK-induced pancreatic secretion was abolished by SR 27897 (15 nmol kg–1 min–1, 55 min) and reduced by PD 135158 (0.15 nmol kg–1 min–1, 55 min). Gastrin-induced enzyme secretion was reduced by PD 135158 (50% to 90%) and to a lesser extent by SR 27897 (50% to 60%). These results demonstrate that CCK and gastrin in the physiological range stimulate pancreatic exocrine secretion in calves and that these effects are partly mediated by CCK-B/G receptors. Although CCK-A receptors are not predominantly expressed, they seem to play a major role in the response of pancreatic exocrine secretion to CCK.

We aimed to create a model for Ifosfamide (IFX) pharmacokinetics for drug monitoring in order to improve protocol dose intensity.We studied ifosfamide pharmacokinetics in 12 patients aged 8-19 years. Sixteen courses were modelled (6 g/m2, on 5 days). The auto-induction of ifosfamide was taken into account in the model. Ifosfamide measurement was performed on serum samples by gas chromatography with thermo-ionic detection. Two pharmacokinetic models were compared. The following parameters were estimated: volume of distribution (Vd), clearance at the beginning of the induction (CLi), clearance extrapolated to infinity (CLf), clearance at the end of infusion (CL120), a rate constant (Kc) indicating the clearance variation with time and the lag time (Lag) indicating the time elapsed between the start of infusion and the start of induction. The Wilcoxon test was used to investigate possible differences between models. We tested the hypothesis that Boddy's model is an acceptable simplification of Levy's model.Four of six parameters were significantly different between the two models (p = 0.05). The best curve fitting was obtained using the Levy's model which provided the following estimates, Cli = 2.46 +/- 0.94 L.h-1.m-2, CLf = 5.22 +/- 1.02 L.h-1.m-2, Kc = 0.024 +/- 0.014 h-1, Vd = 18.84 +/- 5.04 L and Lag = 4.86 +/- 6.61 h. The most important difference is found for the distribution volume.Levy's model is more accurate and takes into account the integration of clearance.

The distribution and organization of diencephalic projections from the subnucleus reticularis dorsalis (SRD) and the neighbouring cuneate nucleus (Cu) were studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin in SRD and Cu and wheat germ agglutinin-apo horseradish peroxidase-gold in some selected thalamic areas. As previously reported, the efferent projections from the Cu were essentially contralateral and terminated mainly in the ventroposterolateral thalamic nucleus. Less dense terminals from the Cu were also observed in the posterior thalamic group, the ventral aspect of the zona incerta and the caudal and dorsal portion of the reuniens area. Retrograde tracer injections in the medial ventroposterolateral thalamic nucleus labeled numerous cells in the contralateral Cu, with a smaller number in the gracile nucleus. From the SRD, terminals were observed in the lateral aspect of the ventromedial thalamic nucleus, the lateral parafascicular area and, to a lesser extent, in the ventral aspect of the zona incerta and the core of the reuniens area. Retrograde tracer injections in the lateral part of the ventromedial thalamic nucleus labeled cells in the caudal medulla, many of which were located in the dorsal-most aspect of the SRD throughout its caudo-rostral extent. The existence of SRD-thalamic connections reinforces the idea that the caudal reticular formation is an important nociceptive relay to the thalamus. Our data shed new light on old hypotheses suggesting that, in addition to spino-thalamic pathways, spino-reticulo-thalamic pathways may play an important role in distributing pain signals to the forebrain.

Conservative resection of bone sarcoma in the lower limbs in children is very likely to be followed by a progressive problem of leg length inequality resulting from removal of the growth cartilage. To overcome this we have been using an expanding prosthesis and we report our experiences during the period 1985 – 1996. The prostheses are made of titanium and comprise 3 parts: an articular component, an expanding mechanism, and tibial and femoral stems. The degree of possible lengthening of the prostheses is virtually unlimited, and they can be inserted in children of 5 or more years of age. We report the use of 28 prostheses in patients aged from 5 to 18 years, of which 4 were tibial, 5 total femur, and 16 distal femur. There were 6 Ewing’s sarcoma, 21 osteosarcoma, and 1 synovial sarcoma. The average follow-up was for 5 years. Five patients died from their disease, and 21 benefited from an average lengthening of 2.6 cm (range: 2 mm – 120 mm). Using the Société Européenne des Tumeurs Osseouses (EMSOS) criteria, the functional results were excellent or very good in 16, fair in 7 and bad in 5. Five patients developed an infection; one required amputation and the others received a new expanding prosthesis. We conclude that an expanding prosthesis is an excellent alternative to amputation in young children. However, the risk of infection associated with repeat surgery has led us to develop a prosthesis which can be lengthened externally, without the need for reopening the wound.

Before the advent of the new treatment protocols, immediate high amputation used to represent the only treatment for sarcomas of the limbs. Unfortunately, this did not prevent the development of metastatic disease in more than 90% of cases of Ewing’s sarcoma, 80% of osteosarcomas and nearly a half of the chondrosarcoma cases.

A specific method for pancreatic elastase II activity analysis was developed. True elastase II activity could be discriminated from that of elastase I and chymotrypsin. The postnatal development of four pancreatic proteases in the duodenal juice of children and in the pancreatic homogenates of calves and piglets was measured. The study was carried out on patients without (14 children) and with (5 children) pancreatic insufficiency. Calves and piglets were either milk-fed or weaned until slaughter at different ages. Profiles of enzyme development were globally similar in milk-fed piglets and calves, while in children without pancreatic insufficiency, no significant change was observed between 4 and 168 months. In children with pancreatic insufficiency, enzyme activity was low. In animals, elastase II and chymotrypsin activities were maximal at birth, decreased with age, and probably were associated with the digestion of milk protein. In contrast, elastase I and trypsin activities increased markedly after weaning in connection with the intake of solid food.

Summary - Bovine whey proteins such as œ-lactalbumin and ~-Iactoglobulin are with bovine caseins the most commonly used proteins in infant formulas owing to their high nutritional value. However, these cow milk components are not always weil tolerated and can induce allergies in infants. The purpose of this study was therefore to investigate the gastric (pepsin) and pancreatic (trypsin, chymotrypsin and elastases 1 and II) enzymatic hydrolysis of ~-Iactoglobulin with the aim of finding a means to reduce its antigenicity. Elastases 1and II were first purified from porcine pancreatic acetone powder. After differential precipitation steps, elastases 1and II were separated by cation-exchange chromatography. The conditions regarding ~-Iactoglobulin hydrolysis by gastric and/or pancreatic enzymes were similar to those used for hypoallergenic milk preparations. Elastase II and to a lesser extent elastase I, were effective in enhancing ~-Iactoglobulin hydrolysis via a mix of pepsin, trypsin and chymotrypsin and in reducing the residual antigenicity ofhydrolytic products. The sarne hydrolytic percentage was observed when elastase 1or II were added, while the residual antigenicity was lower in the presence of elastase II than in the presence of elastase 1.The introduction of elastases in the pancreatic IIUX can therefore be proposed to enhance the hydrolysis of cow milk components in hypoallergenic milk preparations. * Correspondence and reprints ~-Iactoglobulin hydrolysis / pancreatic elastases 1 and II / residual antigenicity / hypoallergenie milk

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Osteocalcin is the most abundant noncollagenous protein of bone. Here we report that the mouse genome contains an osteocalcin cluster composed of three genes arranged within a 23-kilobase span of genomic DNA. We named them osteocalcin gene 1 (OG1), osteocalcin gene 2 (OG2), and osteocalcin-related gene (ORG) in order from the 5' end to the 3' end of the cluster. Hybridization of polymerase chain reaction-amplified cDNAs with specific oligonucleotides and RNase protection assays showed that OG1 and OG2 are expressed only in bone, whereas ORG is transcribed in kidney but not in bone. Furthermore, during embryogenesis, OG1 and OG2 begin to be expressed at day 15.5, while ORG is transcribed as early as day 10.5. The protein encoded by ORG has a similar pattern of expression and identical structural features to nephrocalcin, a calcium-binding protein partially purified from kidney that plays a role in calcium reabsorption and in prevention of nephrolithiasis. The nephrocalcin gene has not been cloned in any species; we propose that ORG is the mouse nephrocalcin gene. The existence of several osteocalcin or osteocalcin-related sequences is not restricted to mouse but is present in every species we examined.

In order to understand why Rosen’s protocol [1] has not been reproduced by most groups [2, 3, 4, 5] that used the same scheme, we started preliminary study in 1984 using T10 to analyze methotrexate (MTX) pharmacokinetics and its correlations with clinical and histological results. From 1985 to 1989 a second pilot study was conducted to optimize the results of Rosen while conducting a pharmacokinetic analysis to understand the reasons for failures in attempts to reproduce T10 and to emphasize the fundamental points for curing osteosarcomas.

The family of nuclear hormone receptors is constantly expanding. To date, it comprises not only receptors for steroid hormones, thyroid hormones, retinoids, and vitamin D3, but also several other new receptors (reviewed in Parker 1991). Since not all of these receptors bind hormones, it is therefore inexact to talk about “nuclear hormone receptors.” For example, several have vitamins as ligands, and others bind chemical agents such as peroxisome proliferators, dioxin, or phenobarbital. In addition, an oncogenic version of one of these receptors, as well as several mutated receptors that are thought to be essential, have lost the ability to bind hormones. Furthermore, a growing number of receptors termed “orphan nuclear receptors” do not even have defined ligands as yet. Consequently, because there is such a wide variety of ligands that nuclear hormone receptors recognize, the more appropriate term “nuclear receptors” will be used in this review.

The long-term regulatory effect of insulin on glucose transport activity and glucose transporter expression was examined in Chinese hamster ovary (CHO) transfectants that overexpress either human insulin receptors of the wild type (CHO-R cells) or human insulin receptors mutated at two major autophosphorylation sites, Tyr1162 and Tyr1163 (CHO-Y2 cells). Previous studies showed that, when acutely stimulated by insulin, CHO-Y2 cells exhibit decreased receptor kinase activity along with decreased signaling of several pathways, including that for glucose transport, as compared with CHO-R cells. We now report the following. (i) When treated for 24 h with insulin (10(-10) to 10(-6) M), CHO-R and CHO-Y2 cells displayed closely similar concentration-dependent increases in 2-deoxyglucose uptake. In both transfectants, the maximal insulin-induced increase (approximately 3.5-fold) in uptake was cycloheximide-sensitive and was paralleled by equivalent increases in the levels of GLUT-1 immunoreactive protein and mRNA. (ii) By contrast, under similar conditions, CHO-Y2 cells exhibited a marked decrease in their response to insulin for [U-14C]glucose incorporation into glycogen (decreased sensitivity and maximal responsiveness) and for [U-14C]leucine incorporation into protein (decreased sensitivity) as compared with CHO-R cells. (iii) After a 24-h treatment with 10(-7) M insulin, CHO-R (but not CHO-Y2) cells showed a decreased ability to respond to a subsequent acute insulin stimulation of either receptor exogenous kinase activity or 2-deoxyglucose uptake as compared with respective untreated controls. These results indicate that (i) insulin receptors mutated at Tyr1162 and Tyr1163 retain normal signaling of the long-term stimulatory effect of insulin on glucose transport activity and GLUT-1 expression, but not on glycogenesis and overall protein synthesis; (ii) these three insulin signaling pathways may be triggered by distinct domains of the insulin receptor beta-subunit; and (iii) wild-type (but not twin-tyrosine mutant) receptors undergo negative regulation by chronic insulin treatment for subsequent signaling of acute biological actions of insulin.