Clermont-Ferrand, France
Clermont-Ferrand, France

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Matsuzaki S.,Estaing University Hospital Center | Matsuzaki S.,Clermont University | Matsuzaki S.,French National Center for Scientific Research | Darcha C.,CHU Clermont Ferrand
Human Reproduction | Year: 2015

STUDY QUESTION How can deep endometriotic stromal cells proliferate and persist in a fibrotic environment? SUMMARY ANSWER The serine/threonine kinase AKT and extracellular regulated kinase (ERK) signaling pathways may co-operate to support growth of deep endometriotic lesions by enhancing endometriotic stromal cell proliferation and survival in a fibrotic microenvironment in vitro. WHAT IS KNOWN ALREADY Endometriosis, particularly deep infiltrating endometriosis, is characterized histologically by dense fibrous tissue that is primarily composed of type I collagen. This tissue may cause pelvic pain and infertility, which are major clinical issues associated with endometriosis. Proliferation of normal fibroblasts is tightly regulated, and fibrillar, polymerized type I collagen inhibits normal fibroblast proliferation. However, no studies to date have investigated how deep endometriotic stromal cells can proliferate and persist in a fibrotic environment. STUDY DESIGN, SIZE, DURATION Endometrial and/or endometriotic tissues from 104 patients (61 with and 43 without endometriosis) of reproductive age with normal menstrual cycles were analyzed. A total of 25 nude mice received a single injection of endometrial fragments from a total of five samples. PARTICIPANTS/MATERIALS, SETTING, METHODS We evaluated cell proliferation, caspase 3/7 activity, and the AKT and ERK signaling pathways in endometrial and endometriotic stromal cells on three-dimensional (3D) polymerized collagen matrices in vitro. In addition, to determine whether aberrant activation of the AKT and ERK pathways is involved during progression of fibrosis in endometriosis in vivo, we evaluated the expression of phosphorylated AKT and ERK1/2 in endometriotic implants in a nude mouse model of endometriosis. Finally, we evaluated the effects of MK2206 (an AKT inhibitor) and U0126 (a MEK inhibitor) on cell proliferation, caspase 3/7 activity, and phosphorylation of AKT and ERK1/2 of endometriotic stromal cells on 3D polymerized collagen matrices. MAIN RESULTS AND THE ROLE OF CHANCE Proliferation of endometriotic stromal cells was significantly less inhibited than that of endometrial stromal cells (P < 0.05) on 3D polymerized collagen. Levels of phosphorylated AKT, phosphorylated p70S6K and phosphorylated ERK1/2 were significantly higher in endometriotic stromal cells than in endometrial stromal cells at 24 h (P < 0.05) and at 72 h (P < 0.05) on 3D polymerized collagen. Phosphorylated AKT expression was significantly increased on Days 21 and 28 compared with those on Days 3 and 7 (all P < 0.05) in endometriotic implants during progression of fibrosis in a nude mouse model of endometriosis. Inhibition of AKT or ERK1/2 with MK2206 or U0126, respectively, did not significantly increase caspase 3/7 activity in endometriotic stromal cells on either two-dimensional or 3D collagen matrices. Western blot analysis showed that MK2206 alone decreased levels of phosphorylated AKT; however, it increased levels of phosphorylated ERK in endometriotic cells compared with vehicle-treated cells (both P < 0.05). In addition, U0126 treatment decreased levels of phosphorylated ERK; however, it resulted in increased levels of phosphorylated AKT in endometriotic stromal cells compared with vehicle-treated cells (both P < 0.05). LIMITATIONS, REASONS FOR CAUTION Endometriosis involves a number of processes, such as invasion, metastasis, angiogenesis, and apoptosis resistance, and a variety of signaling pathways may be involved in promoting development and progression of the disease. In addition, further animal experiments are required to determine whether the AKT and ERK signaling pathways co-operate to support growth of endometriotic lesions in a fibrotic microenvironment in vivo. WIDER IMPLICATIONS OF THE FINDINGS Co-targeting the AKT and ERK pathways may be an effective therapeutic strategy for endometriosis treatment. STUDY FUNDING/COMPETING INTEREST(S) This study was supported in part by Karl Storz Endoscopy & GmbH (Tuttlingen, Germany). No competing interests are declared. © 2015 The Author.


Matsuzaki S.,Estaing University Hospital Center | Matsuzaki S.,University of Auvergne | Darcha C.,CHU Clermont Ferrand
Human Reproduction | Year: 2012

Background Endometrium is derived from intermediate mesoderm via mesenchymal to epithelial transition (MET) during development of the urogenital system. By retaining some imprint of their mesenchymal origin, endometrial epithelial cells may be particularly prone to return to this state, via epithelial to mesenchymal transition (EMT). We hypothesized that pelvic endometriosis originates from retrograde menstruation of endometrial tissue and that EMT-like and MET-like processes might be involved in the pathogenesis of pelvic endometriosis.Methods We investigated commonly used molecular markers for EMT, including cytokeratin, E-cadherin, N-cadherin, vimentin, S100A4 and dephosphorylated beta-catenin by immunohistochemistry in different forms of pelvic endometriosis: deep infiltrating endometriosis, ovarian endometriosis and superficial peritoneal endometriosis (red and black lesions), as well as samples of menstrual endometrium, other benign ovarian cysts (mucinous and serous cyst adenoma), and abdominal scar endometriosis for comparison. Results Epithelial cells of red peritoneal lesions and ovarian endometriosis showed less epithelial marker (cytokeratin, P < 0.0001) expression and more mesenchymal marker (vimentin and/or S100A4, P < 0.0001) expression than those of menstrual endometrium. In contrast, epithelial cells of black peritoneal lesions and deep infiltrating endometriosis showed more epithelial marker (E-cadherin) expression than those of menstrual endometrium (P < 0.03), red peritoneal lesions (P < 0.0001) and ovarian endometriosis (P< 0.0001), but maintained expression of some mesenchymal markers (vimentin, S100A4). In addition, dephosphorylated beta-catenin protein expression was significantly higher in epithelial cells of deep infiltrating endometriosis (P < 0.0001) than in epithelial cells of red and black peritoneal lesions and ovarian endometriosis. Conclusions EMT-like and MET-like processes might be involved in the pathogenesis of pelvic endometriosis. © 2012 The Author.


Matsuzaki S.,Estaing University Hospital Center | Matsuzaki S.,Clermont University | Matsuzaki S.,French National Center for Scientific Research | Darcha C.,CHU Clermont Ferrand
Human Reproduction | Year: 2014

study question: Is epigallocatechin-3-gallate (EGCG) treatment effective in the treatment of fibrosis in endometriosis? summary answer: EGCG appears to have antifibrotic properties in endometriosis. what is known already: Histologically, endometriosis is characterized by dense fibrous tissue surrounding the endometrial glands and stroma. However, only a few studies to date have evaluated candidate new therapies for endometriosis-associated fibrosis. study design, size, duration: For this laboratory study, samples from 55 patients (45 with and 10 without endometriosis) of reproductive age with normal menstrual cycles were analyzed.Atotal of 40 nude mice received single injection proliferative endometrial fragments from a total of 10 samples. participants/materials, setting,methods: The in vitro effects of EGC Gand N-acetyl-L-cysteine on fibrotic markers (alphasmooth muscle actin, type I collagen, connective tissue growth factor and fibronectin) with and without transforming growth factor (TGF)-b1 stimulation, as well as on cell proliferation, migration and invasion and collagen gel contraction of endometrial and endometriotic stromal cells were evaluated by real-time PCR, immunocytochemistry, cell proliferation assays, in vitro migration and invasion assays and/or collagen gel contraction assays. The in vitro effects of EGCG on mitogen-activated protein kinase (MAPK) and Smad signaling pathways in endometrial and endometriotic stromal cellswere evaluated bywestern blotting. Additionally, the effects ofEGCGtreatment on endometriotic implants were evaluated in a xenograft model of endometriosis in immunodeficient nude mice. mainresults andthe role of chance: Treatment with EGCG significantly inhibited cell proliferation, migration and invasion of endometrial and endometriotic stromal cells frompatients with endometriosis. In addition,EGCGtreatment significantly decreased the TGF-b1-dependent increase in the mRNA expression of fibrotic markers in both endometriotic and endometrial stromal cells. Both endometriotic and endometrial stromal cell-mediated contraction of collagen gels were significantly attenuated at 8, 12 and 24 h after treatment with EGCG. Epigallocatechin-3-gallate also significantly inhibited TGF-b1-stimulated activation of MAPK and Smad signaling pathways in endometrial and endometriotic stromal cells. Animal experiments showed that EGCG prevented the progression of fibrosis in endometriosis. limitations, reasons for caution: The attractiveness of epigallocatechin-3-gallate as a drug candidate has been diminished by its relatively low bioavailability. However, numerous alterations to the EGCG molecule have been patented, either to improve the integrity of the native compound or to generate a more stable yet similarly efficacious molecule. Therefore,EGCGand its derivatives, analogs and prodrugs could potentially be developed into agents for the future treatment and/or prevention of endometriosis. wider implications of thefindings: Epigallocatechin-3-gallate is a potential drug candidate for the treatment and/or prevention of endometriosis. © The Author 2014.


Patent
University Dauvergne Clermont I and Estaing University Hospital Center | Date: 2013-01-11

The invention relates to an aqueous lock composition comprising a compound selected from the polysaccharide anti-coagulants and ethanol, and a method for locking an intravascular device implanted in a patient comprising the introduction of said composition into the device.


Tournadre A.,Estaing University Hospital Center | Miossec P.,University of Lyon
Nature Reviews Rheumatology | Year: 2013

The innate and adaptive immune responses contribute to the development of inflammatory myopathies; the innate immune system does so through activation of the type I interferon and Toll-like receptor pathways. Dendritic cells have a pivotal role in the development of both adaptive and innate immune responses. Equipped with a range of pattern-recognition receptors, dendritic cells link innate and adaptive immunity. This Perspectives article discusses novel concepts in myositis, focusing on immature muscle precursors. Of interest, the immature muscle precursors involved in regeneration are associated with upregulation of HLA class I antigens and myositis-associated autoantigens, as well as activation of the Toll-like receptor pathway and production of type I interferon, and could have a critical contribution to the pathogenesis of myositis. These regenerating immature muscle cells might also be a target of the immune response in myositis, thereby explaining why muscle regeneration is not effective in the context of such inflammation. © 2013 Macmillan Publishers Limited. All rights reserved.


Canavese F.,Estaing University Hospital Center | Dimeglio A.,Montpellier University
World Journal of Orthopaedics | Year: 2013

Development of the spine and thoracic cage consists of a complex series of events involving multiple metabolic processes, genes and signaling pathways. During growth, complex phenomena occur in rapid succession. This succession of events, this establishment of elements, is programmed according to a hierarchy. These events are well synchronized to maintain harmonious limb, spine and thoracic cage relationships, as growth in the various body segments does not occur simultaneously at the same magnitude or rate. In most severe cases of untreated progressive earlyonset spinal deformities, respiratory insufficiency and pulmonary and cardiac hypertension (cor pulmonale ), which characterize thoracic insufficiency syndrome (TIS), can develop, sometimes leading to death. TIS is the inability of the thorax to ensure normal breathing. This clinical condition can be linked to costo-vertebral malformations (e.g. , fused ribs, hemivertebrae, congenital bars), neuromuscular diseases (e.g. , expiratory congenital hypotonia), Jeune or Jarcho-Levin syndromes or to 50% to 75% fusion of the thoracic spine before seven years of age. Complex spinal deformities alter normal growth plate development, and vertebral bodies become progressively distorted, perpetuating the disorder. Therefore, many scoliotic deformities can become growth plate disorders over time. This review aims to provide a comprehensive review of how spinal deformities can affect normal spine and thoracic cage growth. Previous conceptualizations are integrated with more recent scientific data to provide a better understanding of both normal and abnormal spine and thoracic cage growth. © 2013 Baishideng.


Gagniere J.,Estaing University Hospital Center
Journal of visceral surgery | Year: 2011

Laparoscopic sleeve gastrectomy (LSG) is performed in certain circumstances after failure of gastric banding. The goal of this study was to evaluate the impact of first-line gastric banding on the morbidity associated with secondary LSG for obesity. The case records of 102 consecutive patients undergoing LSG were studied retrospectively. The technique of LSG was standardized. Two groups were compared: one with patients having undergone LSG after first-line gastric banding (n = 31) and the second, with patients having undergone first-line LSG (n = 71). Endpoints were overall morbidity and intra/postoperative complications including gastric leaks consecutive to staple line disruption as well as other septic or hemorrhagic complications. Multivariable analysis was performed to detect independent risk factors for morbidity. Overall morbidity was significantly higher in patients having undergone LSG after first-line gastric banding compared with those undergoing first-line LSG (32.2% vs. 7%, P = 0.002). Gastric leaks secondary to staple line disruption also occurred statistically significantly more often in patients with first-line gastric banding (16.1% vs. 2.8%, P = 0.043). Waiting 6 months between gastric band removal and performing LSG did not prevent the increased morbidity compared with first-line LSG. Multivariable analysis revealed that among the factors analyzed (age, gender, comorbidity, body mass index, surgeon, first-line gastric banding), the only independent risk factor for staple line disruption was first-line gastric banding with an odds ratio = 6.6 (95% confidence interval = [1.2-36.3]). Undergoing first-line gastric banding increases the risk of complications after secondary LSG. We recommend that patients who undergo LSG after a first-line gastric banding should be warned of the increased risks of morbidity or, alternatively, that LSG be performed preferentially as the initial procedure. Copyright © 2011 Elsevier Masson SAS. All rights reserved.


Constantin J.-M.,Estaing University Hospital Center | Futier E.,Estaing University Hospital Center
Minerva Anestesiologica | Year: 2013

Over the last 25 years, lung imaging has changed our understanding of acute respiratory distress syndrome. Alveolar recruitment, hyperinflation, and positive end-expiratory pressure-induced changes in lung aeration have become evaluable using CT, PET, and ultrasonography. The data have revealed that patients differ, in that the required ventilator settings vary in those with the same syndrome. At the bedside, however, care physicians remain blinded. Bedside tools allowing monitoring of mechanical ventilation, and testing of ventilator settings, are urgently required. The aim of the present review is to consider how lung imaging has facilitated the evolution of knowledge of this syndrome, and to place such knowledge in a clinical perspective.


The replacement device according to the invention makes it possible to replace at least one natural chord (19) making up the mitral valve, said natural chord normally being connected by one end to a pillar (20) formed by a muscular relief on the cardiac wall and, by another end, to a component leaflet (14) of the valve. The replacement device comprises a base (31) that can be fastened on a pillar (20) and on which at least one pair (P3) of chords (34) with predefined lengths are mounted that are suitable for being fastened on the leaflet (14) of the valve. Each pair (P3) of chords is configured in a loop provided with an end reinforcement for fastening on the leaflet (14) of the valve (12) opposite the base (31). The invention also relates to a kit comprising at least two replacement devices.


BACKGROUND:: The main objective of this study was to retrospectively evaluate the clinical and radiographic outcomes of displaced humeral shaft fractures in children treated by Desault’s bandage (DB), external fixation (EF), and elastic stable intramedullary nailing (ESIN). METHODS:: During the study period, 36 consecutive children with displaced humeral shaft fracture were treated by DB (Group A), EF (Group B) or ESIN (Group C). All the patients underwent full-length preoperative and postoperative anteroposterior and lateral radiographs of the injured humerus. One year after the index surgery, patients were asked to answer the short version of the Disabilities of the Arm, Shoulder and Hand outcome questionnaire (Quick DASH). RESULTS:: Ten patients (27.8%) were in Group A, 11 (30%) in Group B, and 15 (41.7%) in Group C. Mean age at the time of injury was 10.8±2.3 years (range, 8 to 15.2 y), 11.7±2.5 years (range, 6.8 to 15.9 y), and 12.7±2.2 years (range, 6.9 to 15.3 y) in Groups A, B, and C, respectively (P=0.08). Groups A, B, and C did not differ significantly in their demographics (P>0.05).Surgical treatment (Groups B and C) provided a better radiologic outcome than nonoperative treatment (Group A) (P=0.05). No statistically significant differences were observed for preoperative, postoperative and at last follow-up mean displacement between Groups B and C (P>0.05).Overall, 9 of 36 patients developed a complication: 2 in Group A (20%), 4 in Group B (37%), and 3 in Group C (20.1) (P=0.92).Mean Quick DASH score was 3±8.6 (range, 0 to 27.3), 1.4±2.9 (range, 0 to 9), and 1.2±4.7 (range, 0 to 18.2) in Groups A, B, and C, respectively. All the patients were able to resume previous physical and sport activities 4 to 6 months after the last fracture reduction procedure. CONCLUSIONS:: Surgery is not contraindicated in children with displaced humeral shaft fractures. EF and ESIN provide a better radiologic outcome, less posttreatment pain and faster mobilization than DB. However, numerical differences, although statistically significant, were not clinically relevant for all variables but immobilization time. Nonoperative treatment was as efficacious as surgical treatment apart from the length of time for immobilization. LEVEL OF EVIDENCE:: Level III. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

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