Daher R.,French Institute of Health and Medical Research |
Daher R.,University Paris Diderot |
Daher R.,Laboratory of Excellence |
Kannengiesser C.,French Institute of Health and Medical Research |
And 39 more authors.
Gastroenterology | Year: 2016
Background & Aims Hereditary hemochromatosis is a heterogeneous group of genetic disorders characterized by parenchymal iron overload. It is caused by defective expression of liver hepcidin, the main regulator of iron homeostasis. Iron stimulates the gene encoding hepcidin (HAMP) via the bone morphogenetic protein (BMP)6 signaling to SMAD. Although several genetic factors have been found to cause late-onset hemochromatosis, many patients have unexplained signs of iron overload. We investigated BMP6 function in these individuals. Methods We sequenced the BMP6 gene in 70 consecutive patients with a moderate increase in serum ferritin and liver iron levels who did not carry genetic variants associated with hemochromatosis. We searched for BMP6 mutations in relatives of 5 probands and in 200 healthy individuals (controls), as well as in 2 other independent cohorts of hyperferritinemia patients. We measured serum levels of hepcidin by liquid chromatography-tandem mass spectrometry and analyzed BMP6 in liver biopsy specimens from patients by immunohistochemistry. The functions of mutant and normal BMP6 were assessed in transfected cells using immunofluorescence, real-time quantitative polymerase chain reaction, and immunoblot analyses. Results We identified 3 heterozygous missense mutations in BMP6 (p.Pro95Ser, p.Leu96Pro, and p.Gln113Glu) in 6 unrelated patients with unexplained iron overload (9% of our cohort). These mutations were detected in less than 1% of controls. p.Leu96Pro also was found in 2 patients from the additional cohorts. Family studies indicated dominant transmission. Serum levels of hepcidin were inappropriately low in patients. A low level of BMP6, compared with controls, was found in a biopsy specimen from 1 patient. In cell lines, the mutated residues in the BMP6 propeptide resulted in defective secretion of BMP6; reduced signaling via SMAD1, SMAD5, and SMAD8; and loss of hepcidin production. Conclusions We identified 3 heterozygous missense mutations in BMP6 in patients with unexplained iron overload. These mutations lead to loss of signaling to SMAD proteins and reduced hepcidin production. These mutations might increase susceptibility to mild-to-moderate late-onset iron overload. © 2016 AGA Institute.
Balossier A.,Service de neurochirurgie |
Balossier A.,Caen University Hospital Center |
Blond S.,Service de neurochirurgie |
Touzet G.,Service de neurochirurgie |
And 4 more authors.
Neurochirurgie | Year: 2015
Background and purpose: Pineal tumours account for 1% to 4% of brain tumours in adults and for around 10% in children. Except in a few cases where germ cell markers are elevated, accurate histological samples are mandatory to initiate the treatment. Open surgery still has a high morbidity and is often needless. Biopsies can either be obtained by endoscopic or stereotactic procedures. Methods: Following an extensive review of the literature (PubMed 1970-2013; keywords pineal tumour, biopsy; English and French), 33 studies were analysed and relevant data compared regarding the type of procedure, diagnosis rate, cerebrospinal fluid diversion type and rate, perioperative mortality, morbidity. Results: Endoscopic and stereotactic biopsies showed a diagnosis rate of 81.1% (20%-100%) and 93.7% (82%-100%), respectively. Endoscopic biopsies involved 21.0% of minor and 2.0% of major complications whereas stereotactic biopsies involved 6.4% of minor and 1.6% of major complications. The most frequently reported complication was haemorrhage for both endoscopic and stereotactic procedures, accounting for 4.8% and 4.3%, respectively. Mortality rate was low for both endoscopic and stereotactic procedures, equal to 0.4% and 1.3%, respectively. Local experience of stereotactic biopsies was also reported and corroborated the previous data. Conclusions: The difference between both procedures is not statistically significant (p>. 0.05) across large series (≥. 20. patients). Nevertheless, tissue diagnosis appears less accurate with endoscopic procedures than with stereotactic procedures (81.1% versus 93.7%, weighted mean across all series). In our opinion, the neuroendoscopic approach is the best tool for managing hydrocephalus, whereas stereotactic biopsies remain the best way to obtain a tissue diagnosis with accuracy and low morbidity. © 2014.
PubMed | Caen University Hospital Center, Service de neurochirurgie and Laboratoire danatomo pathologie
Type: Comparative Study | Journal: Neuro-Chirurgie | Year: 2015
Pineal tumours account for 1% to 4% of brain tumours in adults and for around 10% in children. Except in a few cases where germ cell markers are elevated, accurate histological samples are mandatory to initiate the treatment. Open surgery still has a high morbidity and is often needless. Biopsies can either be obtained by endoscopic or stereotactic procedures.Following an extensive review of the literature (PubMed 1970-2013; keywords pineal tumour, biopsy; English and French), 33 studies were analysed and relevant data compared regarding the type of procedure, diagnosis rate, cerebrospinal fluid diversion type and rate, perioperative mortality, morbidity.Endoscopic and stereotactic biopsies showed a diagnosis rate of 81.1% (20%-100%) and 93.7% (82%-100%), respectively. Endoscopic biopsies involved 21.0% of minor and 2.0% of major complications whereas stereotactic biopsies involved 6.4% of minor and 1.6% of major complications. The most frequently reported complication was haemorrhage for both endoscopic and stereotactic procedures, accounting for 4.8% and 4.3%, respectively. Mortality rate was low for both endoscopic and stereotactic procedures, equal to 0.4% and 1.3%, respectively. Local experience of stereotactic biopsies was also reported and corroborated the previous data.The difference between both procedures is not statistically significant (p>0.05) across large series (20patients). Nevertheless, tissue diagnosis appears less accurate with endoscopic procedures than with stereotactic procedures (81.1% versus 93.7%, weighted mean across all series). In our opinion, the neuroendoscopic approach is the best tool for managing hydrocephalus, whereas stereotactic biopsies remain the best way to obtain a tissue diagnosis with accuracy and low morbidity.
Evrard S.,French Institute of Health and Medical Research |
Bluteau O.,French Institute of Health and Medical Research |
Tulliez M.,Laboratoire dAnatomo pathologie |
Rameau P.,Institute Gustave Roussy |
And 10 more authors.
Blood | Year: 2011
Transforming growth factor-β1 (TGF-β1) is the most important cytokine involved in the promotion of myelofibrosis. Mechanisms leading to its local activation in the bone marrow environment remain unclear. As a recent study has highlighted the role of thrombospondin-1 (TSP-1) in platelet-derived TGF-β1 activation, we investigated the role of TSP-1 in the TPO high murine model of myelofibrosis. Two groups of engrafted mice, WT TPOhigh and Tsp-1-null TPOhigh, were constituted. All mice developed a similar myeloproliferative syndrome and an increase in total TGF-β1 levels in the plasma and in extracellular fluids of marrow and spleen. Surprisingly, we were able to detect the active form of TGF-β1 in Tsp-1-null TPOhigh mice. Accordingly, these mice developed marrow and spleen fibrosis, with intriguingly a higher grade than in WT TPOhigh mice. Our results show that TSP-1 is not the major activator of TGF-β1 in TPO-induced myelofibrosis, suggesting the contribution of another mechanism in the megakaryocyte/platelet compartment. © 2011 by The American Society of Hematology.
Gekas J.,Center Hospitalier Of Luniversite Laval |
Walther G.,Center Hospitalier Of Luniversite Laval |
Walther G.,Laval University |
Skuk D.,Center Hospitalier Of Luniversite Laval |
And 3 more authors.
Clinical and Experimental Medicine | Year: 2010
Recent findings have shown that amniotic fluid (AF) could be a putative new source of multipotent stem cells (SC). We investigated whether these human SC could efficiently differentiate into myogenic lineage in vitro and integrate in vivo skeletal muscle in severe combined immunodeficiency (SCID) mice. C/kit immunomagnetic-sorted AF (AF c/kit+) SC were characterized by immunocytochemistry and Southern blotting for myogenic markers (desmin, MyoD). In vitro, AF c/kit+ SC phenotypic conversion into myogenic cells was assayed by myogenic-specific induction media. AF c/kit+ SC without ex vivo manipulation were transplanted into the tibialis anterior (TA) of (SCID) mice. Acquisition of a myogenic-like phenotype (desmin, MyoD) in AF c/kit+ SC was observed after culture in myogenic-specific induction media. In vivo, transplanted AF c/kit+ SC showed an engraftment in the skeletal muscle of SCID mice, but with unexpected tubular glandular tissue-like differentiation. Importantly, no immuno-rejection, inflammatory response or tumorigenicity of these cells was found. Within these experimental conditions, AF c/kit+ SC were able to differentiate into myogenic cells in vitro, but not in vivo after their transplantation into the skeletal muscle of SCID mice. Because AF c/kit+ SC survived and differentiated into tubular gland-like cells after their transplantation in the TA, an ex vivo engagement in myogenic pathway prior their transplantation could favor their differentiation into myogenic cells in vivo. © 2009 Springer-Verlag.
Meni C.,University Paris Diderot |
Chabrol A.,University Paris Diderot |
Wassef M.,Laboratoire danatomo pathologie |
Gautheret-Dejean A.,University Pierre and Marie Curie |
And 2 more authors.
Revue de Medecine Interne | Year: 2013
Introduction: Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) is a rare clinical entity characterized by the association of enlarged lymph nodes in the posterior cervical region and fever. The disease is more frequent in young women. Case report: We report a 41-year-old African patient who presented with atypical features of Kikuchi's disease including cutaneous lupus, haemophagocytosis, and lymphocytic meningitis. The ethnic origin and the clinical presentation were initially suggestive of tuberculous meningitis. However, microbiological analyses remained negative, histological findings were suggestive of Kikuchi's disease and HHV6 DNA integration was documented in our patient. Conclusion: Kikuchi's disease should be suspected in an African patient when lymphocytic meningitis is associated with enlarged cervical lymph nodes, hemophagocytosis and HHV6 DNA integration. © 2012 Société nationale française de médecine interne (SNFMI).
Desvignes F.,Pole de Gyneco obstetrique reproduction Humaine |
Beaufrere A.-M.,Laboratoire dAnatomo pathologie |
Biard M.,Service de Radiologie Pediatrique |
Dechelotte P.,Laboratoire dAnatomo pathologie |
And 4 more authors.
Journal de Gynecologie Obstetrique et Biologie de la Reproduction | Year: 2013
Fetal brain tumors are rare and have different histologies. Although the definitive diagnosis relies on the histopathology of the tumor, it is useful to distinguish the tumors potentially curable from the tumors rapidly fatal after birth. Nevertheless, some intracranial masses are not tumors. We report four cases of intracerebral masses diagnosed prenatally corresponding to different histological lesions: teratoma, fetus-in-fetu, chraniopharyngioma, hemangioma. We discuss the elements of the differential diagnosis, which can be identified prenatally. © 2013 Elsevier Masson SAS. Tous droits réservés.
Francois P.,CHRU de Tours |
N'Dri D.,CHRU de Tours |
Bergemer-Fouquet A.M.,Laboratoire dAnatomo Pathologie |
Ben Ismail M.,CHRU de Tours |
And 3 more authors.
Acta Neurochirurgica | Year: 2010
We present three cases of meningiomas developing at the site of an old head trauma. We then review the literature regarding the controversies on the development of post-traumatic brain tumors and, finally, we emphasize the medico-legal characteristics of post-traumatic meningiomas, particularly with respect to their cell type which is frequently atypical or anaplastic and which have a poor outcome. © 2010 Springer-Verlag.
Moulouel B.,University Paris Diderot |
Houamel D.,University Paris Diderot |
Delaby C.,University Paris Diderot |
Tchernitchko D.,University Paris Diderot |
And 13 more authors.
Kidney International | Year: 2013
Hepcidin, the key regulatory hormone of iron homeostasis, and iron carriers such as transferrin receptor1 (TFR1), divalent metal transporter1 (DMT1), and ferroportin (FPN) are expressed in kidney. Whether hepcidin plays an intrinsic role in the regulation of renal iron transport is unknown. Here, we analyzed the renal handling of iron in hemochromatosis Hepc-/- and Hjv -/- mouse models, as well as in phenylhydrazine (PHZ)-treated mice. We found a marked medullary iron deposition in the kidneys of Hepc-/- mice, and iron leak in the urine. The kidneys of Hepc-/- mice exhibited a concomitant decrease in TFR1 and increase in ferritin and FPN expression. Increased FPN abundance was restricted to the thick ascending limb (TAL). DMT1 protein remained unaffected despite a significant decrease of its mRNA level, suggesting that DMT1 protein is stabilized in the absence of hepcidin. Treatment of kidney sections from Hepc-/- mice with hepcidin decreased DMT1 protein, an effect confirmed in renal cell lines where hepcidin markedly decreased 55 Fe transport. In the kidneys of Hjv-/- mice exhibiting low hepcidin expression, the iron overload was similar to that in the kidneys of Hepc-/- mice. However, in PHZ mice, iron accumulation resulting from hemoglobin leak was detected in the proximal tubule. Thus, kidneys exhibit a tissue-specific handling of iron that depends on the extra iron source. Hepcidin may control the expression of iron transporters to prevent renal iron overload. © 2013 International Society of Nephrology.
Bemer P.,Nantes University Hospital Center |
Plouzeau C.,Laboratoire Of Bacteriologie |
Tande D.,Brest University Hospital Center |
Leger J.,French Institute of Health and Medical Research |
And 16 more authors.
Journal of Clinical Microbiology | Year: 2014
There is no standard method for the diagnosis of prosthetic joint infection (PJI). The contribution of 16S rRNA gene PCR sequencing on a routine basis remains to be defined. We performed a prospective multicenter study to assess the contributions of 16S rRNA gene assays in PJI diagnosis. Over a 2-year period, all patients suspected to have PJIs and a few uninfected patients undergoing primary arthroplasty (control group) were included. Five perioperative samples per patient were collected for culture and 16S rRNA gene PCR sequencing and one for histological examination. Three multicenter quality control assays were performed with both DNA extracts and crushed samples. The diagnosis of PJI was based on clinical, bacteriological, and histological criteria, according to Infectious Diseases Society of America guidelines. A molecular diagnosis was modeled on the bacteriological criterion (≥ 1 positive sample for strict pathogens and ≥ 2 for commensal skin flora). Molecular data were analyzed according to the diagnosis of PJI. Between December 2010 and March 2012, 264 suspected cases of PJI and 35 control cases were included. PJI was confirmed in 215/264 suspected cases, 192 (89%) with a bacteriological criterion. The PJIs were monomicrobial (163 cases [85%]; staphylococci, n=108; streptococci, n=22; Gram-negative bacilli, n=16; anaerobes, n=13; others, n=4) or polymicrobial (29 cases [15%]). The molecular diagnosis was positive in 151/215 confirmed cases of PJI (143 cases with bacteriological PJI documentation and 8 treated cases without bacteriological documentation) and in 2/49 cases without confirmed PJI (sensitivity, 73.3%; specificity, 95.5%). The 16S rRNA gene PCR assay showed a lack of sensitivity in the diagnosis of PJI on a multicenter routine basis. Copyright © 2014, American Society for Microbiology. All Rights Reserved.