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Daudon M.,APHP | Bouzidi H.,Laboratoire Of Biochimie | Bazin D.,University Paris - Sud
Urological Research | Year: 2010

Calcium phosphate (CaP) stones account for about 15% of all urinary stones, with a marked female pre ponderance, and reflect a wide diversity of etiology. Varia tion of the relative prevalence of CaP urolithiasis over time is disputed, and relevance of CaP stone analysis for etio- logic diagnosis is underestimated or even negated. Based on the analysis of more than 50,000 stones over the past three decades, we evaluated the changes in the relative pro portion of CaP stones between 1980-1989 (period 1) and 2000-2009 (period 2). In addition, using morphologic examination combined with Fourier-transform infrared analysis, we assessed the associations between CaP stone analysis and etiopathogenic factors. Between periods 1 and 2, the overall proportion of struvite-free stones remained essentially unchanged (11.6 vs. 11.1%), with a decreasing proportion of carbapatite stones (10.6 vs. 8.4%, p < 0.001) and a rising proportion of brushite stones (0.8 vs. 2.2%, p < 0.001). Hypercalciuria was associated with 87% of brushite, and 60% of carbapatite stones. Urinary tract infec tion was associated with presence of minor amounts of stru- vite and/or with a carbonation rate of carbapatite > 15%. In CaP stones associated with primary hyperparathyroidism, the main component was carbapatite in 66.9% and brushite in 29.1% of cases. Distal renal tubular acidosis was always associated with carbapatite stones exhibiting a peculiar, vir tually pathognomonic, morphology. In conclusion, compre hensive analysis of stones involving morphologic examination is of clinical relevance for improved etiologic evaluation of patients with CaP urolithiasis. © Springer-Verlag 2010.


Bazin D.,University Paris - Sud | Bazin D.,University Pierre and Marie Curie | Daudon M.,APHP | Combes C.,National Polytechnic Institute of Toulouse | Rey C.,National Polytechnic Institute of Toulouse
Chemical Reviews | Year: 2012

A study was conducted to investigate characterization and some physicochemical aspects of pathological microcalcifications of calcium salts encountered in pathological calcifications and the role of proteins in these processes. The investigations showed the different levels of complexity of pathological calcifications, revealing that such biological entities were present everywhere in the human body. Their origin was complex and was induced by different kinds of abnormalities. It was also revealed that such pathological calcifications had a hierarchical structural organization, which was related to the history of the patient. The study highlighted different specific structural aspects of pathological calcification by scanning electron microscopy (SEM) observations related to major medical aspects. The observations proposed that a morphologic examination be performed before compositional analysis by means of X-ray diffraction or infrared spectroscopy, as this direct SEM examination constituted a simple, rapid, and cheap tool.


Dupuis L.,French Institute of Health and Medical Research | Dupuis L.,University of Strasbourg | Pradat P.-F.,APHP | Ludolph A.C.,University of Ulm | And 2 more authors.
The Lancet Neurology | Year: 2011

Amyotrophic lateral sclerosis (ALS) is characterised by the progressive degeneration of upper and lower motor neurons. Besides motor neuron degeneration, ALS is associated with several defects in energy metabolism, including weight loss, hypermetabolism, and hyperlipidaemia. Most of these abnormalities correlate with duration of survival, and available clinical evidence supports a negative contribution of defective energy metabolism to the overall pathogenic process. Findings from animal models of ALS support this view and provide insights into the underlying mechanisms. Altogether, these results have clinical consequences for the management of defective energy metabolism in patients with ALS and pave the way for future therapeutic interventions. © 2011 Elsevier Ltd.


Ruiz A.,APHP | Ruiz A.,University Pierre and Marie Curie | Lemoinne S.,University Pierre and Marie Curie | Carrat F.,University Pierre and Marie Curie | And 5 more authors.
Hepatology | Year: 2014

Magnetic resonance imaging (MRI) with magnetic resonance cholangiography (MRC) has become the radiologic standard of reference for diagnosis of primary sclerosing cholangitis (PSC). However, natural history of radiologic features of PSC is poorly known. In the current study, we aimed at analyzing the course of PSC using three-dimensional (3D) MRC and liver MRI to find predictive radiologic features of progression. PSC patients, followed up in our center, with at least two 3D MRCs performed in at least a 1-year interval, were retrospectively reviewed. We built an interpretation standard model to score precisely bile ducts and liver parenchyma features. The primary endpoint was overall radiologic course, including worsening, improvement, or stabilization. Radiologic features were analyzed by logistic regression. We reviewed 289 MRIs from 64 patients upon a mean radiologic follow-up of 4 years (range, 1-9). Radiologic features worsened in 37 patients (58%) and stabilized in 27 (42%); no patient showed improvement. Multivariate analysis resulted in two MRI progression risk scores, based on the combination of predictive radiologic features (score without gadolinium administration=1 × dilatation of intrahepatic bile ducts+2 × dysmorphy+1 × portal hypertension; score with gadolinium administration=1 × dysmorphy+1 × parenchymal enhancement heterogeneity). These scores were associated with radiologic progression, with an area under the curve of 80 and 83%±4%. Conclusion: A majority of PSC patients develop radiologic aggravation upon MRI over 4 years. Two simple scores can predict radiologic progression. © 2013 by the American Association for the Study of Liver Diseases.


Roche N.,University Pierre and Marie Curie | Lackmy A.,University Pierre and Marie Curie | Achache V.,University Pierre and Marie Curie | Bussel B.,APHP | Katz R.,University Pierre and Marie Curie
Journal of Physiology | Year: 2011

In recent years, two techniques have become available for the non-invasive stimulation of human motor cortex: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). The effects of TMS and tDCS when applied over motor cortex should be considered with regard not only to cortical circuits but also to spinal motor circuits. The different modes of action and specificity of TMS and tDCS suggest that their effects on spinal network excitability may be different from that in the cortex. Until now, the effects of tDCS on lumbar spinal network excitability have never been studied. In this series of experiments, on healthy subjects, we studied the effects of anodal tDCS over the lower limb motor cortex on (i) reciprocal Ia inhibition projecting from the tibialis anterior muscle (TA) to the soleus (SOL), (ii) presynaptic inhibition of SOL Ia terminals, (iii) homonymous SOL recurrent inhibition, and (iv) SOL H-reflex recruitment curves. The results show that anodal tDCS decreases reciprocal Ia inhibition, increases recurrent inhibition and induces no modification of presynaptic inhibition of SOL Ia terminals and of SOL-H reflex recruitment curves. Our results indicate therefore that the effects of tDCS are the opposite of those previously described for TMS on spinal network excitability. They also indicate that anodal tDCS induces effects on spinal network excitability similar to those observed during co-contraction suggesting that anodal tDCS activates descending corticospinal projections mainly involved in co-contractions. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.


News Article | October 7, 2016
Site: www.cemag.us

The natural presence of fatty acids in the human body leads to increased resistance of Staphylococcus aureus to a class of antimicrobials that target bacterial fatty acid biosynthesis. This discovery, based on research by INRA scientists in collaboration with INSERM, Hôpital Cochin APHP, the Université Paris Descartes, Institut Pasteur, and CNRS scientists, is reported in an article in Nature Communications. While antimicrobial drug discovery is a top research priority, this work reveals that resistance strategies involving host fatty acids can thwart the use of fatty acid synthesis inhibitors to treat staphylococcal infection. Triclosan is an antibacterial agent widely used in household products (mouthwash, toothpaste, lotion, shower gel), and in health care (sanitizers, surgical sutures). It belongs to a family of antimicrobials that inhibit synthesis of fatty acids (called FASII, for type II fatty acid synthesis), which are vital bacterial components. Triclosan was recently removed by the European Commission from its list of approved additives in Type 1 products (household products) due to potential health risks and questionable benefits. The American Food and Drug Administration (FDA) also banned its use in antibacterial soaps in 2016. However, triclosan remains in use, and new FASII inhibitors are in development for future use as antibiotics. In 2009, a study conducted by teams from INRA, Inserm, Hôpital Cochin APHP, the Université Paris Descartes, Institut Pasteur, and the CNRS showed that Gram-positive bacteria (streptococcus, enterococcus, and staphylococcus) can develop in the presence of FASII inhibitors by using the fatty acids found in human blood.  However, the capacity of the major human pathogen Staphylococcus aureus to overcome FASII inhibitors remained in debate. The same teams then focused on Staphylococcus aureus growth in environments containing fatty acids in combination with triclosan. They demonstrated that fatty acids promote about 100-fold increases in mutations that confer triclosan resistance. Some of these resistant bacteria synthesized their own fatty acids in a normal way when triclosan was not present, but then could overcome this FASII inhibitor by efficiently incorporating the environmental fatty acids. A strain with these properties was fully virulent, indicating that the biological cost of the mutation responsible for resistance is low. In fact, database searches of staphylococcal genomes revealed that this mutation is already present in some clinical isolates; as expected, these strains proved to be triclosan resistant. Human skin and nares, which are rich in fatty acids, are naturally colonized by bacteria including staphylococci. These could be privileged locations for developing resistant bacteria when using topical products containing FASII inhibitors like triclosan. This research indicates that treating staphylococcal infections with FASII inhibitors, or using consumer products containing them, may favor the emergence or spread of resistant staphylococci. It highlights the importance of studying bacterial responses to antimicrobials in growth conditions mimicking natural colonization or infection environments — i.e., with human fatty acids — when developing new anti-FASII antibiotics.


The natural presence of fatty acids in the human body leads to increased resistance of Staphylococcus aureus to a class of antimicrobials that target bacterial fatty acid biosynthesis. This discovery, based on research by INRA scientists in collaboration with with INSERM, Hôpital Cochin APHP, the Université Paris Descartes, Institut Pasteur and CNRS scientists, is reported in an article in Nature Communications (5 October 2016). While antimicrobial drug discovery is a top research priority, this work reveals that resistance strategies involving host fatty acids can thwart the use of fatty acid synthesis inhibitors to treat staphylococcal infection. Triclosan is an antibacterial agent widely used in household products (mouthwash, toothpaste, lotion, shower gel), and in health care (sanitizers, surgical sutures). It belongs to a family of antimicrobials that inhibit synthesis of fatty acids (called FASII, for type II fatty acid synthesis), which are vital bacterial components. Triclosan was recently removed by the European Commission from its list of approved additives in Type 1 products (household products) due to potential health risks and questionable benefits. The American Food and Drug Administration (FDA) also banned its use in antibacterial soaps in 2016. However, triclosan remains in use, and new FASII inhibitors are in development for future use as antibiotics. In 2009, a study conducted by teams from INRA, Inserm, Hôpital Cochin APHP, the Université Paris Descartes, Institut Pasteur and the CNRS showed that Gram-positive bacteria (streptococcus, enterococcus, and staphylococcus) can develop in the presence of FASII inhibitors by using the fatty acids found in human blood. However, the capacity of the major human pathogen Staphylococcus aureus to overcome FASII inhibitors remained in debate. The same teams then focused on Staphylococcus aureus growth in environments containing fatty acids in combination with triclosan. They demonstrated that fatty acids promote about 100-fold increases in mutations that confer triclosan resistance. Some of these resistant bacteria synthesized their own fatty acids in a normal way when triclosan was not present, but then could overcome this FASII inhibitor by efficiently incorporating the environmental fatty acids. A strain with these properties was fully virulent, indicating that the biological cost of the mutation responsible for resistance is low. In fact, database searches of staphylococcal genomes revealed that this mutation is already present in some clinical isolates; as expected, these strains proved to be triclosan resistant. Human skin and nares, which are rich in fatty acids, are naturally colonized by bacteria including staphylococci. These could be privileged locations for developing resistant bacteria when using topical products containing FASII inhibitors like triclosan. This research indicates that treating staphylococcal infections with FASII inhibitors, or using consumer products containing them, may favor the emergence or spread of resistant staphylococci. It highlights the importance of studying bacterial responses to antimicrobials in growth conditions mimicking natural colonization or infection environments – i.e., with human fatty acids – when developing new anti-FASII antibiotics. Explore further: Study finds association between consumption of certain fatty acids and developing type 2 diabetes in women More information: Claire Morvan et al. Environmental fatty acids enable emergence of infectious Staphylococcus aureus resistant to FASII-targeted antimicrobials, Nature Communications (2016). DOI: 10.1038/NCOMMS12944


Degos F.,APHP | Perez P.,Bordeaux University Hospital Center | Roche B.,French Institute of Health and Medical Research | Mahmoudi A.,APHP | And 3 more authors.
Journal of Hepatology | Year: 2010

Background & Aims: The diagnostic accuracy of non-invasive liver fibrosis tests that may replace liver biopsy in patients with chronic hepatitis remains controversial. We assessed and compared the accuracy of FibroScan® and that of the main biomarkers used for predicting cirrhosis and significant fibrosis (METAVIR ≥ F2) in patients with chronic viral hepatitis. Methods: A multicenter prospective cross-sectional diagnostic accuracy study was conducted in the Hepatology departments of 23 French university hospitals. Index tests and reference standard (METAVIR fibrosis score on liver biopsy) were measured on the same day and interpreted blindly. Consecutive patients with chronic viral hepatitis (hepatitis B or C virus, including possible Human Immunodeficiency Virus co-infection) requiring liver biopsy were recruited in the study. Results: The analysis was first conducted on the total population (1839 patients), and after excluding 532 protocol deviations, on 1307 patients (non-compliant FibroScan® examinations). The overall accuracy of FibroScan® was high (AUROC 0.89 and 0.90, respectively) and significantly higher than that of biomarkers in predicting cirrhosis (AUROC 0.77-0.86). All non-invasive methods had a moderate accuracy in predicting significant fibrosis (AUROC 0.72-0.78). Based on multilevel likelihood ratios, non-invasive tests provided a relevant gain in the likelihood of diagnosis in 0-60% of patients (cirrhosis) and 9-30% of patients (significant fibrosis). Conclusions: The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Moroch J.,APHP
The American journal of surgical pathology | Year: 2012

Epstein-Barr virus (EBV)-infected B cells with Reed-Sternberg-like cell (RS) features may occur in peripheral T-cell lymphomas (PTCLs), especially in angioimmunoblastic T-cell lymphoma. Here, we report 5 patients presenting with lymphadenopathy whose first biopsies demonstrated nodular lymphoid proliferations containing scattered CD30+, CD15+, EBV+ Hodgkin and Reed-Sternberg-like cells, which led to an initial diagnosis of lymphocyte-rich classical Hodgkin lymphoma. However, the uncommon clinical features and/or the occurrence of relapse as PTCL prompted review of the biopsies with expanded immunohistologic and molecular studies and revision of the diagnoses to follicular variant of PTCL (F-PTCL). All cases had atypical small to medium-sized CD3+ T cells that expressed CD10 (4/5) and the follicular helper T-cell (TFH) antigens BCL6, PD1, CXCL13, and ICOS. All demonstrated clonal T cells with a similar pattern in multiple samples from 4 patients. In 2 cases, flow cytometry demonstrated circulating lymphocytes with an abnormal sCD3+, CD4+, ICOS+ immunophenotype. Two patients had a skin rash at presentation, and 1 had B symptoms. Two of the 4 patients treated with polychemotherapy are alive at 3 and 6 years after first diagnosis. These cases highlight how some F-PTCLs may closely mimic lymphocyte-rich classical Hodgkin lymphoma requiring careful assessment of the T cells before rendering the latter diagnosis. The functional properties of TFH cells might lead to the presence of EBV-positive B blasts with RS-like features in TFH-derived PTCL such as angioimmunoblastic T-cell lymphoma and F-PTCL.


Maillart E.,APHP | Louapre C.,APHP | Lubetzki C.,APHP | Papeix C.,APHP
Multiple Sclerosis Journal | Year: 2014

We report two cases of multiple sclerosis (MS) patients with natalizumab-associated progressive multifocal leukoencephalopathy. Severe MS relapses occurred between four and five months after natalizumab discontinuation. After failure of immunomodulatory treatment, both patients were treated with fingolimod. The outcome was positive on clinical and MRI disease activity, without worsening of the progressive multifocal leukoencephalopathy. These observations suggest that using fingolimod for severe multiple sclerosis after natalizumab-associated progressive multifocal leukoencephalopathy may be an option, under close clinical and radiological monitoring. © The Author(s) 2013.

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