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Aging is characterized, at the systemic level, by the development of low-grade inflammation, which has been identified as determining sarcopenia by blunting postprandial muscle anabolism. The causes of this "inflammageing" is still not clearly defined. An increased intestinal permeability, a microbiota dysbiosis and subsequent generation of intestinal then generalized inflammation have been hypothesized. The objective of this study was to testYoung adult (6 m) and elderly rats (18 m) received Dextran Sodium Sulfate (DSS) for 28 days to generate low-grade intestinal inflammation, and received (PB1 or PB2 groups) or not (DSS group) one of the two S. Thermophilus strains (5 × 10In both adult and old rats, DSS reduced absolute protein synthesis (ASR) in gastrocnemius muscle [-12.4% (PB1) and -9.5% (PB2) vs. PF,The loss of muscle anabolism associated with low-grade intestinal inflammation can be prevented by supplementation with anti-inflammatory CNRZ160 strain. We propose that the moderated gut inflammation by CNRZ160 may result in curtailed amino acids (AA) utilization by the gut, and subsequent restored AA systemic availability to support muscle protein accretion. Therefore, CNRZ160 could be considered as an efficient probiotic to modulate muscle mass loss and limit sarcopenia during aging.

In cancer cells, aberrant DNA methylation is commonly associated with transcriptional alterations, including silencing of tumor suppressor genes. However, multiple epigenetic mechanisms, including polycomb repressive marks, contribute to gene deregulation in cancer. To dissect the relative contribution of DNA methylation–dependent and –independent mechanisms to transcriptional alterations at CpG island/promoter-associated genes in cancer, we studied 70 samples of adult glioma, a widespread type of brain tumor, classified according to their isocitrate dehydrogenase (IDH1) mutation status. We found that most transcriptional alterations in tumor samples were DNA methylation–independent. Instead, altered histone H3 trimethylation at lysine 27 (H3K27me3) was the predominant molecular defect at deregulated genes. Our results also suggest that the presence of a bivalent chromatin signature at CpG island promoters in stem cells predisposes not only to hypermethylation, as widely documented, but more generally to all types of transcriptional alterations in transformed cells. In addition, the gene expression strength in healthy brain cells influences the choice between DNA methylation- and H3K27me3-associated silencing in glioma. Highly expressed genes were more likely to be repressed by H3K27me3 than by DNA methylation. Our findings support a model in which altered H3K27me3 dynamics, more specifically defects in the interplay between polycomb protein complexes and the brain-specific transcriptional machinery, is the main cause of transcriptional alteration in glioma cells. Our study provides the first comprehensive description of epigenetic changes in glioma and their relative contribution to transcriptional changes. It may be useful for the design of drugs targeting cancer-related epigenetic defects.

International audience; Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls ( P = 0.001); half were previously unknown (AF < 0.000002). MYO6 , MYO7A , PTPRQ , and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1 N321I/+ mice, carrying the TMC1 :p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

International audience; Background: Meningeal melanocytoma (MM) is a locally aggressive, low-grade primary melanocytic tumor of the central nervous system (PMN-CNS). According to the literature, GNAQ and GNA11 mutations are relatively frequent. In contrast, BRAF and NRAS mutations are very rare. Other series have reported BAP1 mutation, monosomy 3 and gain of chromosome 6. In this paper, we discussed two cases of MM for whom a FoundationOne CDxTM assay was performed.Results: Case report 1: A 48 year old man was diagnosed with intermediate-grade MM based on histological assessment, which is consistent with the clinical evolution. The FoundationOne CDxTM assay detected a SF3B1 mutation, usually found in 15% of uveal melanomas. This mutation is correlated with improved progression-free survival in uveal melanomas. Case report 2: A 39 year old women was diagnosed with MM. Her evolution wasn’t expected based on histology only; her history didn’t match with rather benign histological features microscopically. The FoundationOne CDxTM assay provided two interesting elements: first, the tumour was positive for CDKN2A p16INK4a M52fs*1 and p14ARF H66fs*106 mutations, most commonly found in cutaneous melanomas. Secondly, a GNA11 Q209L mutation, known to be a marker of aggressiveness in uveal melanoma, was detected.Conclusion: The identification of molecular alterations in PMN-CNS, in addition to immunohistochemical analysis could provide a better understanding of the biological and clinical behaviour of these tumours, a better identification of melanocytic melanomas with poor prognosis and a high risk of relapse or metastasis, and the development of novel therapeutic options for these patients.

Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome in child and adult. The collapsing forms are of poor renal prognosis and are usually secondary to viral infections with, first and foremost, the human immunodeficiency virus. Among other viral etiologies, cytomegalovirus (CMV) is an uncommon cause. We report a case of a 32years-old patient with collapsing focal segmental glomerulosclerosis induced by cytomegalovirus with initial acute renal failure and proteinuria at 12.4g/24h. The treatment associated ganciclovir during 7days followed by valganciclovir during 14days and steroids at 1mg/kg/day. Renal function improved and proteinuria decreased with this treatment. Proteinuria increase again 3weeks after valganciclovir discontinuation while CMV Polymerase chain reaction (PCR) was positive. Therefore, valganciclovir has been resumed allowing renal function normalization and decrease in proteinuria to 4g/24h after negative CMVPCR assay after 15weeks. Anti-CMV therapy combined with steroids seems to provide a renal response in case of FSGS induced by CMV even if long-term prognosis stays uncertain.

Kidney disease in the setting of a hematologic malignancy is common, with the frequency and type of kidney disease varying depending on the specific malignancy. Various glomerular diseases and tumor infiltration of the kidneys have been reported in patients with lymphoproliferative disorders. Descriptions of kidney involvement in myeloproliferative disorders have been much rarer. We report a case of membranous nephropathy accompanied by kidney injury in a patient with primary myelofibrosis with additional features considered related to the patient's myeloproliferative disorder. A 63-year-old patient with primary myelofibrosis underwent kidney biopsy to investigate nephrotic-range proteinuria and reduced kidney function. Histologic analysis revealed mesangial sclerosis and hypercellularity, changes indicative of membranous nephropathy, and infiltration of hematopoietic cells into the renal interstitium, peritubular capillaries, and perirenal tissue consistent with extramedullary hematopoiesis. He was treated with renin-angiotensin blockade and a Janus kinase inhibitor, resulting in improvement in kidney function and proteinuria.

Monoclonal gammopathy of renal significance (MGRS) can manifest in many different ways depending on the nature of the immunoglobulin and its physicochemical properties. MGRS can lead to the discovery of a hematological malignancy. We report the case of a 32-year-old female patient who underwent renal biopsy on account of an impure nephrotic syndrome associated with immunoglobulin (Ig)G κ monoclonal gammopathy. Histological analysis revealed membranoproliferative glomerulonephritis with IgG, IgM, κ, λ, and C3 deposits. Due to an unfavorable progression, a second renal biopsy was performed. Electron microscopy analysis revealed an immunotactoid glomerulopathy. At the same time, a POEMS syndrome diagnosis (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormalities) was confirmed in light of the following: 1) IgG κ monoclonal gammopathy, 2) axonal neuropathy, 3) osteosclerosis, 4) melanoderma, 5) hepatosplenomegaly and adenopathies, 6) Castleman disease, and 7) edema. Our observation is the first case of immunotactoid glomerulopathy leading to the discovery of a POEMS syndrome. Renal involvement in POEMS syndrome typically exhibits a thrombotic microangiopathy-like membranoproliferative glomerulonephritis appearance associated with endothelial lesions stigmata. However, monoclonal immunoglobulin deposition disorder should be considered in the event of an atypical case. In this indication, electron microscopy is the examination of choice for assessing immunoglobulin deposition nephropathy. .

Introduction/objectifs Le cancer du poumon est la premiere cause de mortalite en France et dans le monde. Le cancer bronchique non a petites cellules (CBNPC) est le sous-type histologique le plus frequent. Malgre les progres therapeutiques recents avec notamment l’introduction d’immunotherapie, le CBNPC est souvent diagnostique a stade avance et son pronostic est pejoratif. La dysfonction des telomeres est une etape cle du processus tumoral et l’etude du statut telomerique dans le CBNPC pourrait apporter les nouveaux biomarqueurs pour mieux evaluer le pronostic et la reponse au traitement. Nous avons recherche une correlation entre le statut telomerique et la survie dans le CBNPC metastatique. Patients et methodes Les acides nucleiques (ADN et ARN) ont ete extraits a partir de 89 biopsies tumorales. Le statut telomerique a ete evalue par la longueur des telomeres, l’expression de TERT (telomerase) et des genes du complexe Shelterin impliques dans la regulation de la maintenance des telomeres (TRF1, TRF2, POT1, TPP1, RAP1 et TIN2) par PCR quantitative. Resultats Des telomeres courts et une surexpression de TERT etaient associes a la survie globale (SG) plus courte (p = 0,0053 et p = 0,05, respectivement). Une forte expression de TRF2 (p = 0,025) et une faible expression de RAP1 et TIN2 (p = 0,0037 et p = 0,017, respectivement) etait egalement correlee a la SG reduite. De facon tres interessante, un raccourcissement des telomeres influencait negativement la SG dans le sous-groupe de patients ayant recu une immunotherapie (p = 0,0037). Conclusion A notre connaissance, il s’agit de la premiere etude analysant le statut telomerique dans le CBNPC metastatique. Nous avons demontre que la dysfonction telomerique etait associee au mauvais pronostic et a la resistance au traitement. Ainsi, la determination de ces parametres pourrait permettre d’ajuster les therapies proposees aux patients et represente une voie d’espoir pour le developpement de nouveaux traitements cibles.

BackgroundAberrant DNA methylation is a cancer cell feature that is commonly associated with transcriptional alterations. However, the primary role of this defect in the genome-wide cancer-associated gene deregulation is not clear. Here, we evaluated the relative contribution of DNA methylation-dependent and -independent mechanisms to transcriptional alterations at CpG-island/promoter-associated genes in samples of adult glioma, a widespread type of brain tumor.ResultsExtensive molecular analyses of glioma samples with wild type IDH (IDHwt) and mutated IDH (IDHmut) found DNA hypermethylation only in a minority of genes showing loss or gain of expression. Specifically, in IDHwt samples, more than 75% of aberrantly repressed genes did not display DNA methylation defects at their CpG-island promoter. Conversely, altered H3K27me3 was the predominant molecular defect at deregulated genes. Moreover, the presence of a bivalent chromatin signature at CpG-island promoters in stem cells might not only predispose to hypermethylation, as widely documented, but more generally to all types of transcriptional alterations in transformed cells. In addition, the gene expression strength in healthy brain cells influences the choice between DNA methylation- and H3K27me3-associated silencing in glioma. Our findings support a model whereby the altered control of H3K27me3 dynamics, more specifically defects in the interplay between polycomb protein complexes and the brain-specific transcriptional machinery, is the main cause of transcriptional alteration in glioma cells.ConclusionsOur study provides a comprehensive and updated description of the epigenetic deregulations in glioma that could be useful for the design of drugs to target cancer-related epigenetic defects.

International audience; BACKGROUND: Deregulation of cholesterol metabolism represents a hallmark of prostate cancer (PCa) and promotes its development. OBJECTIVE: To compare cholesterol metabolism on individual paired normal and tumour prostate tissues obtained from patients with PCa. DESIGN, SETTING, AND PARTICIPANTS: Between 2008 and 2012, normal and tumour paired tissue samples were collected from radical prostatectomy specimens from a cohort of 69 patients treated for localised PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tumour and normal tissues were subjected to gene analysis, sterol measurement, and immunohistochemistry. The Wilcoxon paired test and Spearman test were applied for comparison and correlation analyses, respectively. Principal component analysis was also carried out to investigate relationships between quantitative variables. RESULTS AND LIMITATIONS: Overall, cholesterol concentrations were not significantly different between tissue pairs. However, tumour samples were significantly associated with downregulated de novo cholesterol synthesis, but exhibited 54.7% overexpression of SCARB1 that could increase high-density lipoprotein uptake in PCa. Tumour tissues showed different trafficking of available cholesterol, with significantly lower ACAT1, and an altered efflux via APOE. Furthermore, cholesterol metabolism in tumour tissues was characterised by higher accumulation of 7alpha-hydroxycholesterol (OHC), 7betaOHC, and 7-ketosterol, and a lower level of 27OHC. CONCLUSIONS: Focusing on individually paired prostate tissues, our results highlighted several differences between normal and tumour samples linked to a metabolic shift in cholesterol flux. PCa samples exhibited a specific tissue signature characterised by higher SCARB1 expression, higher accumulation of OHC species, and clear downregulation of de novo cholesterol synthesis. PATIENT SUMMARY: Comparing normal and tumour tissues from the same prostates, our study identified a set of alterations in prostate cancer samples in terms of their use of cholesterol. These included higher cholesterol uptake, accumulation of oxidised cholesterol derivatives, and autonomous cellular production of cholesterol. Together, these data provide promising clinical targets to fight prostate cancer.

Rationale: Kidney transplantation is considered the best treatment for patients with end stage renal disease. Ischemia- reperfusion injury (IRI) is an evitable event after deceased donor transplantation and influences short term and long term graft outcome. Few data on IRI's histology in the setting of kidney transplantation are available in the literature despite its frequency and its severity. Patient concerns: A 64-year-old patient was admitted for his 1st kidney transplantation. There were no pre-existing immunization. The surgery proceeded without complications; with cold ischemia estimated at 37 h 50 min and warm ischemia at 44 min. The immunosuppression protocol was as follows: induction by thymoglobulins, mycophelonate mofetil, corticosteroids. Few hours after transplantation, the patient remained anuric and the biological assessment highlighted in addition to renal failure, hyperlactatemia at 5 mmol/L and a high increase in lactate deshydrogenase (LDH) at 5239 U/L. An abdominopelvic angio-scanner was performed urgently to eliminate the hypothesis of thrombosis of the artery or vein of the graft. A kidney biopsy was performed the day after the transplant and revealed massive lesions of acute tubular necrosis including apoptosis, autophagy-associated cell death, and necrosis. Microvascular dysfunction with increased vascular permeability and endothelial cell inflammation were also present. Activation of coagulation is represented by thrombi in the lumens of the glomerular capillaries. Diagnosis: The diagnosis was ischemia reperfusion injury responsible for delayed graft function (DGF). Interventions: Immunosuppressive regimen was delayed use of calcineurin inhibitors, mycophenolate mofetil, and corticosteroids. Outcomes: At 1 year post transplant, the patient has a renal autonomy with a graft function stable and physiological proteinuria. Lessons: The main clinical consequences of IRI in kidney transplant are DGF, acute and chronic graft rejection, and chronic graft dysfunction. Reducing IRI is one of the most relevant challenge in kidney transplantation.

International audience; Signal Transducer and Activator of Transcription 3 (STAT3) is aberrantly activated in glioblastoma and has been identified as a relevant therapeutic target in this disease and many other human cancers. After two decades of intensive research, there is not yet any approved STAT3-based glioma therapy. In addition to the canonical activation by tyrosine 705 phosphorylation, concordant reports described a potential therapeutic relevance of other post-translational modifications including mainly serine 727 phosphorylation. Such reports reinforce the need to refine the strategy of targeting STAT3 in each concerned disease. This review focuses on the role of serine 727 and tyrosine 705 phosphorylation of STAT3 in glioma. It explores their contribution to glial cell transformation and to the mechanisms that make glioma escape to both immune control and standard treatment.

The place of radiosurgery (RS) as an option in the treatment of recurrent malignant glioma is still debated on in the absence of prospective randomized trials.To assess the clinical outcome and MRI response after radiosurgery of recurrent malignant glioma.We evaluated 50 consecutive patients treated in a single institution. Between 2001 and 2008, 34 glioblastoma (GBM) and 16 anaplastic oligodendroglioma (AO) patients were treated with linear accelerator (Linac) RS for recurrence.The median marginal dose was 15 Gy and the median gross tumor volume (GTV) was 6.64 ml. No patient had acute (3 months) neurological morbidity after RS. Ten patients (20%) were reoperated on after RS, histopathological findings included necrosis alone in 3 cases (6%). The median overall survival was 21.5 months for GBM and 57.9 months for AO. The median survival after RS was 9.5 months for GBM and 32.9 months for AO. The median progression-free survival after RS was 6.7 months for GBM and 18 months for AO. MRI volume modifications after RS showed a transitory reduction or stabilization of disease linked to significantly improved survival in 58.8% of patients with GBM, 81.1% of patients with AO. Pathological subtype (AO versus GBM), MRI response, KPS70, marginal dose13 Gy, largest diameter of GTV25 mm and GTV7 ml were the main prognostic factors, associated with improved survival or PFS from RS.The magnitude of the survival increase compared to historical RPA classes may not be due to selection bias alone. Linac RS in selected patients with recurrent malignant glioma was well tolerated, effective and can be considered as one of several re-treatment options.

Background Open lung biopsy (OLB) is a rare procedure in intensive care units (ICUs) for therapeutic management of acute respiratory failure (ARF). The purpose of this study was to analyze the diagnostic yield, therapeutic contribution and complications of OLB in ICU patients with ARF of unclear etiology, including acute respiratory distress syndrome (ARDS) and ARDS mimics. Methods Retrospective study conducted in a 10-bed ICU over a 13-year period. Patients undergoing OLB for ARF with undiagnosed infiltrates on CT scan were included. ARDS was defined according to Berlin criteria, and ARDS mimics as a condition looking like ARDS except for the presence of a known cause. OLB was contributive when the OLB findings yielded a specific diagnosis resulting in a change in the patients' treatment or management. Results Forty six patients were included (sex ratio = 2.5, median and [interquartile range] age = 69 [59-77] years, and admission SAPS II = 42 [33-50]. ARF corresponded to ARDS in 22 patients and to ARDS mimics in 16. OLB yielded 61 diagnoses in 45 patients including diffuse alveolar damage (N = 21), lung fibrosis (N = 18), and organizing pneumonia (N = 11). OLB was contributive in 37 patients (80%), including 13/16 ARDS mimickers. The main contributions of OLB were the introduction or maintenance of steroids (N = 32) and discontinuation of antibiotics (N = 9). In 4 patients OLB resulted directly in the decision to forgo life-sustaining treatment. OLB complications occurred in 16 patients (35%), in one case associated with fatal outcome. Conclusion OLB can play a useful role in the management of ICU patients with ARF of undetermined origin, including ARDS mimickers. Further studies should be done to identify the groups of ICU patients likely to benefit from the procedure with minimum risk.

Objectives Cutaneous manifestations (CM) in ANCA-associated vasculitides (AAV) are frequent, but data on clinical significance and clinical-pathological correlations are lacking. Methods We conducted a multicenter, retrospective study including 1553 AAV patients. Clinical, biological and pathological features have been analyzed, and tissue samples from 46 biopsies were reviewed in a blind manner. Results CM were more frequent in EGPA (53.0%) and MPA (51.9%) than in GPA (36.7%). Lesions more frequently associated with GPA were oral ulcers (4.6% vs. 2.5% in EGPA and 0.3% in MPA), while pyoderma gangrenosum and palpebral xanthoma were specific to GPA. Lesions associated with MPA were segmentary edema (19.5% vs. 12.7% in EGPA and 4.3% in GPA) and livedo (12.4% vs. 0.5% and 2.6%, respectively), whereas those associated with EGPA were urticarial lesions (11.5% vs. 1.9% in GPA and 3.5% in MPA) and nodules (12,2% vs. 8.9% in GPA and 4.7% in MPA). In GPA, CM patients had more frequent vasculitis than granulomatous phenotype, and poorer relapse-free and overall survival. Pathological analysis showed vasculitis and/or granulomatous infiltrates in 87.5% of GPA, in 61.1% of EGPA and in all MPA. Vasculitis was more frequently observed in purpura and nodules, while granulomas were differently located and organized within vessels or interstitium according to the type of lesions. Conclusion Each AAV seemed to be associated with a peculiar pattern of cutaneous lesions. CM are associated with poorer prognosis in GPA. Clinical-pathological correlations showed no specific feature of each AAV, whereas granulomatous infiltrates differ according to the type of lesions.

Revue du rhumatisme - In Press.Proof corrected by the author Available online since vendredi 29 septembre 2017

Radiotherapy is an essential component of glioma standard treatment. Glioblastomas (GBM), however, display an important radioresistance leading to tumor recurrence. To improve patient prognosis, there is a need to radiosensitize GBM cells and to circumvent the mechanisms of resistance caused by interactions between tumor cells and their microenvironment. STAT3 has been identified as a therapeutic target in glioma because of its involvement in mechanisms sustaining tumor escape to both standard treatment and immune control. Here, we studied the role of STAT3 activation on tyrosine 705 (Y705) and serine 727 (S727) in glioma radioresistance. This study explored STAT3 phosphorylation on Y705 (pSTAT3-Y705) and S727 (pSTAT3-S727) in glioma cell lines and in clinical samples. Radiosensitizing effect of STAT3 activation down-modulation by Go6976 was explored. In a panel of 15 human glioma cell lines, we found that the level of pSTAT3-S727 was correlated to intrinsic radioresistance. Moreover, treating GBM cells with Go6976 resulted in a highly significant radiosensitization associated to a concomitant pSTAT3-S727 down-modulation only in GBM cell lines that exhibited no or weak pSTAT3-Y705. We report the constitutive activation of STAT3-S727 in all GBM clinical samples. Targeting pSTAT3-S727 mainly in pSTAT3-Y705-negative GBM could be a relevant approach to improve radiation therapy.

Diffuse adult high-grade gliomas (HGGs) with necrosis encompass anaplastic oligodendrogliomas (AOs) with necrosis (grade III), glioblastomas (GBM, grade IV) and glioblastomas with an oligodendroglial component (GBMO, grade IV). Here, we aimed to search for prognostic relevance of histological classification and molecular alterations of these tumors. About 210 patients were included (63 AO, 56 GBM and 91 GBMO). GBMO group was split into "anaplastic oligoastrocytoma (AOA) with necrosis grade IV/GBMO," restricted to tumors showing intermingled astrocytic and oligodendroglial component, and "GBM/GBMO" based on tumors presenting oligodendroglial foci and features of GBM. Genomic arrays, IDH1 R132H expression analyses and IDH direct sequencing were performed. 1p/19q co-deletion characterized AO, whereas no IDH1 R132H expression and intact 1p/19q characterized both GBM and GBM/GBMO. AOA with necrosis/GBMO mainly demonstrated IDH1 R132H expression and intact 1p/19q. Other IDH1 or IDH2 mutations were extremely rare. Both histological and molecular classifications were predictive of progression free survival (PFS) and overall survival (OS) (P < 10(-4) ). Diffuse adult HGGs with necrosis can be split into three histomolecular groups of prognostic relevance: 1p/19q co-deleted AO, IDH1 R132H-GBM and 1p/19q intact IDH1 R132H+ gliomas that might be classified as IDH1 R132H+ GBM. Because of histomolecular heterogeneity, we suggest to remove the name GBMO.

Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome in child and adult. The collapsing forms are of poor renal prognosis and are usually secondary to viral infections with, first and foremost, the human immunodeficiency virus. Among other viral etiologies, cytomegalovirus (CMV) is an uncommon cause. We report a case of a 32years-old patient with collapsing focal segmental glomerulosclerosis induced by cytomegalovirus with initial acute renal failure and proteinuria at 12.4g/24h. The treatment associated ganciclovir during 7days followed by valganciclovir during 14days and steroids at 1mg/kg/day. Renal function improved and proteinuria decreased with this treatment. Proteinuria increase again 3weeks after valganciclovir discontinuation while CMV Polymerase chain reaction (PCR) was positive. Therefore, valganciclovir has been resumed allowing renal function normalization and decrease in proteinuria to 4g/24h after negative CMVPCR assay after 15weeks. Anti-CMV therapy combined with steroids seems to provide a renal response in case of FSGS induced by CMV even if long-term prognosis stays uncertain.

International audience; Human malignant gliomas exhibit acquisition of either one of two telomere maintenance mechanisms, resulting from either reactivation of telomerase expression or activation of an alternative lengthening of telomeres (ALT) mechanism. In the present study, we analyzed 63 human malignant gliomas for the presence of ALT-specific extrachromosomal circles of telomeric DNA (C-circles) and measured telomerase expression, telomeric DNA content (Telo/Alu method), and telomeric repeat-containing RNAs (TERRA) levels. We also assessed histomolecular markers routinely used in clinical practice. The presence of C-circles significantly correlated with IDH1/2 mutation, MGMT exon 1 methylation, low Ki-67 immunostaining, increased telomeric DNA content, absence of functional ATRX protein and level of HTERT gene expression. In multivariate analysis, we observed a trend to a correlation between elevated TERRA levels and increased survival. Interestingly, the C-circles assay allowed to detect ALT activation in glioblastomas exhibiting wild-type IDH1/2 and ATRX expression. These results suggest that, after the correlations uncovered here have been confirmed on larger numbers of tumors, telomeric markers might be useful in improving diagnosis. They also point out to the utility of using the specific, sensitive and quantitative C-circle and Telo/Alu assays that can work with as few as 30 ng of tumor DNA

Joint Bone Spine - In Press.Proof corrected by the author Available online since samedi 25 fevrier 2017

BACKGROUND: The aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs). METHODS: The MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays. RESULTS: Most of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2. CONCLUSION: In AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume.

In men at high risk for prostate cancer, established clinical and pathological parameters provide only limited prognostic information. Here we analyzed a French cohort of 103 prostate cancer patients and developed a gene panel model predictive of outcome in this group of patients. The model comprised of a 15-gene TaqMan Low-Density Array (TLDA) card, with gene expressions compared to a standardized reference. The RQ value for each gene was calculated, and a scoring system was developed. Summing all the binary scores (0 or 1) corresponding to the 15 genes, a global score is obtained between 0 and 15. This global score can be compared to Gleason score (0 to 10) by recalculating it into a 0–10 scaled score. A scaled score ≥2 suggested that the patient is suffering from a prostate cancer, and a scaled score ≥7 flagged aggressive cancer. Statistical analyses demonstrated a strongly significant linear correlation (p=3.50E-08) between scaled score and Gleason score for this prostate cancer cohort (N=103). These results support the capacity of this designed 15 target gene TLDA card approach to predict outcome in prostate cancer, opening up a new avenue for personalized medicine through future independent replication and applications for rapid identification of aggressive prostate cancer phenotypes for early intervention.

Acute kidney injury (AKI) is a major complication in patients with liver disease. Although hepatorenal syndrome is frequently involved, bile cast nephropathy, characterized by tubular bile cast formation, has been scarcely described in the setting of severe liver failure. Few renal histology studies are available in these patients. We describe a case of bile cast nephropathy in a patient with obstructive cholestasis caused by stones in the common bile duct. The kidney biopsy confirmed this diagnosis, with several green casts in tubular lumens, tubular injury, and bilirubin composition of the tubular casts with Hall stain. The patient had no confounding cause of kidney failure, and complete kidney recovery followed removal of the bile duct obstruction. This case shows that severe cholestasis is sufficient to cause AKI, and that AKI can be reversible after treatment of the biliary obstruction.

Malignant gliomas are the most common primary brain tumors. Grade III and IV gliomas harboring wild-type IDH1/2 are the most aggressive. In addition to surgery and radiotherapy, concomitant and adjuvant chemotherapy with temozolomide (TMZ) significantly improves overall survival (OS). The methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter is predictive of TMZ response and a prognostic marker of cancer outcome. However, the promoter regions the methylation of which correlates best with survival in aggressive glioma and whether the promoter methylation status predictive value could be refined or improved by other MGMT-associated molecular markers are not precisely known. In a cohort of 87 malignant gliomas treated with radiotherapy and TMZ-based chemotherapy, we retrospectively determined the MGMT promoter methylation status, genotyped single nucleotide polymorphisms (SNPs) in the promoter region and quantified MGMT mRNA expression level. Each of these variables was correlated with each other and with the patients' OS. We found that methylation of the CpG sites within MGMT exon 1 best correlated with OS and MGMT expression levels, and confirmed MGMT methylation as a stronger independent prognostic factor compared to MGMT transcription levels. Our main finding is that the presence of only the A allele at the rs34180180 SNP in the tumor was significantly associated with shorter OS, independently of the MGMT methylation status. In conclusion, in the clinic, rs34180180 SNP genotyping could improve the prognostic value of the MGMT promoter methylation assay in patients with aggressive glioma treated with TMZ., ARC -Fondation ARC pour la Recherche sur le Cancer(EML20120904843)

"L'article original est publié par The Endocrine Society"; Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα(-/-)) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα(-/-) prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα(-/-) mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα(-/-) mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.

Joint Bone Spine - In Press.Proof corrected by the author Available online since lundi 20 juin 2016

Resume Les spondylodiscites sont frequentes et posent des problemes diagnostiques aux cliniciens. Si l’atteinte axiale du rhumatisme a cristaux de pyrophosphate de calcium (PPCa) est bien connue concernant le rachis cervical, avec le syndrome de la dent couronnee, d’autres localisations rachidiennes sont probablement meconnues comme dans le cas d’une spondylodiscite aseptique. Nous rapportons ici le cas d’une spondylodiscite aseptique recidivante, comportant un abces epidural, due a un rhumatisme a PPCa prouvee par l’examen de la biopsie vertebrale percutanee et dont l’evolution a ete rapidement favorable grâce a un traitement par colchicine. L’atteinte axiale de ce rhumatisme microcristallin peut prendre l’aspect d’une spondylodiscite infectieuse avec un abces epidural a l’IRM. Les spondylodiscites aseptiques constituent probablement des atteintes meconnues des arthropathies microcristallines. La recherche de microcristaux a l’examen de la biopsie devrait etre systematique en utilisant des coupes fixees par le formol tamponne. Si une atteinte axiale de rhumatisme a PPCa est suspectee, un traitement par la colchicine peut constituer un test therapeutique et eviter une antibiotherapie inutile.

Spondylodiscitis are frequent and clinical challenge for practionners. Axial calcium pyrophosphate dihydrate deposition disease (CPDD) is well known for cervical spine involvement with the crowned dens syndrome but other localisations are probably underdiagnosed in sterile spondylodiscitis. We report a case of recurrent sterile spondylodiscitis with epidural abscess related to CPDD proved by vertebral percutaneous needle biopsy with rapid favourable course under colchicine therapy. Axial CPDD could mimic septic spondylodiscitis with epidural abscess on MRI. Sterile spondylodiscitis are probably underdiagnosed forms of microcrystalline disease. Investigations of the presence of microcrystals should be systematically undertaken with tamponed formalin fixed biopsies. If axial CPDD is suspected, colchicine therapy could be a good therapeutic test and would avoid unnecessary antibiotic treatment.

Background: Gliomas constitute the vast majority of primary central nervous system tumors in adults. Glioblastoma multiforme (GBM) is the most aggressive form of these primary brain tumors. There is a need to define diagnostic and prognostic markers that may help to distinguish GBM from non-GBM tumors. The Krüppel-like factor 6 (KLF6) gene has recently emerged as a promising candidate. The goal of our study was to determine if there is a link between KLF6 splice variants expression and different grades of gliomas. Methods: Fifty-three primary gliomas tumor samples were analyzed using quantitative real-time PCR for the total KLF6, wild-type and alternatively spliced (SV1) KLF6 mRNA. Results: Compared to the non-GBM group, the GBM group had a 2.2-fold increase in the mean level of total KLF6 mRNA expression. GBM showed a 2.1-fold increase in the KLF6 splicing ratio. In addition, KLF6-SV1 mRNA expression levels were also 2.2-fold higher in the GBM group, suggesting that the increase in the KLF6 splicing ratio was due to increased expression of the KLF6-SV1 oncogenic splice variant. Conclusions: Our study demonstrates that quantification of total and spliced forms of KLF6 may provide a new and useful supplementary molecular tool for grading glioma. Clin Chem Lab Med 2010;48:1167–70.

Resume Le Rituximab est un anticorps monoclonal chimerique anti-CD20, dont la toxicite pulmonaire reste exceptionnelle. De nombreux tableaux cliniques peuvent etre observes, pneumopathie interstitielle, hemorragie intra-alveolaire, syndrome de detresse respiratoire aigue. Trois observations de pneumopathie organisee (PO) auparavant appelee bronchiolite obliterante avec pneumopathie organisee (BOOP) ont ete rapportees. Nous avons observe deux cas chez les 25 patients que nous avons traites par Rituximab. L’une est survenue chez une patiente traitee pour une polyarthrite rhumatoide l’autre chez une patiente traitee pour une maladie de Castleman, Le caractere parfois asymptomatique comme dans une de nos observations, nous semble devoir justifier, avant la readministration de Rituximab, la realisation d’une radiographie pulmonaire.

Rituximab, a chimeric monoclonal antibody against CD20, very rarely causes lung toxicity. Clinical presentations include lung infiltrates, alveolar hemorrhage, and adult respiratory distress syndrome. Three cases of organizing pneumoinia (formerly called bronchiolitis obliterans with organizing pneumonia or BOOP) have been reported. In our experience, organizing pneumonia occurred in 2 of 25 patients treated with rituximab, for RA and Castleman's disease, respectively. Because organizing pneumonia may be asymptomatic, as illustrated by one of our cases, we recommend obtaining a chest radiograph routinely before rituximab re-treatment.

International audience; The aim of the present study was to assess the rate of diffuse alveolar damage (DAD) on open lung biopsy (OLB) performed in the ICU for nonresolving ARDS.METHODS:A single-center retrospective study of patients meeting the Berlin definition criteria for ARDS who had undergone OLB for nonresolving ARDS. Patients were classified into mild, moderate and severe ARDS categories and according to the presence or absence of DAD on the OLB. The ARDS categories were assessed at baseline and at the time of the OLB. The OLBs were reviewed by two pathologists blinded to the ARDS classification. The primary endpoint was the rate of DAD according to the ARDS stage in the patients with nonresolving ARDS who had OLB. The secondary endpoint was the ability of DAD to predict ARDS among all the patients who had OLB. The same clinico-histopathological confrontation was cross validated in another ICU.RESULTS:From January 1998 to August 2013, 113 patients underwent OLB for acute hypoxemic respiratory failure, 83 of whom met the inclusion criteria for ARDS. At the time the OLB was performed, 11 of these patients had mild, 56 moderate, and 16 severe ARDS, respectively. The median (1st-3rd quartiles) time to OLB was 13 (10-18) and 9 (6-14) days from the onset of respiratory symptoms and from ARDS onset, respectively, with no statistical difference between the three ARDS groups. DAD was found in 48 (58 %) patients with ARDS, 4 (36 %) in the mild, 33 (59 %) in the moderate, and 11 (69 %) in the severe stage (P = 0.23). For the 113 patients who underwent OLB, the sensitivity and specificity of DAD to the Berlin definition was 0.58 (0.46-0.69) and 0.73 (0.54-0.88), respectively. Similar results were found in the other ICU.CONCLUSIONS:DAD is present in the majority of patients with nonresolving ARDs and its frequency is no different across the three ARDS stages. On this basis, the systematic use of steroids in nonresolving ARDS is not recommended.

Radiotherapy is an essential component of glioma standard treatment. Glioblastomas (GBM), however, display an important radioresistance leading to tumor recurrence. To improve patient prognosis, there is a need to radiosensitize GBM cells and to circumvent the mechanisms of resistance caused by interactions between tumor cells and their microenvironment. STAT3 has been identified as a therapeutic target in glioma because of its involvement in mechanisms sustaining tumor escape to both standard treatment and immune control. Here, we studied the role of STAT3 activation on tyrosine 705 (Y705) and serine 727 (S727) in glioma radioresistance. This study explored STAT3 phosphorylation on Y705 (pSTAT3‐Y705) and S727 (pSTAT3‐S727) in glioma cell lines and in clinical samples. Radiosensitizing effect of STAT3 activation down‐modulation by Gö6976 was explored. In a panel of 15 human glioma cell lines, we found that the level of pSTAT3‐S727 was correlated to intrinsic radioresistance. Moreover, treating GBM cells with Gö6976 resulted in a highly significant radiosensitization associated to a concomitant pSTAT3‐S727 down‐modulation only in GBM cell lines that exhibited no or weak pSTAT3‐Y705. We report the constitutive activation of STAT3‐S727 in all GBM clinical samples. Targeting pSTAT3‐S727 mainly in pSTAT3‐Y705‐negative GBM could be a relevant approach to improve radiation therapy.

Gliomas are the most common of primary brain tumours in humans and form a complex group because of the great variability in degree of malignancy that exists among them. The grade of malignancy is one of the major factors in the prognosis of glioma patients (DeAngelis, 2001). Patients with low-grade tumours typically survive more than 5 years, patients with anaplastic tumours about 3 years, and patients with glioblastoma multiforme (GBM), glioma of the highest grade of malignancy, have the poorest prognosis with median survival of less than 1 year despite modern therapy. Molecular genetic research has led to an increased knowledge of markers that are associated with glioma malignancy and may be useful diagnostic and therapeutic targets. In particular, malignant progression in gliomas has been correlated with the presence of telomerase activity in tumour cells (Langford et al, 1995). Telomerase is a specialised reverse transcriptase enzyme that maintains telomeres by adding telomeric TTAGGG repeats to the ends of human chromosomes (Morin, 1989). Telomerase is repressed in most normal human somatic cells, and without new synthesis of telomeres the chromosomes shorten with progressive cell division, eventually triggering either replicative senescence or apoptosis when telomere length becomes critically short (Harley et al, 1990). In contrast, cells that express a sufficient level of telomerase activity escape from replication limitations and are considered as immortal. Reactivation of telomerase is believed to be an essential step during malignant tumour progression (Counter et al, 1994). A strong association between the presence of telomerase and malignancy has been established in nearly all cancer types (reviewed in Shay et al, 2001). Importantly, high telomerase activity is generally associated with high tumour aggressiveness. Studies of gliomas have shown that more than 50% of tumours have telomerase activity, detection rates increasing with the grade of malignancy (Langford et al, 1995; Nakatani et al, 1997; Le et al, 1998; Sugita et al, 2000). These observations have suggested that the presence of such activity may indicate the malignant potential of a glioma. However, the prognostic value of telomerase in gliomas remains uncertain. Although telomerase activity has been correlated with inferior survival in low-grade and anaplastic astrocytomas, no clear relation has been determined between the detection or relative level of telomerase activity and patient survival in GBMs, the most common and most malignant gliomas (Nakatani et al, 1997; Hiraga et al, 1998; Huang et al, 1999; Kleinschmidt-Demasters et al, 2000). The activation of telomerase is tightly regulated at the transcriptional level of the human telomerase reverse transcriptase (hTERT). Many studies have suggested that the transcription of hTERT represents the rate-limiting step in telomerase expression, and the detection of hTERT transcripts using RT–PCR revealed a strong correlation with telomerase activity in the majority of tumours (reviewed in Pool et al, 2001). A recent method of real-time PCR has greatly facilitated sensitive and quantitative detection of hTERT mRNA. In this study, we evaluated the level of hTERT transcripts in 70 primary gliomas and correlated them with malignancy grade. In GBMs, we also studied the relation between the amount of hTERT mRNA and patient survival. We found that hTERT expression increased with malignancy grade and was highly associated with GBMs. Within this important glioma subgroup, the level of hTERT mRNA was predictive of patient survival.

Background It is well established that genetic and epigenetic alterations are common events in prostate cancer, which may lead to aberrant expression of critical genes. The importance of epigenetic mechanisms in prostate cancer carcinogenesis is increasingly evident. In this study, the focus will be on histone modifications and the primary objectives are to map H3K27me3 marks and quantify RAR beta 2, ER alpha, SRC3, RGMA, PGR, and EZH2 gene expressions in prostate cancer tissues compared to normal tissues. In addition, a data analysis was made in connection with the clinicopathological parameters. Methods 71 normal specimens and 66 cancer prostate tissues were randomly selected in order to assess the proportion of the repressive H3K27me3 mark and gene expression. H3K27me3 level was evaluated by ChIP-qPCR and mRNA expression using RT-qPCR between prostate cancer and normal tissues. Subsequently, western-blotting was performed for protein detection. The analysis of variance (ANOVA) was performed, and Tukey’s test was used to correct for multiple comparisons (p-value threshold of 0.05). The principal component analysis (PCA) and discriminant factorial analysis (DFA) were used to explore the association between H3K27me3 level and clinicopathological parameters. Results The study demonstrated that H3K27me3 level was significantly enriched at the RAR beta 2, ER alpha, PGR, and RGMA promoter regions in prostate cancer tissues compared to normal tissues. After stratification by clinicopathological parameters, the H3K27me3 level was positively correlated with Gleason score, PSA levels and clinical stages for RAR beta 2, ER alpha, PGR, and RGMA. High H3K27me3 mark was significantly associated with decreased RAR beta 2, ER alpha, PGR and RGMA gene expressions in prostate cancer sample compared to the normal one. Moreover, the results showed that mRNA level of EZH2, AR and SRC3 are upregulated in prostate cancer compared to normal prostate tissues and this correlates positively with Gleason score, PSA levels and clinical stages. Obviously, these observations were confirmed by protein level using western-blot. Conclusions This data clearly demonstrated that H3K27me3 level correlated with aggressive tumor features. Also this study revealed that reverse correlation of RAR beta 2, ER alpha, PGR, and RGMA expressions with EZH2, SRC3, and AR expressions in prostate cancer tissues suggests that these genes are the target of EZH2. Therefore, all therapeutic strategies leading to histone demethylation with epigenetic drugs such as histone methyltransferase inhibitor may be relevant treatments against prostate cancer.

BACKGROUND: The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AO). METHODS: The histological characteristics of 203 AO patients enrolled in the French national network POLA were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing. RESULTS: 1p/19q co-deletion was present in 79% of cases and was associated with alpha-internexin expression (p < 10-4), IDH1/2 mutation (p < 10-4), chromosome 4 loss (p < 10-3), and better overall survival (p < 10-4). Based on mitotic index, microvascular proliferation (MVP) and necrosis, 3 groups of 1p/19q co-deleted AO were identified: AO with more than 5 mitoses per 10-HPF, no MVP and no necrosis, (1), AO with MVP and no necrosis (2) and AO with MVP and necrosis (3). Compared to group 1, group 2 and 3 AO had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared to group 2, group 3 AO had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q co-deleted AO, chromosomal instability was associated with shorter progression free survival (p = 0.024) and shorter overall survival (p = 0.023). CONCLUSIONS: The present study shows that oligodendroglioma with classic histological features remains a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q co-deleted AO are also heterogeneous. Interestingly, mitotic index, MVP and necrosis help to classify them into three groups associated with distinct genomic alterations.

International audience

Resume But de l’etude Determiner la capacite de detection d’un adenocarcinome prostatique par une IRM 3 Tesla multi-parametrique avec antenne externe pelvienne, en comparaison de l’anatomopathologie chez des patients ayant subi d’une prostatectomie radicale. Materiel et methodes Etude prospective de 30 mois, incluant 74 patients ayant tous un adenocarcinome prostatique diagnostique sur biopsies prostatiques, et tous eligibles a une prostatectomie radicale. Ils ont tous subi une IRM 3 Tesla avec antenne externe pelvienne en sequences multi-parametriques, comportant des sequences morphologiques et des sequences fonctionnelles de type perfusion et diffusion (avec calcul du coefficient apparent de diffusion). La glande prostatique etait divisee en octants (8 zones), et trois criteres precis ont ete recherches suivant ces zones (capacite de detection, capacite d’estimation du contact capsulaire (CC) et de l’effraction extra-capsulaire [EEC]). Une analyse a ete realisee en comparaison des pieces de prostatectomies radicales. Resultats Cinq cent quatre-vingt-douze octants ont ete etudies avec 124 tumeurs significatives (volume ≥ 0,1 cm3). Pour la capacite generale de detection tumorale, l’IRM 3 T avait une sensibilite, specificite, VPP et VPN respectives de 72,3 %, 87,4 %, 83,2 % et 78,5 %. Cette imagerie avait un fort pouvoir predictif negatif dans l’estimation du CC et de l’EEC avec des specificites et des VPN respectives a 96,4 % et 95,4 % pour le CC, et 97,5 et 97,7 % pour l’EEC. Conclusion L’IRM 3 Tesla multi-parametrique nous est apparue etre une technique d’imagerie fiable dans la detection du cancer prostatique en pratique courante et reguliere. Avec un pouvoir predictif negatif encourageant, l’estimation par une IRM 3 T du CC et de l’EEC est a approfondir. Niveau de preuve 3.

To develop a model of visceral pain in rats using a behavioral approach. Cyclophosphamide (CP), an antitumoral agent known to produce toxic effects on the bladder wall through its main toxic metabolite acrolein, was used to induce cystitis.CP was administered at doses of 50, 100 and 200 mg./kg. i.p. to male rats, and their behavior observed and scored. The effects of morphine (0.5 to 4 mg./kg. i.v.) on CP-induced behavioral modifications were tested administered alone and after naloxone (1 mg./kg. s.c.). In addition, 90 minutes after CP injection, that is, at the time of administration of morphine, the bladder was removed in some rats for histological examination. Finally, to show that the bladder is essential for the CP-induced behavioral modifications, female rats also received CP at doses of 200 mg./kg. i.p. and of 20 mg. by the intravesical route, and acrolein at doses of 0.5 mg. by the intravesical route and of 5 mg./kg. i.v.CP dose-relatedly induced marked behavioral modifications in male rats: breathing rate decrease, closing of the eyes and occurrence of specific postures. Morphine dose-dependently reversed these behavioral disorders. A dose of 0.5 mg./kg. produced a reduction of almost 50% of the behavioral score induced by CP 200 mg./kg. This effect was completely prevented by pretreatment with naloxone. At the time of administration of morphine, histological modifications of the bladder wall, such as chorionic and muscle layer edema, were observed. In female rats, CP 200 mg./kg. i.p. produced the same marked behavioral modifications as those observed in male rats. Administered at the dose of 20 mg. intravesically, CP did not produce any behavioral effects, whereas acrolein at 0.5 mg. intravesically induced behavioral modifications identical to those under CP 200 mg./kg. i.p., with the same maximal levels. Conversely, acrolein 5 mg./kg. i.v. did not produce any behavioral effects at all.Overall, these results indicate that this experimental model of CP-induced cystitis may be an interesting new behavioral model of inflammatory visceral pain, allowing a better understanding of these painful syndromes and thus a better therapeutic approach to them.