Search

Annular lipoatrophy of the ankle is a rare and unique acquired lipoatrophic panniculitis that mainly affects children. There is no consensus on treatment, and the long-term course is not well known. We present four new pediatric cases that contribute to the understanding of this rare disease.

Inflammation is a major contributor to tubular epithelium injury in kidney disorders, and the involvement of blood platelets in driving inflammation is increasingly stressed. CD154, the ligand of CD40, is one of the mediators supporting platelet proinflammatory properties. Although hypoxia is an essential constituent of the inflammatory reaction, if and how platelets and CD154 regulate inflammation in hypoxic conditions remain unclear. Here, we studied the control by CD154 of the proinflammatory cytokine interleukin- (IL-) 6 secretion in short-term oxygen (O2) deprivation conditions, using the HK-2 cell line as a kidney tubular epithelial cell (TEC) model. IL-6 secretion was markedly stimulated by CD154 after 1 to 3 hours of hypoxic stress. Both intracellular IL-6 expression and secretion were stimulated by CD154 and associated with a strong upregulation of IL-6 mRNA and increased transcription. Searching for inhibitors of CD154-mediated IL-6 production by HK-2 cells in hypoxic conditions, we observed that chloroquine, a drug that has been repurposed as an anti-inflammatory agent, alleviated this induction. Therefore, CD154 is a potent early stimulus for IL-6 secretion by TECs in O2 deprivation conditions, a mechanism likely to take part in the deleterious inflammatory consequences of platelet activation in kidney tubular injury. The inhibition of CD154-induced IL-6 production by chloroquine suggests the potential usefulness of this drug as a therapeutic adjunct in conditions associated with acute kidney injury.

A muscle biopsy is currently requested to assess the diagnosis of an idiopathic inflammatory myopathy overlapping with a systemic disease. During the past few years, the classification of inflammatory myopathy subtypes has been revisited progressively on the basis of correlations between clinical phenotypes, autoantibodies and histological data. Several syndromic entities are now more clearly defined, and the aim of the present review is to clarify the contribution of muscle biopsy in a setting of idiopathic inflammatory myopathies overlapping with systemic diseases. .

We report a rare and aggressive case of malignant triton tumor (MTT) at the thoracolumbar junction with foraminal extension mistreated as schwannoma. A 70-year-old man with a 2-year history of lower back pain and left L4 radiculopathy with no history of neurofibromatosis. Pre-operative MRI suggested a typical schwannoma. Upon complete marginal resection, histological findings revealed a MTT. The patient presented with a local and regional recurrence and died 10 months after surgery. MTTs are a subgroup of malignant peripheral nerve sheath tumors, which develop from Schwann cells of peripheral nerves or within existing neurofibromas, and display rhabdomyoblastic differentiation. Based on the Grand Round case and relevant literature, we present a case of a highly aggressive and fast-growing tumor with a very high local and distant recurrence. There is no consensus treatment plan available and patients usually die shortly after diagnosis.

International audience; Obesity predisposes to an increased risk of nonalcoholic fatty liver disease (NAFLD). Hepatic steatosis is the key pathological feature of NAFLD and has emerged as a metabolic disorder in which innate and adaptive arms of the immune response play a central role in disease pathogenesis. Recent studies have revealed unexpected relationships between CD40 signaling and hepatic steatosis in high fat diet rodent models. CD154, the ligand of CD40, is a mediator of inflammation and controls several critical events of innate and adaptive immune responses. In the light of these reports, we discuss potential links between CD40 signaling and hepatic steatosis in NAFLD.

Background Due to the very short T2 of its components, the normal anatomy of Achilles enthesis is impossible to define with "conventional" long echo time (TE) T2 sequences. However, this is a common site affected by rheumatologic disease. Early abnormalities related to inflammatory processes are impossible to detect in this location. Purpose To assess the feasibility of a 3D-UTE (ultrashort echo time) sequence to evaluate normal and pathological Achilles entheses, determining both anterior fibrocartilaginous and posterior collagenic portions at 4.7T, in a rat model of spondyloarthropathy (SpA) with histological correlation. To assess whether this sequence detects SpA enthesopathy prior to long TE T2 sequences, enabling disease monitoring. Study type Prospective case-control study. Animal model Twelve immunocompetent Wistar male rats imaged before (controls); the model was induced in eight rats (16 tendons) imaged at day 6, day 13, and day 21 with regular sacrifice for ex vivo imaging and histological correlation. Field strength 4.7T Bruker Biospec Systems. 3D balanced steady-state free precession (bSSFP) and 3D-UTE sequences, performed at baseline (day 0, n = 12 animals / 24 tendons), day 6 (n = 8/16), 13 (n = 4/8), and day 21 (n = 2/4). Assessment Visual analysis and signal intensity measurements (signal to noise ratio, SNR) of both bSSFP and UTE images were performed by two independent musculoskeletal radiologists at different locations of the Achilles enthesis and preinsertional area. Statistical tests Normal and pathological rat values were compared by Wilcoxon signed-rank tests, as well as interobserver differences. MRI findings were compared against histological data. Results The 3D-UTE sequence identified the anterior fibrocartilage and posterior collagenic areas of Achilles entheses in all cases. Visual analysis and signal intensity measurements distinguished SpA-affected entheses from healthy ones at days 6 and 13 (P = 0.002 and P = 0.006, respectively). Neither the normal anatomy of the enthesis nor its pathological pattern could be identified on T2 bSSFP sequences. Data conclusion Unlike bSSFP T2 sequences, 3D-UTE sequences enable visualization of normal enthesis anatomy and early detection of abnormalities in pathological conditions. Level of evidence 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:127-135.

International audience; C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9-indicative of complement-mediated injury-is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25-73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival (p = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; p = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9- ABMR (median time after transplantation, 28 vs. 85 months; p = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.

Introduction : Le myelome multiple est une pathologie caracterisee par une proliferation plasmocytaire maligne intramedullaire. Il se manifeste par la synthese massive d’une paraproteine monoclonale immunoglobulinique. Lorsqu’il s’agit d’un fragment de chaine legere, il peut se compliquer d’une amylose AL systemique. Les depots amyloides au niveau de la langue peuvent alors etre a l’origine de macroglossies plus ou moins invalidantes. L’atteinte linguale a peu ete decrite dans la litterature. Un nouveau cas severe d’amylose AL linguale est rapporte. Observation : Un patient de 62 ans etait adresse pour une gene linguale importante associee a des douleurs. Il etait atteint d’un myelome multiple depuis 2006, traite initialement par melphalan et autogreffe, puis par plusieurs lignes de chimiotherapie en fonction des episodes evolutifs. Une amylose AL avait ete evoquee en 2014 suite a la survenue d’un syndrome du canal carpien bilateral. Lors de son traitement chirurgical, une biopsie synoviale avait revele la presence de depots amyloides. A l’examen clinique, on retrouvait une macroglossie avec indentations laterales. La langue etait ankylosee, induree et douloureuse a la palpation. Le patient rapportait une grande difficulte a s’alimenter (dysphagie, odynophagie, incapacite a deglutir les aliments solides) a l’origine d’une alteration de l’etat general avec amaigrissement. La phonation etait alteree et l’hygiene orale compromise. La biopsie et l’examen anatomopathologique confirmerent la localisation linguale de lesion d’amylose. Un ajustement occlusal au niveau des dents cuspidees ainsi qu’une infiltration locale de triamcinolone furent realises, mais aucune amelioration clinique ne fut obtenue. Discussion : L’amylose est une pathologie definie par le depot et l’accumulation extracellulaire d’une substance proteique dite « amyloide ». Elle peut toucher un ou plusieurs organes, dont elle perturbe l’architecture et la fonction. L’amylose AL (amylose « primitive ») est typiquement secondaire a une proliferation plasmocytaire comme dans le myelome multiple. Dans celle-ci, les fibrilles de la substance amyloide sont constituees par la polymerisation de fragments monoclonaux de chaines legeres d’immunoglobulines. Les manifestations orales sont parfois les premiers signes de la maladie. Le principe du traitement est de reduire la charge proteique en agissant sur la proliferation monoclonale sous-jacente. Le pronostic depend de la reduction de la concentration serique en chaines legeres libres. En raison d’un manque de donnees et de l’absence de preuve scientifique, il n’existe pas de consensus sur la gestion specifique de la macroglossie due a une amylose systemique. Le traitement chirurgical par glossectomie partielle peut etre envisage en cas d’impotence fonctionnelle ou esthetique majeure, dans la mesure ou la proliferation monoclonale sous-jacente est supprimee. Dans le cas present, l’importance de la gene fonctionnelle consecutive a la macroglossie necessitait une prise en charge symptomatique. Le risque de recidive, l’impredictibilite du resultat postoperatoire et l’importante morbidite inherente a la glossectomie ont contre-indique ce traitement en premiere intention. Pour les cas evolutifs d’amylose systemique avec blocage pharynge, des mesures alternatives comme la tracheotomie et la gastrostomie peuvent etre les meilleures solutions pour permettre une qualite de vie acceptable. Conclusion : L’amylose AL est une pathologie multisystemique de pronostic sombre, dont l’esperance de vie sans traitement est inferieure a 1 an. En presence de cas evolutifs, le maintien de la qualite de vie du patient et la protection des fonctions vitales sont essentiels.

Reticular (retiform) perineurioma is a rare variant of soft tissue perineurioma developed from the perineurium. This benign tumor is characterized by strands of spindle cells in a fibro-myxoid matrix surrounding pseudocystic mucoid spaces. We report a tibial nerve reticular perineurioma in a 35-year-old patient.

Matrix remodeling is a key feature of glomerulosclerosis secondary to diabetes or hypertension. Podocytes contribute to glomerular basement membrane (GBM) turnover by producing matrix components and matrix remodelling enzymes, including matrix metalloproteinases (MMPs). The CD40/CD154 signaling pathway modulates matrix remodeling through the synthesis of MMPs and tissue inhibitors of MMPs. Platelets are a primary blood reservoir of CD154. Here we studied, the impact of the CD154/CD40 pathway on MMP-9 expression by cultured human podocytes. The role of CD40/CD154 was evaluated upon exposure of podocytes to recombinant human CD154 (rhCD154) or activated platelet supernatants from healthy human subjects. We first showed by protein and mRNA expression that CD40 was synthesized by podocytes and detectable on kidney tissue sections. CD40 expression was acquired during podocyte differentiation and enhanced upon exposure to rhCD154. In podocytes, rhCD154 induced an increase of MMP-9 production as shown by RT-PCR, Western blot and and gelatin zymography. Activated platelet supernatants induced MMP-9 mRNA synthesis in podocytes, an effect reduced by anti-CD40 antibody. Our results underscore a potential role for platelets through the CD40/CD154 signaling pathway in the control of GBM synthesis and degradation, via its regulatory role on MMP-9 production. CD154 secretion by activated platelets may contribute to GBM alterations in proteinuric nephropathies. J. Cell. Biochem. 117: 2737-2747, 2016. © 2016 Wiley Periodicals, Inc.

Introduction : Le syndrome APECED (Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy) est une maladie autosomique recessive caracterisee par l’association d’une atteinte endocrinienne auto-immune, d’une candidose cutaneo-muqueuse et d’une atteinte des tissus ectodermiques. Observation : Le cas d’un patient de 19 ans atteint d’un syndrome APECED est rapporte. Les signes retrouves etaient une maladie d’Addison, une keratopathie et une alopecie. Le diagnostic de candidose cutaneo-muqueuse a ete plusieurs fois porte mais jamais formellement prouve chez ce patient. Un lichen plan atrophique a ete diagnostique cliniquement et histologiquement sur la muqueuse buccale. Il a ete traite par clobetasol topique. Discussion : L’apparition d’un lichen plan est inhabituelle dans ce syndrome. La question du caractere fortuit ou non du lichen et de la confusion diagnostique avec une candidose est posee. Conclusion : Les praticiens specialistes de la cavite orale devraient connaitre cette dystrophie muqueuse car elle peut etre associee a des manifestations orales plus communes comme le lichen plan ou la candidose orale.

It is widely accepted that HLA donor-specific antibodies (DSA) are associated with antibody-mediated rejection and graft loss. However, in many transplant programs, preformed anti-HLA-Cw and anti-HLA-DP DSA are not considered in organ allocation policies because their clinical relevance is still uncertain.We analyzed the clinical impact of Cw/DP DSA through a retrospective study, comparing 48 patients transplanted with isolated preformed Cw/DP DSA (Cw/DP DSA group) with (i) 104 matched HLA-sensitized kidney transplant recipients with No DSA at D0 (No DSA group) and (ii) 47 kidney transplant recipients with preformed A, -B, -DR, -DQ DSA (A/B/DR/DQ DSA group).A positive flow cytometry crossmatch in the Cw/DP DSA group was more frequent than in the No DSA group and as frequent as in the A/B/DR/DQDSA group. Two years after transplantation, the biopsy-proven acute rejection-free survival was worse in the Cw/DP and A/B/DR/DQ DSA groups than in the No DSA group (65%, 84%, 93%, P = 0.001 and P = 0.05, respectively). Accordingly, graft survival was lower in the Cw/DP and the A/B/DR/DQ DSA groups than in the No DSA group (87%, 89%, 95%, P = 0.02 and P = 0.1, respectively).These results suggest that preformed anti-HLA-Cw and anti-HLA-DP DSA are as deleterious as anti-HLA A/B/DR/DQ DSA. It justifies their inclusion in kidney allocation programs and in immunological risk stratification algorithms.

Intraneural perineurioma is a benign tumor developed from the perineurium and responsible for localized nerve hypertrophy. This uncommon tumor is characterized by a proliferation of perineural cells with a "pseudo-onion bulb" pattern. We report a sciatic nerve intraneural perineurioma in a 39-year-old patient.

There are various histopathological forms of idiopathic nephrotic syndrome, including minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). Whereas some relapse predictor factors have been identified in renal transplantation, the clinical future of idiopathic nephrotic syndrome in the native kidney remains uncertain. We designed a multicentric retrospective descriptive cohort study including all patients aged 15 years and over whose renal biopsy confirmed MCD or FSGS between January 2007 and December 2014. We studied 165 patients with idiopathic nephrotic syndrome, 97 with MCD and 68 with FSGS. In the MCD cohort, 91.7% of patients were treated with corticosteroids for a median total duration of 13 months. During 45 months of follow-up, 92.8% of patients achieved remission and 45.5% experienced relapse. In this cohort, 5% of patients experienced terminal kidney disease. With respect to FSGS patients, 51.5% were treated with corticosteroids for a median total duration of 15 months. During 66 months of follow-up, 73.5% of patients achieved remission and 20% experienced relapse. In this cohort, 26.5% of patients experienced terminal kidney disease. No statistical association was observed between clinical and biological initial presentation and relapse occurrence. This study describes the characteristics of a cohort of patients with the nephrotic idiopathic syndromes of MCD and FSGS from the time of renal biopsy and throughout follow-up.

Background Pathogenicity of donor-specific antibodies (DSAs) can be assessed using the single-antigen flow beads (SAFB) assays through mean fluorescence intensity (MFI) with or without serum ethylenediaminetetraacetic acid (EDTA) treatment, measurement of C1q or C3d binding and/or their intragraft detection [graft-bound donor-specific antibody (gDSA)]. We aimed to investigate which of these markers best associates with antibody-mediated rejection (ABMR) and kidney allograft loss at the time of a for-cause biopsy. Methods This retrospective, single-centre study included 77 kidney transplant recipients who underwent a for-cause biopsy between December 2004 and July 2013. All displayed serum DSAs were identified on the same day as the biopsy. Sera were tested in parallel with the classical SAFB assay with or without serum EDTA treatment, C1q- and C3d-binding assays. gDSAs were eluted from biopsy fragments and identified with SAFB. Results The median time between transplantation and biopsy was 25 months (range 0.5-251). The median follow-up was 36 months (range 0-140). ABMR was histologically proven in 40% of recipients. The sensitivity and specificity of C1q, C3d and gDSA assays for predicting ABMR were 68% and 61%, 52% and 70% and 64.5% and 56.5%, respectively. At the time of biopsy, only the DSA MFI after EDTA treatment and C3d positivity were associated with graft loss. In multivariate analyses, glomerular filtration rate, transplant glomerulopathy and C4d positivity were the only factors associated with graft loss. Conclusions Our findings weaken the rationale for systematically implementing C1q, C3d or gDSA assays in this situation, because they do not independently predict ABMR and graft loss.

Abnormal regulation of the alternative pathway of the complement system is a well-described trigger of microangiopathy leading to atypical hemolytic uremic syndrome (aHUS). However, the involvement of complement dysregulation in distal angiopathy has not been reported in adults. We describe the clinical course of a patient with severe distal angiopathy (amputation of all fingers and toes) followed 3 years later by aHUS with end-stage renal disease. This course was attributed to a circulating monoclonal immunoglobulin A λ light chain (IgAλ) with unusual properties: it bound complement factor H (CFH) and impaired CFH-glycosaminoglycan interaction and cell-surface protection. Local complement activation with distal angiopathy and microvascular injury was suggested by deposition of IgA, C4d, and C5b-9 in limb and preglomerular arteries. We therefore postulated that the monoclonal IgAλ inhibited activity of endothelial cell-bound CFH, which led to local activation of complement, vasoconstriction (distal angiopathy), and aHUS. While the patient was dependent on dialysis and plasma exchange, treatment with the anti-C5 antibody eculizumab induced remission of distal angiopathy and aHUS. During eculizumab treatment, kidney transplantation was performed. The patient had normal kidney function at the 3-year follow-up. We suggest that the association of distal angiopathy and aHUS in this patient is clearly linked to anti-CFH properties of the monoclonal IgAλ.

Vitiligo is the most common depigmenting disorder resulting from the loss of melanocytes from the basal epidermal layer. The pathogenesis of the disease is likely multifactorial and involves autoimmune causes, as well as oxidative and mechanical stress. It is important to identify early events in vitiligo to clarify pathogenesis, improve diagnosis, and inform therapy. Here, we show that E-cadherin (Ecad), which mediates the adhesion between melanocytes and keratinocytes in the epidermis, is absent from or discontinuously distributed across melanocyte membranes of vitiligo patients long before clinical lesions appear. This abnormality is associated with the detachment of the melanocytes from the basal to the suprabasal layers in the epidermis. Using human epidermal reconstructed skin and mouse models with normal or defective Ecad expression in melanocytes, we demonstrated that Ecad is required for melanocyte adhesiveness to the basal layer under oxidative and mechanical stress, establishing a link between silent/preclinical, cell-autonomous defects in vitiligo melanocytes and known environmental stressors accelerating disease expression. Our results implicate a primary predisposing skin defect affecting melanocyte adhesiveness that, under stress conditions, leads to disappearance of melanocytes and clinical vitiligo. Melanocyte adhesiveness is thus a potential target for therapy aiming at disease stabilization.

A 59-year-old man, ex-professional boxer, met clinical criteria for probable Alzheimer's disease. The patient agreed to be included in a clinico-pathological study with donation to the brain bank, and he died at 71. The brain was grossly atrophic, with a prominent atrophy of the entorhinal cortex and hippocampus, and with pallor of the substantia nigra. Immunohistochemistry with anti-τ A4 revealed abundant and diffuse deposits in the neo-cortex, whereas amyloid angiopathy was absent. Coupled anti-τ AT8 immunohistochemistry and Congo red staining showed no neuritic plaques. τ-AT8-positive glial tangles and neurofibrillary tangles involved preferentially the superficial cortical layers, and were irregularly concentrated in the depth of cortical sulci and near vessels. Neurofibrillary degeneration was marked in amygdala, hippocampus, substantia nigra, and locus ceruleus. Enlarged and/or distorted axons were numerous in hippocampus and mid-brain. TDP 43-positive neuronal inclusions were numerous in amygdala and hippocampus. There was no synucleinopathy. These observations are in accordance with the previously reported data on chronic traumatic encephalopathy. The discussion is focused on professional boxing as it becomes evident that repetitive trauma on the brain provokes the deposition of abnormal proteins involved in neurodegeneration.

Outcome of patients with transplant glomerulopathy (TG) is poor. Using B-cell targeting molecules represent a rational strategy to treat TG during chronic antibody-mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post-biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24-month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor-specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody-mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events.

Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.

Primary diffuse leptomeningeal gliomatosis (PDLG) is characterized by diffuse infiltration of the leptomeningeal space by neoplastic glial cells without evidence of intra-parenchymatous primary tumor. We report a case of PDLG in a 68-year-old man, who died 1 month after onset of symptoms. The diagnosis was made on autopsy data. We discuss the particularities of this entity, which is not registered in the WHO classification of tumors of the central nervous system (2016). In case of an unexplained inflammatory meningeal process and in the presence of atypical cells in the cerebrospinal fluid, PDLG needs to be considered. This diagnosis of PDLG has to be confirmed by meningeal imaging-guided biopsy, which must be repeated if necessary. .

Allograft pathology, antibody–tissue interaction as demonstrated by C4d deposition and serological evidence of donor-specific antibodies (DSA) are the cardinal diagnostic features of antibody-mediated lesions (AML) in kidney transplantation. However, discrepancy between histological and serological findings is common, and more reliable diagnostic tools are called for. Here, we asked whether the in situ detection of DSA could serve as marker for AML. To that end, we applied the anti-HLA single antigen flow bead assay to eluates from 51 needle core graft biopsies performed for cause. Intragraft antibody profiles were correlated to serum DSA (sDSA), histological data and transplant outcome. The prevalence and the mean number of intragraft DSA (gDSA) were lower than that of sDSA (15/51 gDSA+ vs. 37/51 sDSA+ patients; 1.64 gDSA vs. 2.24 sDSA per patient). DSA were detected in all anti-HLA antibody-positive biopsies (15/15). The presence of gDSA was significantly associated with (1) microcirculation lesions taken individually (g, cg) and analyzed in functional clusters (ptc + g + cg > 0, cg + mm > 0), (2) C4d positivity and (3) a worse short-term transplant outcome (p = 0.05). These associations were not found for patients presenting only sDSA. Taken together, these results indicate that gDSA is a severity marker of antibody-mediated pathogenic process.

Introduction La lipoatrophie annulaire des chevilles (LAC) est une pathologie rare d’etiologie mal connue, avec uniquement 17 cas rapportes dans la litterature, dont 14 chez l’enfant. Son evolution et son traitement sont peu connus. Nous rapportons 4 nouveaux cas de LAC dont un cas avec un suivi de plus de dix ans. Observations Quatre enfants, 2 garcons et 2 filles, âges de 5 a 9 ans au moment du diagnostic, dont 3 avec un terrain auto-immun (AI) (personnel ou familial), consultaient pour des nodules ou plaques apparus autour des chevilles et mollets et ayant evolue en quelques mois vers l’atrophie sous-cutanee des 2 jambes sans sclerose, evoquant alors une LAC. Etaient associes une hyperpigmentation sequellaire (n = 1), une hyperpilosite des chevilles atteintes (n = 1), un reseau veineux proeminent (n = 1). La severite etait variable ; l’enfant presentant l’atrophie la plus prononcee rapportait des crampes. Aucun facteur declenchant n’etait trouve. Sur le plan biologique, on notait un faible taux d’anticorps antinucleaires (n = 1), une elevation moderee des IgG et M (n = 1), des anticorps antithyroidiens (n = 1). Les biopsies montraient une panniculite lobulaire aspecifique associee a un infiltrat lymphohistiocytaire, avec image de lipophagie, sans signe de vasculite (n = 4). Il n’y avait pas d’atteinte musculo-squelettique (n = 4) a l’imagerie (radiographies, echographies, TDM, IRM). L’IRM montrait dans un cas une atrophie circonferentielle complete de l’hypoderme. Un garcon etait traite a 6 mois d’evolution par methotrexate (1 an) et corticotherapie orale (4 mois) en raison de crampes. Ces dernieres regressaient en 5 mois mais l’atrophie restait stable a 1 an. Aucun traitement n’etait introduit pour les 3 autres vus a 4 mois d’evolution. Les deux premiers etaient reevalues a 6 mois avec une stabilite. Le troisieme etait reevalue 12 ans plus tard avec un aspect atrophique plus discret ( Fig. 1 et 2 ). Discussion Peu de donnees sont disponibles concernant la LAC et aucun cas rapporte dans la litterature n’a fait l’objet d’un suivi de plus de 2 ans. Un de nos patients a pu avoir un suivi de 12 ans, montrant une stabilite apres la phase aigue independamment du traitement. Notre serie tend a demontrer que la LAC est une entite a part entiere sans lien avec une connectivite ou une maladie auto-immune, malgre le terrain AI sur lequel elle survient (principalement thyroidien). Un bilan biologique standard avec anticorps antinucleaires et antithyroidiens et une biopsie cutanee peuvent etre realises en cas de suspicion diagnostique. Le pronostic semble donc lie a une atrophie parfois affichante et un suivi pendant la phase aigue est indique. Une chirurgie reconstructrice avec injection de graisse autologue peut etre envisagee a distance, en fonction du prejudice esthetique et du retentissement psychologique. Conclusion La LAC a une presentation stereotypee qui doit etre connue des cliniciens.

International audience; Hepatitis E virus (HEV) has been identified as a cause of chronic viral hepatitis in immunocompromised patients. Some glomerular diseases were found to be associated with this infection. We report the first case, to our knowledge, of a kidney transplant recipient who developed an HEV infection and de novo membranous nephropathy (MN) concomitantly. The patient displayed a hepatic cytolysis first and a nephrotic syndrome occurred 3 months later. HEV infection was diagnosed upon positive polymerase chain reaction on plasma and stool samples, and renal allograft biopsy revealed de novo MN. Typical causes of MN were definitively excluded. A 3-month course of ribavirin monotherapy allowed the patient to mount a sustained viral response that was rapidly followed by complete remission of the nephrotic syndrome. The chronology of the onset and remission of both diseases is highly suggestive of a causal relationship between hepatitis E and MN.

Summary Background Imatinib mesylate is a potent inhibitor of platelet-derived growth factor and transforming growth factor-β signalling pathways which may play a role in systemic sclerosis (SSc)-associated skin changes. Objectives We aimed primarily at assessing the efficacy of imatinib mesylate in scleroderma skin fibrosis. Methods We performed a phase II double-blinded trial on patients with scleroderma with either morphoea involving > 20% of body surface area or SSc with extensive skin involvement: modified Rodnan Skin Score (mRSS) ≥ 20/51. Each patient was randomized to receive either imatinib mesylate 400 mg or placebo daily for a total of 6 months, and then was followed up 6 months after therapy discontinuation. Skin fibrosis was assessed by mRSS and measurement of the dermal thickness using skin biopsies performed at inclusion and at 6 months of treatment. In addition, quality of life (Dermatology Life Quality Index and modified Health Assessment Questionnaire for Scleroderma) was recorded at each visit, and pulmonary function before and after intervention. Results Twenty-eight patients were included in the study with a mean age of 48·9 years (range 30–71): 25 had a diagnosis of a SSc and three of diffuse cutaneous scleroderma. Demographic data, frequency of organ involvement of SSc and mRSS were comparable between groups. At 6 months, the proportion of variation of mRSS from inclusion was not statistically significantly different between the two groups (median +0·10 in imatinib group vs. −0·16 in placebo group, P = 0·098). Similarly, changes in dermal thickness, quality of life and diffusion capacity for carbon monoxide were not significantly different between groups. Conclusions This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements.

International audience; C1q-binding ability may indicate the clinical relevance of de novo donor-specific anti-HLA antibodies (DSA). This study investigated the incidence and risk factors for the appearance of C1q-binding de novo DSA and their long-term impact. Using Luminex Single Antigen Flow Bead assays, 346 pretransplant nonsensitized kidney recipients were screened at 2 and 5 years after transplantation for de novo DSA, which was followed when positive by a C1q Luminex assay. At 2 and 5 years, 12 (3.5%) and eight (2.5%) patients, respectively, had C1q-binding de novo DSA. De novo DSA mean fluorescence intensity \textgreater6237 and \textgreater10,000 at 2 and 5 years, respectively, predicted C1q binding. HLA mismatches and cyclosporine A were independently associated with increased risk of C1q-binding de novo DSA. When de novo DSA were analyzed at 2 years, the 5-year death-censored graft survival was similar between patients with C1q-nonbinding de novo DSA and those without de novo DSA, but was lower for patients with C1q-binding de novo DSA (P=0.003). When de novo DSA were analyzed at 2 and 5 years, the 10-year death-censored graft survival was lower for patients with C1q-nonbinding de novo DSA detected at both 2 and 5 years (P\textless0.001) and for patients with C1q-binding de novo DSA (P=0.002) than for patients without de novo DSA. These results were partially confirmed in two validation cohorts. In conclusion, C1q-binding de novo DSA are associated with graft loss occurring quickly after their appearance. However, the long-term persistence of C1q-nonbinding de novo DSA could lead to lower graft survival.

Erdheim–Chester disease (ECD) is a non-Langerhans histiocytosis affecting multiple organs. Stroke as symptom onset of ECD with intracranial vasculitis is unusual. We report the case of a 64-year-old man who presented with an acute ischemic stroke associated with a moderate leukoencephalopathy and intracranial arteries stenosis. Four years later, he developed movement disorders with dysarthria and cognitive impairment. Neuroradiological findings demonstrated a rapidly progressive and diffuse leukoencephalopathy associated with brain atrophy and infiltration of the intracranial vertebral artery wall. Brain postmortem evaluation confirmed the diagnosis of ECD. This diagnosis should be evoked in patients with cryptogenic stroke, progressive leukoencephalopathy, and infiltration of the arterial wall.

The case presented here points towards the fact that skin lesion observed with a cowpox virus is a rare event but should be considered more as the number of cases has increased in the last years. Cowpox virus (CPXV) belongs to the Poxviridae family. The transmission of CPXV to humans is caused by wild rodents or mostly by domestic animals and pet rats. In humans, CPXV is responsible for localized skin lesions regularly accompanied by lymphadenopathy. The lesions remain localized but self-inoculation from the primary lesions could occur. Then physicians have to be vigilant concerning bandages. In this case report, a necrotic and ulcerated lesion of a CPXV infection in a young boy is reported. The CPXV was possibly transmitted by wild rodents. The importance of performing the diagnosis is also pointed out. Virus information was obtained from phylogenetic analyses showing that the CPXV isolate was distinct from outbreaks of human cowpox which occurred in 2009 in France and Germany but was close to the CPXV Brighton Red strain. For several years, cases of viral zoonosis caused by CPXV have increased and physicians should be made aware that people could be infected without history of direct contact with animals.

Background: The anterior gradient protein-2 (AGR2) is overexpressed in numerous tumours such as breast, prostate or pancreas carcinomas and recently reported in fibrolamellar hepatocellular carcinoma (HCC). Aims: In the present study, we further describe AGR2 expression patterns all along the adult and fetal biliary tree and in cholangiocarcinomas. Methods: Immunohistochemistry using anti-AGR2 antibodies was performed in adult and fetal livers, gallbladders as well as cholangiocarcinomas and HCCs. Results: In adult and fetal liver, the tall epithelial cells covering the large bile ducts as well as gallbladder epithelial cells showed strong AGR2 staining. Hilar and extrahepatic cholangiocarcinomas, and a subset of intrahepatic cholangiocarcinomas, which displayed a morphological mucus-excreting feature, also displayed AGR2 expression. In contrast, AGR2 expression was not detected in typical HCCs. Conclusion: Our study shows that the differential expression of AGR2 is a phenotypic feature of the cholangiocytes covering different segments of the biliary tree. This pattern of expression is conserved during fetal and adult life, as well as during biliary carcinogenesis.

Ductal plate malformations (DPMs) are developmental anomalies considered to result from lack of ductal plate remodeling during bile duct morphogenesis. In mice, bile duct development is initiated by the formation of primitive ductal structures lined by two cell types, namely ductal plate cells and hepatoblasts. During ductal plate remodeling, the primitive ductal structures mature to ducts as a result from differentiation of the ductal plate cells and hepatoblasts to cholangiocytes. Here, we report this process is conserved in human fetal liver. These findings prompted us to evaluate how DPMs develop in three mouse models, namely mice with livers deficient in hepatocyte nuclear factor 6 (HNF6), HNF1β, or cystin-1 (cpk [congenital polycystic kidney] mice). Human liver from a patient with a HNF1B/TCF2 mutation, and from fetuses affected with autosomal recessive polycystic kidney disease (ARPKD) were also analyzed. Despite the epistatic relationship between HNF6, HNF1β, and cystin-1, the three mouse models displayed distinct morphogenic mechanisms of DPM. They all developed biliary cysts lined by cells with abnormal apicobasal polarity. However, the absence of HNF6 led to an early defect in ductal plate cell differentiation. In HNF1β-deficient liver, maturation of the primitive ductal structures was impaired. Normal differentiation and maturation but abnormal duct expansion was apparent in cpk mouse livers and in human fetal ARPKD. CONCLUSION: DPM is the common endpoint of distinct defects initiated at distinct stages of bile duct morphogenesis. Our observations provide a new pathogenic classification of DPM.

Inflammation and lipid metabolism pathways are linked, and deregulation of this interface may be critical in hepatic steatosis. The importance of the dialog between inflammatory signaling pathways and the unfolded protein response (UPR) in metabolism has been underlined. Herein, we studied the role of CD154, a key mediator of inflammation, in hepatic steatosis. To this end, Balb/c mice, wild-type or deficient in CD154 (CD154KO), were fed a diet rich in olive oil. In vitro, the effect of CD154 was studied on primary hepatocyte cultures and hepatocyte-derived cell lines. Results showed that CD154KO mice fed a diet rich in olive oil developed hepatic steatosis associated with reduced apolipoprotein B100 (apoB100) expression and decreased secretion of very low-density lipoproteins. This phenotype correlated with an altered UPR as assessed by reduced X-Box binding protein-1 (XBP1) messenger RNA (mRNA) splicing and reduced phosphorylation of eukaryotic initiation factor 2α. Altered UPR signaling in livers of CD154KO mice was confirmed in tunicamycin (TM) challenge experiments. Treatment of primary hepatocyte cultures and hepatocyte-derived cell lines with soluble CD154 increased XBP1 mRNA splicing in cells subjected to either oleic acid (OA) or TM treatment. Moreover, CD154 reduced the inhibition of apoB100 secretion by HepG2 cells grown in the presence of high concentrations of OA, an effect suppressed by XBP1 mRNA silencing and in HepG2 cells expressing a dominant negative form of inositol requiring ER-to-nucleus signaling protein-1. The control of the UPR by CD154 may represent one of the mechanisms involved in the pathophysiology of hepatic steatosis. Conclusion: Our study identifies CD154 as a new mediator of hepatic steatosis. (HEPATOLOGY 2010)

Resume Les fibres elastiques sont constituees de microfibrilles contenant la fibrilline-1 et d’une composante elastique, l’elastine. Les microfibrilles peuvent ne pas etre associees a l’elastine. Au niveau du foie adulte, la fibrilline-1 et l’elastine sont coexprimees dans le stroma et dans la paroi des vaisseaux de l’espace porte. La fibrilline-1 est exprimee seule autour des canaux biliaires et dans l’espace de Disse. Peu d’etudes existent sur l’organisation des fibres elastiques au cours du developpement hepatique fœtal. Nous avons etudie l’expression de la fibrilline-1 et de l’elastine par immunohistochimie sur 20 echantillons de foie fœtal. Pendant le developpement de l’espace porte, les deux composantes sont coexprimees au niveau des fibres elastiques interstitielles et dans la paroi des vaisseaux, tandis que la fibrilline-1 est exprimee seule autour des structures biliaires en maturation. Contrairement a l’adulte, la fibrilline-1 est peu exprimee dans l’espace de Disse, sous forme d’un reseau discontinu. Notre etude montre qu’au niveau de l’espace porte, la matrice elastique se met en place en phase avec les differentes structures, notamment biliaires, mais reste inachevee dans l’espace de Disse. A ce niveau, leur maturation ulterieure peut etre en relation avec le nouveau schema de la circulation sanguine hepatique apres la naissance.

Background: The debate concerning the potential remodelling and/or reversibility of cirrhotic lesions and biliary fibrosis is still open. Aims/Methods: In this work, we have used the precision-cut liver slice (PCLS) model, which maintains cell–cell and cell–matrix interactions to study, by immunohistochemistry, the behaviour of the different fibrogenic cells, i.e. hepatic stellate cells (HSC) and portal fibroblasts, in cultured (for 1 week) PCLS derived from normal and fibrotic human livers. Results: In normal liver, before and after culture, α-smooth muscle (SM) actin was present only in the vessel walls. Platelet-derived growth factor (PDGF) receptor-β was expressed before and after culture by portal fibroblasts, and appeared after culture in HSC. Before culture, CD 34 was not expressed in parenchyma, but appeared after culture in sinusoidal endothelial cells. In cirrhotic lesions, before culture, α-SM actin, PDGF receptor-β and Thy-1 were expressed in septa; after culture, α-SM actin expression disappeared but the expression of the PDGF receptor-β and Thy-1 was maintained. In cholestatic liver specimens, α-SM actin, PDGF receptor-β and Thy-1 expression, which was present before culture in enlarged portal areas, disappeared after culture, and apoptosis was detected. In the parenchyma of both cirrhotic and cholestatic livers, the expression of the PDGF receptor-β and of CD 34, which was not observed before culture, was present in HSC and sinusoidal endothelial cells, respectively, after culture. Conclusions: These results indicate that during remodelling of pathological tissues in cultured liver slices, the myofibroblastic cells derived from HSC or from portal fibroblasts show different behaviours, suggesting different mechanisms of activation/deactivation.

Chantier qualité GA; Cholangiocarcinoma is an adenocarcinoma of the liver which has increased in incidence over the last thirty years to reach similar levels to other liver cancers. Diagnosis of this disease is usually late and prognosis is poor, therefore it is of great importance to identify novel candidate markers and potential early indicators of this disease as well as molecules that may be potential therapeutic targets. We have used a proteomic approach to identify differentially expressed proteins in peripheral cholangiocarcinoma cases and compared expression with paired non-tumoral liver tissue from the same patients. Two-dimensional fluorescence difference gel electrophoresis after labeling of the proteins with cyanines 3 and 5 was used to identify differentially expressed proteins. Overall, of the approximately 2,400 protein spots visualised in each gel, 172 protein spots showed significant differences in expression level between tumoral and non-tumoral tissue with p

Summary Background Psoriasiform eruptions occur in association with antitumour necrosis factor (TNF)-α treatments in autoinflammatory diseases. The major reported clinical presentation is palmoplantar pustulosis, sometimes accompanied with plaque-like psoriasis. In some reports, histological findings suggest psoriasis whereas others favour a lichenoid drug reaction. We present a case series with a comprehensive clinical, histopathological and immunohistochemical study. Objectives To investigate the mechanism involved in psoriasiform eruptions in patients receiving anti-TNF-α inhibitors. Methods Between July 2004 and May 2008, 13 patients with psoriasiform eruptions arising under anti-TNF-α treatment were enrolled in the study. Punch biopsy specimens of lesions were processed for standard and immunohistochemical analyses using antibodies against CD3, CD4, CD8, CD20, CD1a, KP1, CXCR3, CXCL9, Tia1 and MxA, which is specifically induced by type I interferons (IFNs). Additionally, we analysed biopsies from lesional skin of patients with cutaneous discoid lupus erythematosus, lichen planus and psoriasis. Control biopsies were taken from unaffected skin. Results All patients developed psoriasiform plaques on the body accompanied with palmoplantar keratoderma or pustulosis in three patients. Histological and immunohistochemical findings showed a psoriasiform pattern with focal lichenoid and spongiotic features. We detected strong production of the MxA protein in inflammatory cells, indicating involvement of type I IFNs, and the expression was higher than in control psoriasis samples. Expression of MxA was closely associated with the recruitment of CXCR3+ lymphocytes in the skin bearing markers of cytotoxic capacity. Conclusions Results support the hypothesis that psoriasiform eruptions are a new model of drug reaction characterized by an increased expression of type I IFNs induced by anti-TNF-α.

A 72-year-old man presented with a Merkel cell carcinoma (MCC) of the left cheek with concomitant nodal spread. A 61-year-old man presented with an MCC of the right thigh with rapid nodal recurrence.Skin biopsy samples proved the MCC nature of the neoplasm in both patients. Staging procedure included clinical and radiological investigations.Advanced stage II MCC.Neoadjuvant cisplatin, etoposide and cyclophosphamide (EPC) regimen led to local control in the first patient and allowed curative surgery associated with adjuvant radiation therapy. Complete remission was maintained for 32 months. The second patient was treated by surgery plus radiation therapy. Nodal and cutaneous recurrences were treated with a neoadjuvant EPC regimen leading to a 5-year complete remission.

Objective Expression of tissue inhibitors of matrix metalloproteinases (TIMPs) is one way that activated platelets intervene in tissue remodeling and angiogenesis. Our study was designed to investigate their synthesis in megakaryocytes (MKs) and their storage in platelets. Materials and Methods TIMP expression in MKs derived from blood CD34 + progenitor cells of normal donors and a megakaryocytic cell line (CHRF-288-11) grown in serum-free conditions and platelets from normal donors or two patients with gray platelet syndrome was studied by immunofluorescence labeling, reverse transcription-polymerase chain reaction, and western blotting. Results Biosynthesis of TIMPs 1−4 in MKs was indicated by presence of their messenger RNAs as shown by polymerase chain reaction and of their proteins. Immunofluorescence labeling suggested a primarily granular localization of TIMPs in MKs and platelets. But when colocalization with von Willebrand factor, fibrinogen, P-selectin, and other α-granule proteins was assessed in platelets by confocal microscopy, TIMP-1, -2, and -4 were localized as distinct fluorescent patches apart from the established α-granule markers and largely independent of platelet metalloproteinases. TIMP-3 differed for it also had an α-granule location. Western blotting confirmed the presence of TIMPs 1−4 in platelets and thrombin activation resulted in their extensive release to the medium. Platelets from two patients with gray platelet syndrome, congenitally deficient in α-granules, showed sparse labeling of von Willebrand factor and fibrinogen confined to vestigial α-granules; however, localization of the TIMPs was unchanged. Conclusions TIMPs are synthesized and organized in MKs and platelets independently of other secreted proteins present in α-granule pools.

Resume Objectif L’objectif de cette etude etait d’evaluer l’impact diagnostique, therapeutique et economique des avis en cancerologie donnes par les pathologistes referents en Aquitaine. Materiel et methodes Une etude quantitative retrospective a ete effectuee sur tous les avis et relectures demandes dans deux centres pathologistes referents. Un echantillon des avis regionaux adresses pour tumeurs lymphoides, melaniques et conjonctives a ete selectionne. La proposition diagnostique du pathologiste initial a ete comparee au diagnostic du pathologiste expert. L’impact diagnostique etait determine majeur lorsque l’avis etait envoye pour tumeur maligne a typer ou a identifier, doute benin/malin, diagnostic non precise ou si les diagnostics etaient discordants (malin/benin). L’impact therapeutique etait juge fort si l’avis engendrait une modification radicale du traitement. Le cout des avis pour les deux structures et le cout de la prise en charge therapeutique pour un diagnostic discordant ont ete evalues. Resultats En 2006, les centres de reference ont recu 5077 dossiers, dont 3769 etaient des avis diagnostiques (75 %), 1324 avis provenaient de la region et parmi eux, 751 correspondaient a des tumeurs lymphoides (55 %), conjonctives (30 %) et melaniques (15 %). L’avis donne par l’expert a induit un impact diagnostique majeur dans 75 % des cas, un impact therapeutique fort dans 46 % des cas et un impact pronostique dans 38 % des cas. L’economie de sante realisee sur 53 cas discordants (malins diagnostiques benins) est estimee a environ 500 000 € en termes de prise en charge therapeutique. Conclusion Notre etude montre la necessite des avis diagnostiques non seulement pour la prise en charge du patient, mais egalement pour des raisons economiques.