Guillain-Barré Syndrome after Chikungunya Infection

International audienceno abstrac

Phosphatidylinositol 3-Monophosphate Is Involved in Toxoplasma Apicoplast Biogenesis

Apicomplexan parasites cause devastating diseases including malaria and toxoplasmosis. They harbour a plastid-like, non-photosynthetic organelle of algal origin, the apicoplast, which fulfils critical functions for parasite survival. Because of its essential and original metabolic pathways, the apicoplast has become a target for the development of new anti-apicomplexan drugs. Here we show that the lipid phosphatidylinositol 3-monophosphate (PI3P) is involved in apicoplast biogenesis in Toxoplasma gondii. In yeast and mammalian cells, PI3P is concentrated on early endosomes and regulates trafficking of endosomal compartments. Imaging of PI3P in T. gondii showed that the lipid was associated with the apicoplast and apicoplast protein-shuttling vesicles. Interference with regular PI3P function by over-expression of a PI3P specific binding module in the parasite led to the accumulation of vesicles containing apicoplast peripheral membrane proteins around the apicoplast and, ultimately, to the loss of the organelle. Accordingly, inhibition of the PI3P-synthesising kinase interfered with apicoplast biogenesis. These findings point to an unexpected implication for this ubiquitous lipid and open new perspectives on how nuclear encoded proteins traffic to the apicoplast. This study also highlights the possibility of developing specific pharmacological inhibitors of the parasite PI3-kinase as novel anti-apicomplexan drugs

Mutation HNF-1 beta, maladie rénale kystique, diabète MODY 5 et cancer rénal à cellules chromophobes

Nous présentons le cas d'une famille porteuse d'une mutation du gène TCF2, codant pour le facteur de transcription, HNF-1b. Le cas index est une femme de 40 ans qui a présenté un carcinome rénal à cellules chromophobes récidivant après une néphrectomie partielle. Le bilan d'un cancer rénal récidivant chez un sujet jeune associé à des kystes rénaux bilatéraux a entraîné la découverte chez le cas index, puis chez sa mère et ses deux enfants d'une mutation de HNF-1b. A ce jour, 40 mutations de HNF-1b ont été décrites mais il n'avait jamais été rapporté la mutation 46 delC/L16fsX17, identifiée dans la famille étudiée. Initialement, la mutation de HNF-1b a été associée au diabète de type MODY 5. Cependant, le diabète est retrouvé chez seulement la moitié des sujets porteurs de la mutation de HNF-1b. Par contre, l'atteinte rénale, hétérogène, est constante avec des kystes rénaux, des malformations rénales, une maladie glomérulaire kystique rénale familiale avec hypoplasie ou une néphropathie familiale juvénile hyperuricémique. Une insuffisance rénale modérée est habituelle. Les autres traits phénotypiques les plus fréquents secondaires à la mutation de HNF-1b sont une atrophie pancréatique, des malformations de l'appareil génital et une perturbation des tests hépatiques. Il a été retrouvé chez le cas index, une inactivation biallélique de HNF-1b au niveau de la tumeur rénale. Ainsi, comme cela a été démontré au niveau hépatique pour HNF-1alpha, HNF-1b pourrait être un gène suppresseur de la tumeur. C'est la double inactivation allélique, germinale et somatique au niveau de la tumeur qui serait responsable de la survenue du carcinome rénal à cellules chromophobes. En conclusion, le syndrome "renal cysts and diabetes", phénotype le plus caractéristique de la mutation de HNF-1b, n'est présent que dans la moitié des cas. La découverte de reins hyperéchogènes en péridode anténatale, d'un dibaète héréditaire chez un sujet jeune ou d'une maladie glomérulokystique doit faire rechercher une mutation de HNF-1b. De plus, la surveillance des reins par échographie est justifiée chez les sujets porteurs d'une mutation HNF-1b pour dépister un éventuel cancer rénal à cellules chromophobes.ROUEN-BU Médecine-Pharmacie (765402102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Voxelwise principal component analysis of dynamic [s-methyl-11 c]methionine pet data in glioma patients

Recent works have demonstrated the added value of dynamic amino acid positron emission tomography (PET) for glioma grading and genotyping, biopsy targeting, and recurrence diagnosis. However, most of these studies are based on hand-crafted qualitative or semi-quantitative features extracted from the mean time activity curve within predefined volumes. Voxelwise dynamic PET data analysis could instead provide a better insight into intra-tumor heterogeneity of gliomas. In this work, we investigate the ability of principal component analysis (PCA) to extract relevant quantitative features from a large number of motion-corrected [S-methyl-11 C]methionine ([11 C]MET) PET frames. We first demonstrate the robustness of our methodology to noise by means of numerical simulations. We then build a PCA model from dynamic [11 C]MET acquisitions of 20 glioma patients. In a distinct cohort of 13 glioma patients, we compare the parametric maps derived from our PCA model to these provided by the classical one-compartment pharmacokinetic model (1TCM). We show that our PCA model outperforms the 1TCM to distinguish characteristic dynamic uptake behaviors within the tumor while being less computationally expensive and not requiring arterial sampling. Such methodology could be valuable to assess the tumor aggressiveness locally with applications for treatment planning and response evaluation. This work further supports the added value of dynamic over static [11 C]MET PET in gliomas.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Voxelwise principal component analysis of dynamic [S-methyl-11C]methionine PET data in glioma patients: Prepublication on arXiv:2011.09325

Recent works have demonstrated the added value of dynamic amino acid positron emission tomography (PET) for glioma grading and genotyping, biopsy targeting, and recurrence diagnosis. However, most of these studies are exclusively based on hand-crafted qualitative or semi-quantitative dynamic features extracted from the mean time activity curve (TAC) within predefined volumes. Voxelwise dynamic PET data analysis could instead provide a better insight into intra-tumour heterogeneity of gliomas. In this work, we investigate the ability of the widely used principal component analysis (PCA) method to extract meaningful quantitative dynamic features from high-dimensional motion-corrected dynamic [S-methyl-11C]methionine PET data in a first cohort of 20 glioma patients. By means of realistic numerical simulations, we demonstrate the robustness of our methodology to noise. In a second cohort of 13 glioma patients, we compare the resulting parametric maps to these provided by standard one- and two-tissue compartment pharmacokinetic (PK) models. We show that our PCA model outperforms PK models in the identification of intra-tumour uptake dynamics heterogeneity while being much less computationally expensive. Such parametric maps could be valuable to assess tumour aggressiveness locally with applications in treatment planning as well as in the evaluation of tumour progression and response to treatment. This work also provides further encouraging results on the added value of dynamic over static analysis of [S-methyl-11C]methionine PET data in gliomas, as previously demonstrated for O-(2-[18F]fluoroethyl)-L-tyrosine.info:eu-repo/semantics/publishe

A scaffold-free graft for large critical size bone defect: preclinical evidence to clinical proof of concept

Background & Aim : Large critical-sized bone defect (CBD) remains a challenging pathology in orthopaedics. The direct application of adipose stem cells (ASCs) remains limited by a low homing efficiency and a low survival rate. This study aims to show the osteogenic role of ASCs in a scaffold-free approach. [...

A scaffold-free graft for large critical size bone defect: preclinical evidence to clinical proof of concept

INTRODUCTION: Large critical size bone defect is one of the most challenging pathologies in orthopaedic surgery. This study aims to demonstrate the potential of a scaffold-free osteogenic approach. METHODS: The bioactivity of the scaffold-free graft was in vivo studied in 2 nude rat models: (i) the comparison of fresh/decellularized grafts in term of angiogenesis (up to 1 month) in a fibrotic tissue (in a cauterized muscular pocket,n=20);(ii) the in vivo osteogenicity of the scaffold-free graft (in comparison to HA/bTCP bone substitute) was assessed, at 1/2/3 months postimplantation, in an irreversible femoral critical size bone defect (n=28). The angiogenesis was quantified by histomorphometry while the osteogenesis was studied by micro-CTscan and Q-RTPCR (for osteogenic genes expression) on graft explants. A 5-year-old boy with congenital pseudarthrosis of the tibia was proposed for the autologous scaffold-free graft approach. At 3 months post-AT procurement, the 3D-graft was placed into the defect in view to be followed clinically/radiologically. RESULTS: After intra-muscular transplantation, cellular survival (with major osteogenic genes expression) of human ASCs and the promotion of angiogenesis was found at 1month postimplantation. A complete integration and bone fusion were found (at 4/8 weeks postimplantation in the femoral defect) for the 3D graft in comparison to the bone substitute alone which revealed a lack of tissue remodelling and osteogenesis. Specific genes of the skeletal development were overexpressed in the bone defect treated with the 3D grafts (at 4/8 weeks post-implantation) while no osteoinduction was found for the HA/bTCP alone. A large volume (>15cm3) of the 3D graft was manufactured in GMP and then implanted without any modification of the surgical procedure. The graft was easily handled and implanted. The graft demonstrated a continuous remodelling (with bone formation) up to 14 months post-implantation to obtain a sufficient bone fusion (allowing walk without pain) and no recurrence of the disease. CONCLUSION: The scaffold-free 3D-graft (made of ASCs) play a major role to promote ASCs engraftment and consequence to induce osteogenesis in a fibrotic environment and to recover a bone fusion in a critical-sized bone defect

Initial condition assessment for reaction-diffusion glioma growth models: A translational MRI/histology (in)validation study: Prepublication on arXiv:2102.01719

Diffuse gliomas are highly infiltrative tumors whose early diagnosis and follow-up usually rely on magnetic resonance imaging (MRI). However, the limited sensitivity of this technique makes it impossible to directly assess the extent of the glioma cell invasion, leading to sub-optimal treatment planing. Reaction-diffusion growth models have been proposed for decades to extrapolate glioma cell infiltration beyond margins visible on MRI and predict its spatial-temporal evolution. These models nevertheless require an initial condition, that is the tumor cell density values at every location of the brain at diagnosis time. Several works have proposed to relate the tumor cell density function to abnormality outlines visible on MRI but the underlying assumptions have never been verified so far. In this work we propose to verify these assumptions by stereotactic histological analysis of a non-operated brain with glioblastoma using a tailored 3D-printed slicer. Cell density maps are computed from histological slides using a deep learning approach. The density maps are then registered to a postmortem MR image and related to an MR-derived geodesic distance map to the tumor core. The relation between the edema outlines visible on T2 FLAIR MRI and the distance to the core is also investigated. Our results suggest that (i) the previously suggested exponential decrease of the tumor cell density with the distance to the tumor core is not unreasonable but (ii) the edema outlines may in general not correspond to a cell density iso-contour and (iii) the commonly adopted tumor cell density value at these outlines is likely overestimated. These findings highlight the limitations of using conventional MRI to derive glioma cell density maps and point out the need of validating other methods to initialize reaction-diffusion growth models and make them usable in clinical practice.info:eu-repo/semantics/publishe

Kidney biopsy in very elderly patients: indications, therapeutic impact and complications

International audienceBackground: Few data is available on the risk/benefit balance of native kidney biopsy (KB) in very elderly patients. Methods: Multicenter retrospective cohort study in the Aix-Marseille area: the results of KB and medical charts of all patients over 85 years biopsied between January 2010 and December 2018 were reviewed. Results: 104 patients were included. Median age was 87 years. Indications for KB were: acute kidney injury (AKI) in 69.2% of patients, nephrotic syndrome (NS) with AKI in 13.5%, NS without AKI in 12.5%, and proteinuria in 4.8%. Median serum creatinine was 262 μmol/L, 21% of patients required dialysis at the time of KB. Significant bleeding occurred in 7 (6.7%) patients, requiring blood cell transfusion in 4 (3.8%), and radiological embolization in 1 (1%). The most frequent pathological diagnoses were: non-diabetic glomerular diseases (29.8%, including pauci-immune crescentic glomerulonephritis in 9.6%), hypertensive nephropathy (27.9%), acute interstitial nephritis (16.3%), renal involvement of hematological malignancy (8.7%), and acute tubular necrosis (6.7%). After KB, 51 (49%) patients received a specific treatment: corticosteroids (41.3%), cyclophosphamide (6.7%), rituximab (6.7%), bortezomib (3.8%), other chemotherapies (3.8%). Median overall survival was 31 months. Conclusions: KB can reveal a diagnosis with therapeutic impact even in very elderly patients. Severe bleeding was not frequent in this cohort, but KB may have not been performed in more vulnerable patients