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Objectives Mediation analyses were conducted to measure the extent to which musculoskeletal (MSK) flares and depression affected physical health through excessive fatigue. Methods Mediation analyses were performed in a large multicentre cohort of SLE patients. Domains of the LupusQoL and SLEQOL questionnaires were selected as outcomes, MSK flares according to the SELENA-SLEDAI flare index (SFI-R) score and depression defined by Center for Epidemiologic Studies-Depression scale (CES-D) scale as exposures and different fatigue domains from MFI-20 and LupusQoL questionnaires as mediators. For each model, total, direct, indirect effects and proportion of effect mediated by fatigue (i.e. proportion of change in health-related quality of life) were determined. Results Of the 336 patients, 94 (28%) had MSK flares at inclusion and 99 (29.5%) were considered with depression. The proportion of the total effect of MSK flares on physical health impairment explained by fatigue ranged from 59.6% to 78% using the LupusQOL ‘Physical health’ domain and from 51.1% to 73.7% using the SLEQOL ‘Physical functioning’ domain, depending on the fatigue domain selected. The proportion of the total effect of depression on physical health impairment explained by fatigue ranged from 68.8% to 87.6% using the LupusQOL ‘Physical health’ domain and from 79.3% to 103.2% using the SLEQOL ‘Physical functioning’ domain, depending on the fatigue domain selected. Conclusions The effect of MSK flares and depression on physical health impairment is largely mediated by fatigue. Thus, the patient’s perception of disease activity as measured by physical health is largely influenced by fatigue. In addition, fatigue has a significant negative impact on quality of lifeof SLE patients with depression. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904812.

Introduction Giant cell arteritis (GCA) is a frequent granulomatous vasculitis. In the diagnosis of large vessel GCA, FDG-PET/CT imaging has been recommended and its use has steadily increased. The objective of this prospective study was to evaluate the diagnostic performance of digital FDG-PET imaging with a head and neck dedicated protocol, especially to detect cranial arteries involvement, using different visual grading scores, and to assess the inter-reader agreement. Material and Methods FDG-PET/CT scans with a 10-min acquisition time on the head and neck were performed in patients suspected of having recent GCA. A score including 20 segments due to the inclusion of cranial segments and a score established only for the cranial segments were compared to the Total Vascular Score (TVS) established on 7 arterial segments. These scores were assessed by two nuclear medicine physicians on a blinded manner and, in case of disagreement, a consensus was established with a third nuclear medicine physician. Results GCA diagnosis was retained for 15 of the 52 patients included. Sensitivity and specificity of the 20-segment or the cranial scores were higher than those of TVS (sensitivity and specificity of 80% of 97% for both scores vs 73% and 89% for TVS, respectively). The inter-reader agreement was substantial in the 20-segment score (weighted kappa = 0.68) but better in the cranial segments than other segments. Conclusion This study shows the usefulness of grading scores able to highlight involvement of cranial arteries in GCA with a better inter-reader agreement in cranial segments than other segments.

Objectives To investigate the performance of cranial PET/CT for the diagnosis of GCA. Methods All patients with a suspected diagnosis of GCA were prospectively enrolled in this study and had a digital PET/CT with evaluation of cranial arteries if they had not started glucocorticoids >72 h previously. The diagnosis of GCA was retained after at least 6 months of follow-up if no other diagnosis was considered by the clinician and the patient went into remission after at least 6 consecutive months of treatment. Cranial PET/CT was considered positive if at least one arterial segment showed hypermetabolism similar to or greater than liver uptake. Results For cranial PET/CT, sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) were 73.3%, 97.2%, 91.7% and 89.7%, respectively. For extracranial PET/CT, diagnostic performance was lower (Se = 66.7%, Sp = 80.6%, PPV = 58.8%, NPV = 85.3%). The combination of cranial and extracranial PET/CT improved overall sensitivity (Se = 80%) and NPV (NPV = 90.3%) while decreasing overall specificity (Sp = 77.8%) and PPV (PPV = 60%). Conclusion Cranial PET/CT can be easily combined with extracranial PET/CT with a limited increase in examination time. Combined cranial and extracranial PET/CT showed very high diagnostic accuracy for the diagnosis of GCA. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT05246540.

Objectives To describe the characteristics, treatment and outcome of patients with immune thrombocytopenia with clinical significance (ITPCS) associated with SLE. Methods This retrospective multicentre study included SLE patients who experienced ≥1 ITPCS (defined as ITP with attributable bleeding disorders and/or a platelet count 8 and/or WHO score >2. Results A total of 90 patients were included, the median (range) follow-up duration was 80 (6–446) months. ITP was diagnosed before SLE in 25 patients. They presented a high rate of autoimmune haemolytic anaemia (15%), antiphospholipid antibody (62%) and antiphospholipid syndrome (19%). The 25 (28%) patients who experienced MBG had significantly more bleedings at ITP diagnosis and higher bleeding scores, and serositis and thrombosis during follow-up. They required significantly more treatment lines, transfusions and hospitalizations. The 11 (12%) patients who experienced no bleeding event presented a significantly more restricted SLE phenotype (cutaneous and/or articular). Patients received a mean (range) of 4.2 (1–11) treatment lines. Corticosteroids and HCQ allowed ITPCS overall response in one-third of patients. The median relapse-free survival of rituximab (n = 34), AZA (n = 19), MMF (n = 8), thrombopoietin-receptor agonists (n = 16) and splenectomy (n = 19) were 53, 31.5, 61, 24.5 and 78 months, respectively. Four patients experienced thrombotic events after splenectomy and one occurred under thrombopoietin-receptor agonist treatment. Conclusion SLE-ITCS patients displayed a high rate of haematological abnormalities and MBG patients exhibited higher morbidity. Management of thrombocytopenia was highly heterogeneous and many options seem viable.

We evaluated whether pre-existing brain damage may explain greater severity in cognitively-impaired patients with ischemic stroke (IS).IS patients were retrieved from the population-based registry of Dijon, France. Pre-existing damage (leukoaraiosis, old vascular brain lesions, cortical and central brain atrophy) was assessed on initial CT-scan. Association between prestroke cognitive status defined as no impairment, mild cognitive impairment (MCI), or dementia, and clinical severity at IS onset assessed with the NIHSS score was evaluated using ordinal regression analysis. Mediation analysis was performed to assess pre-existing brain lesions as mediators of the relationship between cognitive status and severity.Among the 916 included patients (mean age 76.8 ± 15.0 years, 54.3% women), those with pre-existing MCI (n = 115, median NIHSS [IQR]: 6 [2-15]) or dementia (n = 147, median NIHSS: 6 [3-15]) had a greater severity than patients without (n = 654, median NIHSS: 3 [1-9]) in univariate analysis (OR=1.69; 95% CI: 1.18-2.42, p = 0.004, and OR=2.06; 95% CI: 1.49-2.84, p 0.001, respectively). Old cortical lesion (OR=1.53, p = 0.002), central atrophy (OR=1.41, p = 0.005), cortical atrophy (OR=1.90, p 0.001) and moderate (OR=1.41, p = 0.005) or severe (OR=1.84, p = 0.002) leukoaraiosis were also associated with greater severity. After adjustments, pre-existing MCI (OR=1.52; 95% CI: 1.03-2.26, p = 0.037) or dementia (OR=1.94; 95% CI: 1.32-2.86, p = 0.001) remained associated with higher severity at IS onset, independently of confounding factors including imaging variables. Association between cognitive impairment and severity was not mediated by pre-existing visible brain damages.Impaired brain ischemic tolerance in IS patients with prior cognitive impairment could involve other mechanisms than pre-existing visible brain damage.

Cystic fibrosis (CF) is a genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) for which there is no overall effective treatment. Recent work indicates tissue transglutaminase (TG2) plays a pivotal intracellular role in proteostasis in CF epithelia and that the pan TG inhibitor cysteamine improves CFTR stability. Here we show TG2 has another role in CF pathology linked with TGFβ1 activation and signalling, induction of epithelial-mesenchymal transition (EMT), CFTR stability and induction of matrix deposition. We show that increased TG2 expression in normal and CF bronchial epithelial cells increases TGFβ1 levels, promoting EMT progression, and impairs tight junctions as measured by Transepithelial Electric Resistance (TEER) which can be reversed by selective inhibition of TG2 with an observed increase in CFTR stability. Our data indicate that selective inhibition of TG2 provides a potential therapeutic avenue for reducing fibrosis and increasing CFTR stability in CF.

SummaryPotent-selective peptidomimetic inhibitors of tissue transglutaminase (TG2) were developed through a combination of protein-ligand docking and molecular dynamic techniques. Derivatives of these inhibitors were made with the aim of specific TG2 targeting to the intra- and extracellular space. A cell-permeable fluorescently labeled derivative enabled detection of in situ cellular TG2 activity in human umbilical cord endothelial cells and TG2-transduced NIH3T3 cells, which could be enhanced by treatment of cells with ionomycin. Reaction of TG2 with this fluorescent inhibitor in NIH3T3 cells resulted in loss of binding of TG2 to cell surface syndecan-4 and inhibition of translocation of the enzyme into the extracellular matrix, with a parallel reduction in fibronectin deposition. In human umbilical cord endothelial cells, this same fluorescent inhibitor also demonstrated a reduction in fibronectin deposition, cell motility, and cord formation in Matrigel. Use of the same inhibitor in a mouse model of hypertensive nephrosclerosis showed over a 40% reduction in collagen deposition.

International audience

Die Reformation hat mit einer neuen Art Bücher die Welt verändert. Diese Bücher waren schmaler, handlicher, deutschsprachig und häufig bebildert. Die Bilder in diesen Büchern erfüllten viele Aufgaben, beginnend beim Versuch, komplexe theologische Lehren darzustellen und endend mit der höhnischen Verspottung des ideologischen Gegners. Diese Ausstellung zeigt Beispiele solcher Bilder.

The combination of X-Ray Tomography as a 3D nondestructive imaging technic and the digital volume correlation (DVC) which uses two images to measure displacement fields, paved the way to the quantitative exploitation of in situ mechanical testing.This thesis has contributed to broaden the scope of these technics by developing two axes :- On one hand the mechanical regularization which overcomes the lack of microstructural contrast by adding an a priori knowledge of the material’s mechanical behavior. Initially designed for and linear elastic behavior, this strategy has been extended to tests where plastic strain occurs in two directions while preserving the isochoric characteristic of the deformation. This technic has been tested on images of Aluminum plates obtained by laminography to show that localized plastic strain occurs way before plastic damage (i.e. germination and growth of plastic cavities).- On the other hand, from a reconstructed volume, a DVC technic has been developed which measure the kinematic of a sampled on the radios. This strategy allows to reduce greatly the number of necessary projections à each loading step, and therefore to improve greatly the temporal resolution by minimizing acquisition time. This technic has been used on an example of fatigue crack propagation of a cast iron.- At last, the combine use of these two strategies pave the way to appealing perspectives of fast mechanical test with 4D kinematics measurements, where the temporal resolution can be improve by more than two order of magnitude without any loss in the quality of the measure. One can realized that experimental data are redundant, so the validation (or not) of the hypotheses used is obtained at the end of the procedure.These two axes show the gain of using pre-knowledge, either on mechanical behavior, either on the microstructure o the sample, in the resolution of inverse problem for kinematics measurements.; La combinaison de la tomographie à rayons X comme technique d’imagerie 3D non destructive, et de la corrélation d’images numériques (DVC) qui permet de mesurer les champs de déplacements à partir de paires de telles images, a ouvert la voie à l’exploitation quantitative d’expérimentations mécaniques in situ. Cette thèse contribue à élargir le champ d’application de ces techniques en développant deux axes :- d’une part la régularisation mécanique qui permet de pallier le manque de contraste microstructurale en compensant ce déficit par une connaissance a priori sur le comportement mécanique du matériau. Initialement destinée à rendre compte d’un comportement élastique linéaire, nous avons étendu cette stratégie à des essais montrant une propension à la localisation de la déformation plastique dans deux directions tout en préservant le caractère isochore de la transformation. Cette technique a été testée sur des images de laminographie de tôle d’un alliage d’Aluminium pour montrer que la déformation plastique localisée précède très sensiblement l’endommagement plastique (au sens de l’apparition et la croissance de cavités plastiques).- d’autre part, à partir d’un volume de référence reconstruit, nous avons développé une technique de corrélation d’images volumiques qui apprécie la cinématique de l’objet étudié directement sur les projections (radiographies). Cette stratégie permet de diminuer très fortement le nombre de projections nécessaires à chaque instant du chargement, et donc d’augmenter très fortement la résolution temporelle de la technique en minimisant le temps d’acquisition. Cette technique a été utilisée sur un exemple de propagation de fissure de fatigue dans une fonte à graphite sphéroïdal.- enfin l’utilisation conjointe de ces deux stratégies ouvre des perspectives séduisantes d’essais rapides avec suivi cinématique 4D où la résolution temporelle peut être augmentée de plus de deux ordres de grandeur sans compromission sur la qualité de la mesure. Enfin, il est à noter que les données expérimentales restent redondantes, si bien que la validation (ou non) des hypothèses utilisées est naturellement obtenu à l’issue du traitement. Ces deux axes soulignent le bénéfice engendré par l’infusion d’une pré-connaissance, que ce soit sur le comportement mécanique ou sur la microstructure de l’éprouvette, dans la résolution du problème inverse des mesures cinématiques.

International audience; Double-stranded DNA minicircles of less than 1000 bp in length have great interest in both fundamental research and therapeutic applications. Although minicircles have shown promising activity in gene therapy thanks to their good biostability and better intracellular trafficking, minicircles down to 250 bp in size have not yet been investigated from the test tube to the cell for lack of an efficient production method. Herein, we report a novel versatile plasmidfree method for the production of DNA minicircles comprising fewer than 250 bp. We designed a linear nicked DNA double-stranded oligonucleotide bluntended substrate for efficient minicircle production in a ligase-mediated and bending protein-assisted circularization reaction at high DNA concentration of 2 mu M. This one pot multi-step reaction based-method yields hundreds of micrograms of minicircle with sequences of any base composition and position and containing or not a variety of site-specifically chemical modifications or physiological supercoiling. Biochemical and cellular studies were then conducted to design a 95 bp minicircle capable of binding in vitro two NF-kappa B transcription factors per minicircle and to efficiently inhibiting NF-kappa B-dependent transcriptional activity in human cells. Therefore, our production method could pave the way for the design of minicircles as new decoy nucleic acids.

The combination of X-Ray Tomography as a 3D nondestructive imaging technic and the digital volume correlation (DVC) which uses two images to measure displacement fields, paved the way to the quantitative exploitation of in situ mechanical testing.This thesis has contributed to broaden the scope of these technics by developing two axes :- On one hand the mechanical regularization which overcomes the lack of microstructural contrast by adding an a priori knowledge of the material’s mechanical behavior. Initially designed for and linear elastic behavior, this strategy has been extended to tests where plastic strain occurs in two directions while preserving the isochoric characteristic of the deformation. This technic has been tested on images of Aluminum plates obtained by laminography to show that localized plastic strain occurs way before plastic damage (i.e. germination and growth of plastic cavities).- On the other hand, from a reconstructed volume, a DVC technic has been developed which measure the kinematic of a sampled on the radios. This strategy allows to reduce greatly the number of necessary projections à each loading step, and therefore to improve greatly the temporal resolution by minimizing acquisition time. This technic has been used on an example of fatigue crack propagation of a cast iron.- At last, the combine use of these two strategies pave the way to appealing perspectives of fast mechanical test with 4D kinematics measurements, where the temporal resolution can be improve by more than two order of magnitude without any loss in the quality of the measure. One can realized that experimental data are redundant, so the validation (or not) of the hypotheses used is obtained at the end of the procedure.These two axes show the gain of using pre-knowledge, either on mechanical behavior, either on the microstructure o the sample, in the resolution of inverse problem for kinematics measurements., La combinaison de la tomographie à rayons X comme technique d’imagerie 3D non destructive, et de la corrélation d’images numériques (DVC) qui permet de mesurer les champs de déplacements à partir de paires de telles images, a ouvert la voie à l’exploitation quantitative d’expérimentations mécaniques in situ. Cette thèse contribue à élargir le champ d’application de ces techniques en développant deux axes :- d’une part la régularisation mécanique qui permet de pallier le manque de contraste microstructurale en compensant ce déficit par une connaissance a priori sur le comportement mécanique du matériau. Initialement destinée à rendre compte d’un comportement élastique linéaire, nous avons étendu cette stratégie à des essais montrant une propension à la localisation de la déformation plastique dans deux directions tout en préservant le caractère isochore de la transformation. Cette technique a été testée sur des images de laminographie de tôle d’un alliage d’Aluminium pour montrer que la déformation plastique localisée précède très sensiblement l’endommagement plastique (au sens de l’apparition et la croissance de cavités plastiques).- d’autre part, à partir d’un volume de référence reconstruit, nous avons développé une technique de corrélation d’images volumiques qui apprécie la cinématique de l’objet étudié directement sur les projections (radiographies). Cette stratégie permet de diminuer très fortement le nombre de projections nécessaires à chaque instant du chargement, et donc d’augmenter très fortement la résolution temporelle de la technique en minimisant le temps d’acquisition. Cette technique a été utilisée sur un exemple de propagation de fissure de fatigue dans une fonte à graphite sphéroïdal.- enfin l’utilisation conjointe de ces deux stratégies ouvre des perspectives séduisantes d’essais rapides avec suivi cinématique 4D où la résolution temporelle peut être augmentée de plus de deux ordres de grandeur sans compromission sur la qualité de la mesure. Enfin, il est à noter que les données expérimentales restent redondantes, si bien que la validation (ou non) des hypothèses utilisées est naturellement obtenu à l’issue du traitement. Ces deux axes soulignent le bénéfice engendré par l’infusion d’une pré-connaissance, que ce soit sur le comportement mécanique ou sur la microstructure de l’éprouvette, dans la résolution du problème inverse des mesures cinématiques.

International audience; Based on the assumption that the time evolution of a sample observed by computed tomography requires much less parameters than the definition of the microstructure itself, it is proposed to reconstruct these changes based on the initial state (using computed tomography) and very few radiographs acquired at fixed intervals of time. This paper presents a proof of concept that for a fatigue cracked sample, its kinematics can be tracked from no more than two radiographs in situations where a complete 3D view would require several hundreds of radiographs. This two order of magnitude gain opens the way to a " computed " 4D tomography, which complements the recent progress achieved in fast or ultra-fast computed tomography, which is based on beam brightness, detector sensitivity, and signal acquisition technologies.

International audience; Nuclear factor-kappa B (NF-кB) comprises a family of protein transcription factors that have a regulatory function in numerous cellular processes and are implicated in the cancer cell response to antineoplastic drugs, including cisplatin. We characterized the effects of DNA adducts of cisplatin and ineffective transplatin on the affinity of NF-кB proteins to their consensus DNA sequence (кB site). Although the кB site-NF-κB protein interaction was significantly perturbed by DNA adducts of cisplatin, transplatin adducts were markedly less effective both in cell-free media and in cellulo using a decoy strategy derivatized-approach. Moreover, NF-κB inhibitor JSH-23 [4-methyl-N¹-(3-phenylpropyl)benzene-1,2-diamine] augmented cisplatin cytotoxicity in ovarian cancer cells and the data showed strong synergy with JSH-23 for cisplatin. The distinctive structural features of DNA adducts of the two platinum complexes suggest a unique role for conformational distortions induced in DNA by the adducts of cisplatin with respect to inhibition of the binding of NF-кB to the platinated кB sites. Because thousands of κB sites are present in the DNA, the mechanisms underlying the antitumor efficiency of cisplatin in some tumor cells may involve downstream processes after inhibition of the binding of NF-κB to κB site(s) by DNA adducts of cisplatin, including enhanced programmed cell death in response to drug treatment.

Wenn man die Ausstellung „Leipziger Buchkultur um 1500“ der Universitätsbibliothek Leipzig betritt, kann man den Johannes Schmiedhöfer genauso besuchen wie den Drucker Martin Landsberg, den Buchbinder Valentin Bormann und viele andere mehr. Die Ausstellung umfasst zwanzig Vitrinen, die in ihrer Anordnung einen Rundgang durch die Buchstadt Leipzig um 1500 ermöglichen. Jede Vitrine hat eine ganz konkrete Adresse, repräsentiert ein ehemals (oder auch heute noch) vorhandenes Gebäude; so findet beispielsweise der Besucher den Buchbinder Valentin Bormann in der Ritterstr. 22.