Multiple Sclerosis (MS) is caused by a still unknown interplay between genetic and environmental factors. Epigenetics, including DNA methylation, represents a model for environmental factors to ...influence MS risk.
Twenty-six affected and 26 unaffected relatives from 8 MS multiplex families were analysed in a multicentric Italian study using MeDIP-Seq, followed by technical validation and biological replication in two additional families of differentially methylated regions (DMRs) using SeqCap Epi Choice Enrichment kit (Roche®).
Associations from MeDIP-Seq across families were combined with aggregation statistics, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypo-methylated regions, which point to NTM and BAI3 genes, and to 2 hyper-methylated regions in PIK3R1 and CAPN13.
These 4 novel regions contain genes of potential interest that need to be tested in larger cohorts of patients.
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•The 233 genetic loci associated with MS explain less than 40% of disease heritability, leaving a role to epigenetics in disease risk•We compared whole-genome methylation profiles in whole blood of affected and unaffected relatives of 8 multiplex MS families•We used MeDIP-seq and technical and biological replication in 2 additional families using a custom panel•Due to the heterogeneity of results in families, we adopted a method which leveraged consistency of signal across families•Filtering criteria lead to 2 hypo- and 2 hyper-methylated DMRs which relate to NTM, BAI3, PIK3R1 and CAPN13 genes•Replication of these signals is needed in additional cohort of MS patients
Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even ...antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in CXCL12-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands.
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•Neutrophils have variable lifetimes in tissues•Neutrophils acquire distinct phenotypic and functional properties in tissues•Tissue-derived signals drive rapid adaptation of neutrophils•Neutrophil reprogramming in the lungs occurs in CXCL12+ niches.
Neutrophils demonstrate plasticity in form and function depending upon the tissue types.
The responses of CD8
T cells to hepatotropic viruses such as hepatitis B range from dysfunction to differentiation into effector cells, but the mechanisms that underlie these distinct outcomes remain ...poorly understood. Here we show that priming by Kupffer cells, which are not natural targets of hepatitis B, leads to differentiation of CD8
T cells into effector cells that form dense, extravascular clusters of immotile cells scattered throughout the liver. By contrast, priming by hepatocytes, which are natural targets of hepatitis B, leads to local activation and proliferation of CD8
T cells but not to differentiation into effector cells; these cells form loose, intravascular clusters of motile cells that coalesce around portal tracts. Transcriptomic and chromatin accessibility analyses reveal unique features of these dysfunctional CD8
T cells, with limited overlap with those of exhausted or tolerant T cells; accordingly, CD8
T cells primed by hepatocytes cannot be rescued by treatment with anti-PD-L1, but instead respond to IL-2. These findings suggest immunotherapeutic strategies against chronic hepatitis B infection.
Abstract Objective Chipping and/or delamination represent a clinical failure of porcelain fused to zirconia (PFZ) prostheses. Causes and solutions have not been completely clarified. The present ...study was aimed at evaluating the effects of number of firings on the flexural strength of PFZ specimen. Methods Forty-five zirconia specimens in shape of bars were cut, sintered and divided in 3 groups ( n = 15). Group 1: veneering ceramic was layered “in bulk” and fired. Group 2: veneering ceramic was layered in three layers, individually fired. Group 3: veneering ceramic was layered in five layers, individually fired. Each layer thickness was controlled by the use of calibrated molds. The total veneering ceramic thickness for all the specimens was 1.2 mm, and the total thickness of the specimen of 2.0 mm. Three-point bending test was performed. Fracture load was recorded in Newton and MPa value was calculated taking into account the bi-layered nature of the specimen. Data were statistically analyzed. Results Specimens obtained with on single firing cycle obtained a statistically significant ( p < 0.001) lower flexural strength (54.61 ± 8.98 MPa) than specimens veneered with 3 or 5 firing cycles. The last two obtained very similar results (77.63 ± 13.17 MPa and 73.62 ± 12.38 MPa respectively) and the differences was not statistically significant. Significance In bi-layered PFZ specimen, three to five layers and firings determine higher flexural resistance when compared to a single firing. Thus, a 3-layers veneering procedure is recommended to increase flexural resistance. If a 5-layer procedure is necessary to improve esthetics, it does not decrease flexural resistance.
L’article analyse la représentation et la perception des Grandes invasions à la fin du xix e siècle et au début du xx e siècle : des mouvements de groupes ethniques cohérents, conduits par des héros ...masculins. Ce modèle a été suggéré à partir d’un type spécifique de sagas mythiques du haut Moyen Âge, les Origines gentium qui, s’appuyant sur différentes sources anciennes, présentaient l’échiquier complexe des déplacements, des guerres et des alliances entre les barbares et l’Empire comme des exodes linéaires de tribus cohérentes vers une terre promise. Les archéologues et les ostéologues ont appliqué littéralement ce modèle : les biens funéraires et les types de squelettes permettaient à leurs yeux d’identifier les membres des différentes tribus et de suivre leurs routes migratoires. Ils ont privilégié les tombes avec des armes et les squelettes masculins et souligné ainsi l’agentivité des hommes. Cependant, les découvertes archéologiques examinées de plus près nous racontent une histoire complètement différente : dans les cimetières du haut Moyen Âge, les femmes avaient une plus grande visibilité que les hommes.
This paper examines the diagnostic potential of multislice computed tomography enteroclysis (MSCT-E) to detect and assess different diseases affecting the small bowel, emphasising the increasingly ...important role assumed by the technique in the study of this anatomical region. After a short summary of the technical aspects, we discuss the different findings that can be observed during an MSCT-E study and that enable detection of small-bowel disease and, if necessary, assessment of the extent and stage of disease.
The aim of this study was to evaluate the role of digital cineradiography associated with the water siphon test (WST) in the diagnosis of gastroesophageal reflux and to compare the results with ...oesophageal motility study, pH monitoring and endoscopy associated with biopsy and histology.
One hundred and sixty consecutive patients underwent digital cineradiography with WST, motility study, pH monitoring and endoscopy with biopsy. The presence of gastroesophageal reflux, oesophagitis, Barrett's oesophagus and intestinal metaplasia was evaluated.
WST vs. pH monitoring showed sensitivity of 71%, specificity of 31%, positive predictive value (PPV) of 53% and negative predictive value (NPV) of 50%; when middle-proximal refluxes only were considered, sensitivity decreased to 45% and specificity increased to 55%. Furthermore, the association between reflux and oesophagitis demonstrated by the chi-square (chi(2)) test proved to be statistically significant both for WST and pH monitoring, whereas the association between reflux and Barrett's oesophagus was not significant for either WST or for pH monitoring. With regard to intestinal metaplasia, WST (middle-proximal refluxes) showed higher sensitivity (64% vs. 58%) and specificity (63% vs. 51%) than pH monitoring, whereas the statistical association between reflux and metaplasia proved to be significant for WST but not for pH monitoring.
WST is a simple, inexpensive and reliable test that might be useful in the diagnosis of gastroesophageal reflux disease (GERD). A positive WST might be an additional indication for endoscopy with biopsy.
To describe the plain and enhanced MRI findings of lingual venous malformations and to discuss the importance of contrast medium in the differential diagnosis of high intensity lesions of the tongue ...on T(2) weighted images.
The clinical records and MR images of eight patients affected by a lingual venous malformation were retrospectively reviewed. Patients presented with a palpable submucosal bluish-red soft mass in the tongue. MRI examinations were performed on a 0.5 T superconducting unit. Plain and enhanced SE (spin echo) T(1) weighted and FSE (fast spin echo) T(2) weighted images were acquired in axial, sagittal and coronal planes. Axial SPGR (spoiled gradient recalled echo) T(1) weighted images were also obtained before and after intravenous (i.v.) injection of paramagnetic contrast medium.
Five of eight venous malformations were located at the tip of the tongue. The other three involved the whole tongue and had an extralingual extent; two extended into the submandibular space and one into the glossoepiglottic valleculae. The largest diameter ranged from 2.5 cm to 8 cm. All lingual venous malformations presented as lobulated masses that were slightly hyperintense or isointense on T(1) weighted images and highly hyperintense on T(2) weighted images with respect to normal tongue and/or surrounding muscles. They showed a slow and homogeneous filling following iv injection of contrast medium. Millimetre-sized hypointense foci and linear hypointense strands were sometimes noticed, which were owing to phleboliths, flow void or septation.
Knowledge of MRI findings of lingual venous malformations is useful for differential diagnosis with other high intensity lingual lesions on T(2) weighted images. This discrimination is achievable using iv paramagnetic contrast medium.
In recent years digital videofluorography (VFG) with water siphon test (WST) has been proposed just for diagnosing hiatal hernia and/or gastroesophageal reflux.
Fifteen patients undergone ...Laparoscopic Nissen (LN) for complicated GERD associated to hiatal hernia, were referred for VFG and WST in order to evaluate the functional results of surgery. At one-month videofluorographic control thirteen patients had just a minimal prolonged esophageal transit time but only six of these had an early postoperative dysphagia, whereas at six months control the prolonged esophageal transit time was present in three patients two of which complained a very light dysphagia. One patient at one month control had a severe dysphagia, her videofluorography showed a very prolonged esophageal transit time and she had to redo surgery. She had a complete resolution of dyspagia and at the six months videofluorographic control she had a normal esophageal and esophagogastric transit time. One patient, underwent surgery in another hospital, complained a persistent and moderate dysphagia and at one month videofluorografic control was evident a malposition of wrap around the upper part of the stomach and a WST positive for reflux and at six months control clinical finding was worst. He will be evaluated for further endoscopic or surgical treatment.
In our experience we believe that VFG is a valid test to identificate the postoperative outcomes giving the surgeons a visual evaluation of their work.
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