Notch2 with retinoic acid license IL-23 expression by intestinal EpCAM+ DCIR2+ cDC2s in mice.

Despite the importance of IL-23 in mucosal host defense and disease pathogenesis, the mechanisms regulating the development of IL-23-producing mononuclear phagocytes remain poorly understood. Here, we employed an Il23aVenus reporter strain to investigate the developmental identity and functional regulation of IL-23-producing cells. We showed that flagellin stimulation or Citrobacter rodentium infection led to robust induction of IL-23-producing EpCAM+ DCIR2+ CD103- cDC2s, termed cDCIL23, which was confined to gut-associated lymphoid tissues, including the mesenteric lymph nodes, cryptopatches, and isolated lymphoid follicles. Furthermore, we demonstrated that Notch2 signaling was crucial for the development of EpCAM+ DCIR2+ cDC2s, and the combination of Notch2 signaling with retinoic acid signaling controlled their terminal differentiation into cDCIL23, supporting a two-step model for the development of gut cDCIL23. Our findings provide fundamental insights into the developmental pathways and cellular dynamics of IL-23-producing cDC2s at steady state and during pathogen infection.

An outward-rectifying plant K+ channel SPORK2 exhibits temperature-sensitive ion-transport activity.

Temperature sensing is critical for the survival of living organisms.1,2 Thermosensitive transient receptor-potential (TRP) cation channels function as thermosensors in mammals.2,3,4,5,6 In contrast to animals, land plants lack TRP genes.7,8,9 Previous patch-clamp studies in plant cells suggested the presence of ion channels whose activities are related to temperature, implying the presence of TRP-like channels.10,11,12,13,14 However, the molecular entities of such temperature-sensitive ion channels were still unknown in land plants. In this study, we observed that the unique rainfall-induced leaf-folding movement of the legume tree Samanea saman15 was temperature-sensitive by using a rainfall-mimicking assay. Chilling-induced leaf folding in S. saman was shown to be related to the swelling of the motor cells16,17 at the base of the leaflet. This swelling suggested involvement of temperature-sensitive inactivation of K+ currents, independent of fluctuations in ion channel gene expression in motor cells. These findings led us to examine the temperature sensitivity of an outward-rectifying K+ channel, SPORK2, which was reported as an ion channel responsible for the nyctinastic (circadian-rhythmic) leaf movement of S. saman.18 We also discovered that SPORK2 exhibits temperature-sensitive K+ transport activity in the Xenopus oocyte expression system. Using chimeric channels, we showed that two domains of SPORK2 regulated the temperature sensitivity. Furthermore, heterologously expressed SPORK2 in Arabidopsis guard cells induced temperature-dependent stomatal closure. Therefore, SPORK2 is an ion channel in land plants with temperature-sensitive ion-transport activity that functions similarly to mammalian TRP channels. Our current findings advance the molecular understanding of temperature-sensing mechanisms in plants.

How to approach and take care of minor adolescents whose situations raise ethical dilemmas? a position paper of the European academy of pediatrics.

In the care of adolescents, health care providers often face situations raising ethical concerns or dilemmas, such as refusal of a treatment or hospitalization, or request of confidentiality while engaging in risky behaviors or facing unplanned pregnancy. This position paper provides concrete avenues as how to assess the adolescent's capacity for autonomous decision making, e.g. the patient's competence in a specific situation, and how to elicit informed choice or consent. To do so, professionals need to be sensitized and trained as how to assess the cognitive and socio-psychological development of the young patient. Another challenge for the health professionals is to balance the needs to support patient's autonomy while offering secure guidance and protection if needed. To optimize such a process, they establish a climate of trust and empathy that will allow the patient to participate freely in the decision. In addition, especially when the decisions have potentially important consequences on the health and life, the professionals include, with the adolescent's permission, parents, caregivers or other significant adults, as well as they may request the opinion of other members of the health care team or expert colleagues such as ethicists.

A Case of Pancreatic Neuroendocrine Tumor G3 Which Responded Remarkably to Chemotherapy.

Pancreatic neuroendocrine carcinoma (NEC) as classified in the World Health Organization (WHO) 2010 was reclassified in the WHO 2017 as either neuroendocrine tumor (NET) G3 or NEC. An accurate diagnosis based on the WHO 2017 classification is important in order treating this disease appropriately. We report a case diagnosed as NET G3 that responded remarkably well to treatment with streptozocin. The patient would likely not have received the streptozocin treatment if she had been diagnosed with NEC. The WHO 2017 classification is reasonable for the treatment of advanced pancreatic neuroendocrine neoplasms.

Alteration of coracoacromial ligament thickness at the acromial undersurface in patients with rotator cuff tears.

Background: Some researchers have stated that magnetic resonance imaging (MRI) is useful for assessing the coracoacromial ligament (CAL) at the acromial undersurface. However, few studies have investigated the reliability and clinical significance of MRI findings for the CAL at the acromial undersurface. The purpose of this study was to determine the association between CAL thickness at the acromial undersurface and rotator cuff tear size. Methods: The CAL thickness at the acromial undersurface was evaluated in 182 patients with rotator cuff tears (mean age: 64.9 ± 8.4 years) using a 3.0-Tesla MRI system. The association between CAL thickness at the acromial undersurface and rotator cuff tear size determined by the DeOrio and Cofield classification (partial; small: <1 cm; medium: 1-3 cm; and large or massive: >3 cm) was analyzed statistically. The intraobserver and interobserver reliabilities for MRI measurements of CAL thickness at the acromial undersurface were determined by calculation of intraclass correlation coefficients and their 95% confidence intervals. Results: The mean CAL thickness at the acromial undersurface was 2.7 ± 1.4 mm (range: 0-6.5 mm). Increasing rotator cuff tear size was significantly associated with decreasing CAL thickness at the acromial undersurface (P = .004). The intraobserver and interobserver intraclass correlation coefficients for CAL thickness at the acromial undersurface were almost perfect (0.98 and 0.91, respectively). Conclusion: The present study clarified that (1) MRI was a reliable tool for evaluation of CAL thickness at the acromial undersurface and (2) increasing rotator cuff tear size was significantly associated with decreasing CAL thickness at the acromial undersurface. These findings may assist toward understanding the progressive pathology in rotator cuff disease.

[Actively supporting youth participation and autonomous decision-making in health matters]. / Soutenir activement la participation et les prises de décisions des adolescent-e-s dans le domaine de la santé.

The adolescent's process of brain maturation has important consequences for their ability to reason in decision-making processes. The notion of evolving capacity, for which age is not a sufficient indicator, implies a progressive vision of the nature and degree of participation according to the level of maturity. Health professionals are at the forefront of actively promoting young people's participation, supporting their decision-making about their own health, and seeing them as true partners and agents of change. The active participation of young people in all decisions that concern them is essential to make real progress in the field of adolescent health. This step implies a paradigm shift from "thinking for them" to "thinking with them".

Le processus de maturation cérébrale des adolescents a des conséquences importantes sur leur capacité de raisonnement dans les processus de décision. La notion de capacité évolutive, dont l'âge n'est pas un indicateur suffisant, implique une vision progressive de la nature et du degré de participation en fonction du niveau de maturité. Les professionnel-le-s de la santé sont aux premières loges pour favoriser activement la participation des jeunes, en soutenant leurs prises de décision concernant leur propre santé et en les considérant comme de véritables partenaires et acteurs de changement. La participation active des jeunes dans toutes les décisions qui les concernent est indispensable pour réellement progresser dans le domaine de la santé des adolescents. Cette étape implique un changement de paradigme de penser « avec eux ¼ plutôt que « pour eux ¼.

Deep convolutional neural network-based algorithm for muscle biopsy diagnosis.

Histopathologic evaluation of muscle biopsy samples is essential for classifying and diagnosing muscle diseases. However, the numbers of experienced specialists and pathologists are limited. Although new technologies such as artificial intelligence are expected to improve medical reach, their use with rare diseases, such as muscle diseases, is challenging because of the limited availability of training datasets. To address this gap, we developed an algorithm based on deep convolutional neural networks (CNNs) and collected 4041 microscopic images of 1400 hematoxylin-and-eosin-stained pathology slides stored in the National Center of Neurology and Psychiatry for training CNNs. Our trained algorithm differentiated idiopathic inflammatory myopathies (mostly treatable) from hereditary muscle diseases (mostly non-treatable) with an area under the curve (AUC) of 0.996 and achieved better sensitivity and specificity than the diagnoses done by nine physicians under limited diseases and conditions. Furthermore, it successfully and accurately classified four subtypes of the idiopathic inflammatory myopathies with an average AUC of 0.958 and classified seven subtypes of hereditary muscle disease with an average AUC of 0.936. We also established a method to validate the similarity between the predictions made by the algorithm and the seven physicians using visualization technology and clarified the validity of the predictions. These results support the reliability of the algorithm and suggest that our algorithm has the potential to be used straightforwardly in a clinical setting.

'Demystifying' the encounter with adolescent patients: a qualitative study on medical students' experiences and perspectives during training with adolescent simulated patients.

Training with adolescent simulated patients (ASP) is increasingly recognized as an effective form of teaching interviewing skills with adolescent patients. Beyond the acknowledged effectiveness and satisfaction of training with ASP, little is known on medical students' actual experience and specific learning needs related to simulated encounters with ASP, as well as factors influencing their learning experience.The aim of this study was an in-depth exploration of medical students' perspectives about training with ASP.Using a qualitative design with grounded theory methods, we conducted in-field observation of training sessions with ASP and individual interviews with eighteen fourth-year medical students participating in training.When provided with an actual experience in a simulated setting, students go through a process of anticipating then modulating the challenge of the encounter with an adolescent patient. This challenge is influenced and modulated within 3 main dimensions: preconceptions about adolescents, level of experience with adolescent patients and professional distance. This process is also influenced by how students perceive and cope with the educational setting.Training with ASP, as a first concrete experience of an adolescent consultation, is an opportunity to address important aspects of students' attitudes towards adolescent patients such as students' preconceptions, personal experiences and feelings that could influence the doctor-patient relationship later on. Training should focus on ways to reflect upon and handle such attitudes and the emotional resonance experienced by medical students.

Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1ß production and chronic inflammation in Th17-mediated autoimmune arthritis.

Programmed necrosis, such as necroptosis and pyroptosis, is a highly pro-inflammatory cellular event that is associated with chronic inflammation. Although there are various triggers of pyroptosis and necroptosis in autoimmune tissue inflammation and subsequent lytic forms of cell death release abundant inflammatory mediators, including damage-associated molecular patterns and IL-1ß, capable of amplifying autoimmune Th17 effector functions, it remains largely unclear whether the programs play a crucial role in the pathogenesis of autoimmune arthritis. We herein report that Gasdermin D (Gsdmd) and receptor interacting serine/threonine kinase 3 (Ripk3)-key molecules of pyroptosis and necroptosis, respectively-are upregulated in inflamed synovial tissues, but dispensable for IL-1ß production and the development of IL-17-producing T helper (Th17) cell-mediated autoimmune arthritis in SKG mice. Gsdmd-/-, Ripk3-/-, or Gsdmd-/- Ripk3-/- SKG mice showed severe arthritis with expansion of arthritogenic Th17 cells in the draining LNs and inflamed joints, which was comparable to that in wild-type SKG mice. Despite the marked reduction of IL-1ß secretion from Gsdmd-/- or Ripk3-/- bone marrow-derived DCs by canonical stimuli, IL-1ß levels in the inflamed synovium were not affected in the absence of Gsdmd or Ripk3. Our results revealed that T cell-mediated autoimmune arthritis proceeds independently of the pyroptosis and necroptosis pathways.

Foxp3+ Regulatory T Cells Inhibit CCl4-Induced Liver Inflammation and Fibrosis by Regulating Tissue Cellular Immunity.

Foxp3+ regulatory T (Treg) cells are pivotal in maintaining immunological self-tolerance and tissue homeostasis; however, it remains unclear how tissue Treg cells respond to liver injury and regulate chronic inflammation, which can cause liver fibrosis. We report here that hepatic Treg cells play a critical role in preventing liver pathology by suppressing inflammatory cellular immunity that can promote liver damage and fibrosis. Chronic liver inflammation induced by injections of carbon tetrachloride (CCl4) led to preferential expansion of hepatic Treg cells that prevented liver fibrosis. In contrast, depletion of Treg cells in the CCl4-induced liver fibrosis model exacerbated the severity of liver pathology. Treg depletion unleashed tissue cellular immunity and drove the activation and expansion of the pro-fibrotic IL-4-producing T helper 2 cells, as well as CCR2high Ly-6Chigh inflammatory monocytes/macrophages in the inflamed liver. Although Treg expression of amphiregulin plays a key role in tissue remodeling and repair in various inflammation models, amphiregulin from hepatic Treg cells, the largest producer among liver immune cells, was dispensable for maintaining liver homeostasis and preventing liver fibrosis during CCl4-induced chronic inflammation. Our results indicate that Treg cells control chronic liver inflammation and fibrosis by regulating the aberrant activation and functions of immune effector cells. Harnessing Treg functions, which effectively regulate tissue cellular immunity, may be a therapeutic strategy for preventing and treating liver fibrosis.

Deep learning shows the capability of high-level computer-aided diagnosis in malignant lymphoma.

A pathological evaluation is one of the most important methods for the diagnosis of malignant lymphoma. A standardized diagnosis is occasionally difficult to achieve even by experienced hematopathologists. Therefore, established procedures including a computer-aided diagnosis are desired. This study aims to classify histopathological images of malignant lymphomas through deep learning, which is a computer algorithm and type of artificial intelligence (AI) technology. We prepared hematoxylin and eosin (H&E) slides of a lesion area from 388 sections, namely, 259 with diffuse large B-cell lymphoma, 89 with follicular lymphoma, and 40 with reactive lymphoid hyperplasia, and created whole slide images (WSIs) using a whole slide system. WSI was annotated in the lesion area by experienced hematopathologists. Image patches were cropped from the WSI to train and evaluate the classifiers. Image patches at magnifications of ×5, ×20, and ×40 were randomly divided into a test set and a training and evaluation set. The classifier was assessed using the test set through a cross-validation after training. The classifier achieved the highest levels of accuracy of 94.0%, 93.0%, and 92.0% for image patches with magnifications of ×5, ×20, and ×40, respectively, in comparison to diffuse large B-cell lymphoma, follicular lymphoma, and reactive lymphoid hyperplasia. Comparing the diagnostic accuracies between the proposed classifier and seven pathologists, including experienced hematopathologists, using the test set made up of image patches with magnifications of ×5, ×20, and ×40, the best accuracy demonstrated by the classifier was 97.0%, whereas the average accuracy achieved by the pathologists using WSIs was 76.0%, with the highest accuracy reaching 83.3%. In conclusion, the neural classifier can outperform pathologists in a morphological evaluation. These results suggest that the AI system can potentially support the diagnosis of malignant lymphoma.

Where and what damage occurs at the acromial undersurface in patients with rotator cuff tears?

BACKGROUND: The gross pathology of the acromial undersurface in shoulders with rotator cuff tears with subacromial impingement is not completely understood. Many researchers have focused on damage to the anterior one-third area of the acromial undersurface, but few have studied the middle and posterior one-third areas. The purpose of this study was to clarify where and what damage occurs at the acromial undersurface in patients with rotator cuff tears. METHODS: We performed arthroscopic shoulder (n = 182, all with rotator cuff tears; mean age, 64.9 ± 8.4 years) and cadaveric shoulder (n = 23, 14 intact cuffs and 9 rotator cuff tears; mean age, 74.8 years) evaluations to observe the extent and degree of damage to the acromial undersurface. We statistically analyzed the association between the severity of the damage to the acromial undersurface (assessed using the Copeland-Levy classification as A0, normal; A1, minor scuffing; A2, major damage; or A3, visualization of bare bone area) and rotator cuff tear size (assessed using the classification of DeOrio and Cofield as partial; small, <1 cm; medium, 1-3 cm; or large or massive, >3 cm). RESULTS: The anterior, middle, and posterior one-thirds of the acromial undersurface were somewhat damaged (class A1-A3) in 92.6%, 90.1%, and 78.6% of shoulders with rotator cuff tears, respectively, according to arthroscopic evaluation. Increasing cuff tear size was significantly associated with worsening degree of damage to the acromial undersurface (P < .001). In the 9 cadaveric shoulders with rotator cuff tears, class A1-A3 damage was identified in the anterior one-third area in 100%, in the middle one-third area in 88.9%, and in the posterior one-third area in 33.3%. In the 14 cadaveric shoulders with a normal rotator cuff, class A1-A3 damage was identified in the anterior one-third area in 35.7%, in the middle one-third area in 14.3%, and in the posterior one-third area in 0.71%. CONCLUSION: Damage to the acromial undersurface in patients with rotator cuff tears occurred at the middle, posterior, and anterior one-third areas, and the degree of damage was related to cuff tear size. Surgeons should evaluate the entire acromial undersurface to check for subacromial impingement damage at the middle and posterior one-third areas as well as the anterior one-third area of the acromial undersurface; this might aid in the treatment of patients with rotator cuff disease or subacromial impingement syndrome.

[«â€ Let's talk about sex†¼â€ : adolescent boys' sexual health in the primary care setting]. / «â€ Parlons de sexe avec eux aussi†¼â€ : ­la santé sexuelle des adolescents garçons en médecine de premier recours.

Despite obvious needs, adolescent boys do not access information and care in the field of sexual and reproductive health as easily as adolescent girls. The primary care setting gives the opportunity to tackle sexuality topics with boys. It allows to defuse frequent causes of concern in this crucial developmental phase, in a proactive and open-minded way, while focusing on strengths rather than on risks. It also allows to discuss masculine norms and their impact on health, and to come up with essential prevention elements. It is -necessary to focus on boys' health to have them involved in a -changing process on behalf of their own health but also on behalf of girls' and young women's health.

Malgré des besoins évidents en matière de santé sexuelle, les adolescents garçons accèdent moins à l'information et aux soins dans ce domaine que les filles. Toute consultation en médecine de premier recours avec un garçon fournit dès lors l'occasion d'élargir l'entretien aux questions de sexualité. Grâce à une ­approche proactive, ouverte, centrée sur les ressources plutôt que sur les risques, l'entretien permet d'aborder des inquiétudes courantes en cette période développementale cruciale, de discuter les modèles masculins et leur impact sur la santé ou encore d'évoquer des éléments incontournables de prévention. Porter notre attention sur la santé des garçons est essentiel afin de les engager en tant qu'acteurs de changement pour leur propre ­santé, mais aussi pour celle des filles et jeunes femmes.

[AN ADULT CASE OF PERIODIC FEVER, APHTHOUS STOMATITIS, PHARYNGITIS, AND ADENITIS (PFAPA) SYNDROME DEVELOPED IN CHILDHOOD AND DIAGNOSED AFTER PROGRESS MORE THAN 30 YEARS].

We report an adult case of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, who had a tonsillectomy at 10 years old and relapsed later. An early 40's-year-old man had been suffering from recurrent fever attack once in 1-2 months during childhood. He was accompanied by fever which was persist for several days, aphthous stomatitis, tongued tonsillitis with moss, pharyngitis, and submandibular lymphadenitis with tenderness. He was not doing well during fare-up. At the time of admission, CRP level was 12.5mg/dl and the remarkably increased expression of CD64 on neutrophils was found. Bacterial infections and collagen diseases were excluded by the several examinations. We suspected PFAPA syndrome, and treated with cimetidine, but cimetidine was not effective. At the time of flare up, administration of prednisolone was remarkably effective. We diagnosed PFAPA syndrome on the basis of clinical courses. Genetic analysis of responsible gene of familial Mediterranean fever, MEFV showed E148Q heterozygous mutation in exon 2.Since an adult case of PFAPA syndrome is likely to be made misunderstanding for infectious recurrent pharyngitis, it is important to note that we should consider PFAPA syndrome as a differential diagnosis when we meet with the adult patient of recurrent fever.

Impaired T cell receptor signaling and development of T cell-mediated autoimmune arthritis.

Mutations of the genes encoding T-cell receptor (TCR)-proximal signaling molecules, such as ZAP-70, can be causative of immunological diseases ranging from T-cell immunodeficiency to T-cell-mediated autoimmune disease. For example, SKG mice, which carry a hypomorphic point mutation of the Zap-70 gene, spontaneously develop T-cell-mediated autoimmune arthritis immunopathologically similar to human rheumatoid arthritis (RA). The Zap-70 mutation alters the sensitivity of developing T cells to thymic positive/negative selection by self-peptides/MHC complexes, shifting self-reactive TCR repertoire to include a dominant arthritogenic specificity and also affecting thymic development and function of autoimmune suppressive regulatory T (Treg) cells. Polyclonal self-reactive T cells, including potentially arthritogenic T cells, thus produced by the thymus recognize self-peptide/MHC complexes on antigen-presenting cells (APCs) in the periphery and stimulate them to produce cytokines including IL-6 to drive the arthritogenic T cells to differentiate into arthritogenic T-helper 17 (Th17) cells. Insufficient Treg suppression or activation of APCs via microbial and other environmental stimuli evokes arthritis by activating granulocyte-macrophage colony-stimulating factor-secreting effector Th17 cells, mediating chronic bone-destructive joint inflammation by activating myeloid cells, innate lymphoid cells, and synoviocytes in the joint. These findings obtained from the study of SKG mouse arthritis are instrumental in understanding how arthritogenic T cells are produced, become activated, and differentiate into effector T cells mediating arthritis, and may help devising therapeutic measures targeting autoimmune pathogenic Th17 cells or autoimmune-suppressing Treg cells to treat and prevent RA.

[PROFILES: typical portrait of the future Swiss doctors]. / PROFILES: portrait-type de nos futurs médecins !

In each professional practice, a greater or lesser part of the activity is devoted to teaching. Indeed, the transmission of the medical knowledge is an essential objective for the training of students and residents, but also an opportunity to adapt one's own practices to the current context, since fast changes are not necessarily easy to follow and assimilate. If the relationship with Medical school is rather straightforward in the university hospitals, it is not always the same for those who are more distant, but whose participation in teaching is desired, and clearly growing. In this way, it is therefore crucial that everyone is informed about recent changes to the undergraduated learning objectives (PROFILES) and the resulting needs for educational reforms for all Medical schools in Switzerland.

Dans chaque pratique professionnelle, une part plus ou moins grande de l'activité est dévolue à l'enseignement. En effet, la transmission de l'art médical représente un objectif essentiel pour la formation des étudiant·e·s et des jeunes collègues, mais aussi une opportunité pour adapter ses pratiques au contexte actuel, car les changements, rapides, ne sont pas forcément faciles à assimiler. Si, dans les hôpitaux universitaires, le contact avec les Facultés de médecine est plutôt aisé, il n'en va pas toujours de même pour ceux qui en sont plus distants, mais dont la participation à l'enseignement est souhaitée et croissante. En ce sens, il apparaît crucial que tou·te·s soient informé·e·s sur les modifications récentes des objectifs d'apprentissage prégradué (PROFILES) et sur les réformes qui en découlent pour les Facultés de médecine en Suisse.

Synovial Tissue Inflammation Mediated by Autoimmune T Cells.

In rheumatoid arthritis (RA), various hematopoietic and non-hematopoietic cells present in the synovial tissue secrete numerous inflammatory mediators including pro-inflammatory cytokines critical for the induction of chronic joint inflammation and bone destruction. Fibroblast-like synoviocytes (FLSs) in the non-hematopoietic cell compartment are key inflammatory cells activated in inflamed joints and driving the disease; yet how synovial tissue inflammation is modulated by autoimmune T cells is not fully understood. In this review, mainly based on recent findings with a mouse model of spontaneous autoimmune arthritis, we discuss the mechanism of Th17-mediated synovial tissue inflammation; that is, what environmental stimuli and arthritogenic self-antigens trigger arthritis, how arthritogenic T cells initiate joint inflammation by stimulating FLSs, and how the cellular sources of GM-CSF from lymphoid and tissue stromal cells in the synovium contribute to the development of arthritis. We also highlight possible plasticity of Th17 cells toward pathogenic GM-CSF producers, and the functional instability of regulatory T cells under inflammatory conditions in RA joints.