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.

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.

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.

[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 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.

[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.

[«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.

[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.

Plant nyctinasty - who will decode the 'Rosetta Stone'?

Nyctinasty is the circadian rhythmic nastic movement of leguminous plants in response to the onset of darkness, a unique and intriguing phenomenon that has attracted attention for centuries. The movement itself is caused by the asymmetric volume change of motor cells between the adaxial and abaxial sides of the leaflet. Recently, we identified the ion channels responsible for the volume change of motor cells during the leaf-opening process of Samanea saman; the asymmetric expression of SsSLAH1, which is under the control of SsCCA1, was found to play a key role in this process. Here, we summarize the history of the study of nyctinasty, our current results and several insights for further study.

[Fatigue in the adolescent athlète]. / La fatigue chez l'athlète adolescent.

Adolescent athletes frequently complain of fatigue. Acute fatigue after intense training is physiological and necessary in order to develop capacity and increase performance. However, healthcare practitioners must question persistant fatigue, which causes are multiple, sometimes clear, though mostly multifactorial. A comprehensive and holistic approach is especially required in adolescents, with a complete somatic, psychosocial and athletic history. The role of healthcare professionals is to quickly identify specific signs and complex diagnoses, which can lead to physical and psychological consequences in the long term (overtraining, burnout, abuse, eating disorders). Finally, in a time where overweight and inactivity is rampant in the youth, we must imperatively avoid adolescents dropping out of sports and activity.

La fatigue est un motif de consultation fréquent chez l'athlète adolescent. Une fatigue aiguë après un effort intensif est physiologique, voire même recherchée dans le but d'améliorer les performances. Une fatigue qui s'installe doit interpeller. Les causes sont multiples, parfois bien précises, mais souvent multifactorielles. Une approche holistique est indispensable, surtout chez l'adolescent, avec une anamnèse somatique, psychosociale et sportive détaillée. Le rôle du professionnel de la santé est de détecter au plus vite les premiers signes, certains diagnostics difficiles à poser pouvant avoir de lourdes conséquences physiques et psychiques à long terme (surentraînement, burnout, abus, trouble du comportement alimentaire). En cette ère d'épidémie de surpoids chez les jeunes, l'abandon du sport est à éviter absolument.

Presepsin as a predictor of positive blood culture in suspected neonatal sepsis.

BACKGROUND: Although the incidence of neonatal sepsis is decreasing, neonatal sepsis remains a severe life-threatening disease. No current biochemical marker can provide perfect diagnostic accuracy for neonatal sepsis. The aim of this study was therefore to evaluate the accuracy of presepsin (P-SEP) as a novel biomarker of bacterial infection for neonatal sepsis diagnosis. METHODS: We prospectively studied newborns with sepsis (sepsis group; n = 13) during the first 30 days after birth and compared them with control preterm newborns (control group; n = 18). In addition, we evaluated term newborns with some clinical signs of early onset sepsis (non-sepsis term group; n = 35). RESULTS: P-SEP in the sepsis group was significantly higher than in the control group (P < 0.001) The area under the curve for P-SEP was 0.868 (95%CI: 0.71-1.00). A P-SEP cut-off of 795 pg/mL was established, with 85% sensitivity and 89% specificity. The positive and negative predictive values were 85% and 89%, respectively. In the non-sepsis term group, P-SEP had better stability than white blood cells and C-reactive protein for 3 days after birth. CONCLUSIONS: P-SEP can better discriminate between infections and non-infectious inflammatory conditions than the currently used biomarkers.

[Lost in transition: crossed looks on the 18-25 years old]. / Lost in transition :regards croisés sur les 18-25 ans.

Social determinants have an impact on patients' access to care and on their health at any age. Young adults are a population at risk of being affected in their health because of a lack of social protection or unavailability of healthcare system adapted to their specific needs. Primary healthcare providers need to identify that window of social vulnerability in order to avoid a discontinuation in healthcare and to prevent biopsychosocial co-morbidity leading to ongoing consequences on their health.

L'impact des déterminants sociaux sur l'accès aux soins des patients et sur leur santé concerne toutes les catégories d'âge. Les jeunes adultes sont une population particulièrement à risque d'être pénalisés dans leur santé par un défaut de protection sociale ou de réseau de soins adapté à leurs besoins spécifiques. Le médecin de premier recours, pédiatre ou généraliste, doit identifier cette fenêtre de vulnérabilité sociale afin d'éviter une rupture de soins et prévenir les comorbidités biopsychosociales ayant des conséquences durables sur la santé.

Cardiovascular Remodeling and Dysfunction Across a Range of Growth Restriction Severity in Small for Gestational Age Infants　- Implications for Fetal Programming.

BACKGROUND: The purpose of this study was to clarify cardiovascular structure and function in small for gestational age (SGA) infants across a range of intrauterine growth restriction (IUGR) severity. METHODS AND RESULTS: This prospective study included 38 SGA infants and 30 appropriate for gestational age (AGA) infants. SGA infants were subclassified into severe and mild SGA according to the degree of IUGR. Cardiovascular structure and function were evaluated using echocardiography at 1 week of age. Compared with the AGA infants, both the severe and mild SGA infants showed increased left ventricular diastolic dimensions (severe SGA 10.2±2.4, mild SGA 8.2±1.3, and AGA 7.3±0.7 mm/kg, P<0.05 for all) and decreased global longitudinal strain (severe -21.1±1.6, mild -22.5±1.8, and AGA -23.8±1.8%, P<0.05 for all). Severe SGA infants showed a decreased mitral annular early diastolic velocity (severe 5.6±1.4 vs. AGA 7.0±1.3 cm/s, P<0.01) and increased isovolumic relaxation time (severe 51.3±9.2 vs. AGA 42.7±8.2 ms, P<0.01). Weight-adjusted aortic intima-media thickness and arterial wall stiffness were significantly greater in both SGA infant groups. These cardiovascular parameters tended to deteriorate with increasing IUGR severity. CONCLUSIONS: SGA infants, including those with mild SGA, showed cardiovascular remodeling and dysfunction, which increased with IUGR severity. (Circ J 2016; 80: 2212-2220).

ORF13 in the Type III secretion system gene cluster of Edwardsiella tarda binds to the mammalian factor Cugbp2.

The Type III secretion system (TTSS) is essential for the intracellular replication of Edwardsiella tarda in phagocytes of fish and mammals, and a hypothetical gene (orf13) located in the TTSS gene cluster is required for intracellular replication and virulence of E. tarda. Here, we show that under TTSS-inducing conditions, the protein ORF13 was secreted into culture supernatant. Then, using a yeast 2-hybrid screen, we show that the mammalian factor Cugbp2, which regulates apoptosis in breast cancer cells, directly interacts with ORF13. A pull-down assay revealed that ORF13 binds to the C-terminal region of Cugbp2. Our results suggest that ORF13 may facilitate E. tarda replication in phagocytes by binding to Cugbp2.

Type III secretion system genes of Edwardsiella tarda associated with intracellular replication and virulence in zebrafish.

The Type III secretion system (T3SS) is essential for intracellular replication of Edwardsiella tarda in phagocytes of fish and mammals. Two possible effector candidate genes (eseE and eseG) and 7 hypothetical genes (esaB, escC, orf13, orf19, orf26, orf29, and orf30) located in the T3SS gene cluster were inactivated by an allelic exchange method, and we found that E. tarda strains carrying insertion mutations in escC, orf13, orf19, orf29, and orf30 were unable to replicate within J774 macrophages and HEp-2 epithelial cells. Furthermore, the virulence of these mutants to zebrafish was severely attenuated as well. These data suggest that the escC, orf13, orf19, orf29, and orf30 genes are required for intracellular replication and virulence of E. tarda.

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.

[Atopic dermatitis in children: general principles of management]. / Dermatite atopique de l'enfant: principes généraux de la prise en charge.

Atopic dermatitis is the most frequent dermatosis in childhood. Numerous studies underscored the central role of skin barrier alterations in the pathogenesis of the inflammatory skin lesions. The management of atopic dermatitis has to be multidimensional. It combines among others some daily local care and a sporadic topical anti-inflammatory treatment during the acute flare-ups. The objective of this article is to summarize, in light of the recent European guidelines, the general principles of management of atopic dermatitis, for the general practitioner.