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Streptococcal infections are known to trigger autoimmune disorders, affecting millions worldwide. Recently, we found an association between post-streptococcal autoantibodies against Protein Disulphide Isomerase (PDI), an enzyme involved in insulin degradation and insulin resistance. This led us to evaluate associations between post-streptococcal antibodies and metabolic syndrome, as defined by the updated National Cholesterol Education Program definition, 2005. Metabolic data (HDL, triglycerides, fasting glucose, blood pressure, waist circumference, BMI, smoking), post-streptococcal antibodies (anti-Streptolysin O (ASO) and anti-PDI), and C-reactive protein (CRP, as a general inflammatory marker), were assessed in 1156 participants of the Wisconsin Sleep Cohort Study. Anti-PDI antibodies were found in 308 participants (26.6%), ASO≥100 in 258 (22.3%), and 482 (41.7%) met diagnostic criteria for metabolic syndrome. Anti-PDI antibodies but not ASO were significantly associated with metabolic syndrome [n = 1156, OR 1.463 (95% CI 1.114, 1.920), p = 0.0062; adjusted for age, gender, education, smoking]. Importantly, the anti-PDI-metabolic syndrome association remained significant after adjusting for CRP and fasting insulin. Post-streptococcal anti-PDI antibodies are associated with metabolic syndrome regardless of fasting insulin and CRP levels. Whereas these data are in line with a growing body of evidence linking infections, immunity and metabolism, additional studies are necessary to establish the post-streptococcal-metabolic syndrome association.

Post-streptococcal autoimmunity affects millions worldwide, targeting multiple organs including the heart, brain, and kidneys. To explore the post-streptococcal autoimmunity spectrum, we used western blot analyses, to screen 310 sera from healthy subjects with (33%) and without (67%) markers of recent streptococcal infections [anti-Streptolysin O (ASLO) or anti-DNAse B (ADB)]. A 58 KDa protein, reacting strongly with post-streptococcal sera, was identified as Protein Disulfide Isomerase (PDI), an abundant protein with pleiotropic metabolic, immunologic, and thrombotic effects. Anti-PDI autoantibodies, purified from human sera, targeted similar epitopes in Streptolysin O (SLO, P51-61) and PDI (P328-338). The correlation between post-streptococcal status and anti-human PDI auto-immunity was further confirmed in a total of 2987 samples (13.6% in 530 ASLO positive versus 5.6% in 2457 ASLO negative samples, p<0.0001). Finally, anti-PDI auto-antibodies inhibited PDI-mediated insulin degradation in vitro (n = 90, p<0.001), and correlated with higher serum insulin (14.1 iu/ml vs. 12.2 iu/ml, n = 1215, p = 0.039) and insulin resistance (Homeostatic Model Assessment (HOMA) 4.1 vs. 3.1, n = 1215, p = 0.004), in a population-based cohort. These results identify PDI as a major target of post-streptococcal autoimmunity, and establish a new link between infection, autoimmunity, and metabolic disturbances.

Emmanuel Mignot and colleagues report genome-wide association analyses identifying a new susceptibility locus for narcolepsy. They identify associated variants in the 3′ untranslated region of P2RY11 , a purinergic receptor that modulates immune cell viability. Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11 , the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10 −10 , odds ratio = 1.28, 95% CI 1.19–1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8 + T lymphocytes (72% reduced, P = 0.003) and natural killer (NK) cells (70% reduced, P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes ( P = 0.0007) and natural killer cells ( P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.

Transference-Focused Psychotherapy for Adolescents With Severe Personality Disorders offers clinicians a comprehensive, compassionate presentation of this specialized psychodynamic psychotherapy. Like the transference-focused psychotherapy model developed for borderline personality disorder (BPD) in adults, the version for adolescents is based on contemporary psychoanalytic object relations theory as developed by the leading thinker in the field, Otto Kernberg, one of the authors of this insightful manual. The book fills an acute need: Currently, there is relatively little research on promising treatments for adolescents with PDs, in part because clinicians hesitate to diagnose PD in patients so young (because of stigma and other factors), although it is evident that a constellation of symptoms can be observed in children and adolescents. However, these personality issues are unlikely to resolve without interventions developed explicitly to treat adolescents. In TFP-A, the psychotherapist provides patients with a safe space to examine emotions, relationships, and past trauma, with the focus on helping them gain better behavioral control; increase affect regulation; develop more intimate and gratifying relationships with family, peers, or close friends; and engage in a productive life aimed at realizing current and future goals. Noteworthy themes and features of the text include: • Emphasis on the therapist as \"third voice, \" acting as interpreter and mediator between the adolescent, the parental couple, and conventional society and its values, with the ultimate goal of fostering ego integration sufficient to allow the adolescent to proceed under his own agency.• Detailed coverage of the techniques of TFP-A, including creating a holding environment, assuming an active stance, engaging in the interpretive process, analyzing transference and countertransference, achieving technical neutrality, and ensuring interventions are developmentally informed.• Practical and accessible review of TFP-A \"tactics, \" including establishing the treatment frame, collaborating with parents, and other interventions that maintain the conditions necessary for working effectively with the adolescent and for protecting treatment integrity.• Thoughtful review of the attributes that make a clinician a good \"fit\" for transference-focused psychotherapy. For example, therapists must have their own lives \"together, \" because they will have to use countertransference reactions to identity and understand what is projected onto them.• A rich and useful repository of assessment scales and forms in the Appendices, as well as extended and illustrative patient interviews. Navigating adolescence is fraught under the best of circumstances, but patients with PDs are hampered in their quest for individuation. Transference-Focused Psychotherapy for Adolescents With Severe Personality Disorders fills a critical gap in the treatment literature and is an eminently useful guide for clinicians serving this vulnerable population.

Nat. Genet. 43, 66–71 (2011); published online 19 December 2010; corrected after print 22 September 2011 In the version of this article initially published, the percentage reduction of P2RY11 expression in CD8+ T lymphocytes was incorrectly given as 339%, when it should have been 72%. The percentagewas not given for NK cells and should have been 70%.

Unter einer harten Schale steckt ein weicher Kern. Das Sprichwort trifft zu 100% auf ein Objekt zu, das seit dem Mesolithikum aus den vorgeschichtlichen Siedlungen und Jagdlagern nicht mehr wegzudenken ist: der Echte Zunderschwamm – »Fomes fomentarius«. Unterschiedlichste Verwendungsmöglichkeiten zeichnen diesen Alleskönner aus: Medizin und Zahnmedizin, Fischerei, zum Feuermachen und als Stoffersatz. Zwei Eigenschaften verdankt der Pilz seinen Erfolg: Brennbarkeit und Saugfähigkeit.

My decision to get tested was motivated by the knowledge that these mutations are common among women of Jewish Ashkenazi descent, and also due to my family history of breast cancer (I had these tests performed at the Genetic Institute at TASMC/lchilov, long before becoming Sourasky Medical Center's representative in the U.S.). I distinctly remember that my mother did not want to have these tests performed, preferring not to know, but I felt to the contrary. [Angelina Jolie]'s decision inspires me as a woman - a woman who truly cares that other women take responsibility for their health by choosing to act, to accept change and to make a difference. Lately, I am seeing more and more women, such as Angelina Jolie and Facebook COO Sheryl Sandberg (author of \"Lean In\"), deciding to take action: women who are not ashamed to use their voice, who believe in their choices, who inspire. Karin Weiner-Lachmi, Ph.D., is a life sci- ences entrepreneur and scientist based in Silicon Valley. She is the founder and chief science officer of DynamicBio, Inc. and the U.S. director of devel- opment for Tel Aviv Sourasky Medical Center. Weiner earned her Ph.D. in gene therapy related to brain and breast cancer at Tel Aviv University.

We have previously reported the molecular signature of murine pathogenic T H 17 cells that induce experimental autoimmune encephalomyelitis (EAE) in animals. Here we show that human peripheral blood IFN-γ + IL-17 + (T H 1/17) and IFN-γ − IL-17 + (T H 17) CD4 + T cells display distinct transcriptional profiles in high-throughput transcription analyses. Compared to T H 17 cells, T H 1/17 cells have gene signatures with marked similarity to mouse pathogenic T H 17 cells. Assessing 15 representative signature genes in patients with multiple sclerosis, we find that T H 1/17 cells have elevated expression of CXCR3 and reduced expression of IFNG , CCL3 , CLL4 , GZMB , and IL10 compared to healthy controls. Moreover, higher expression of IL10 in T H 17 cells is found in clinically stable vs. active patients. Our results define the molecular signature of human pro-inflammatory T H 17 cells, which can be used to both identify pathogenic T H 17 cells and to measure the effect of treatment on T H 17 cells in human autoimmune diseases. CD4 + T cells secreting interleukin-17 (T H 17) have diverse functions in modulating autoimmune diseases. Here the authors show via transcriptome analyses that a subset of human T H 17 co-expressing interferon-γ (T H 1/17) has a molecular signature similar to “pathogenic” mouse T H 17 but distinct from “non-pathogenic” mouse T H 17.

Aims: Myocardial inflammation in cardiac amyloidosis is associated with poor clinical outcomes. This study aimed to (a) investigate the relationship between peripheral blood cytokine levels and the presence of inflammatory cells within the myocardium, and to (b) evaluate the potential of cytokines as predictors of major adverse cardiovascular events (MACE) in transthyretin (ATTR) and immunoglobulin light chain (AL) cardiac amyloidosis. Methods: Peripheral blood samples were collected from 50 patients with cardiac ATTR or AL amyloidosis between 2018 and 2023 at baseline and every three months during follow-up visits. Cytokine analysis was performed using Olink’s Proximity Extension Assay. For MACE prediction analysis, only patients with MACE occurring within ±14 days of a study visit were included (n = 16). Associations were evaluated using linear models. Results: No significant associations were identified between the EMB-confirmed myocardial presence of inflammatory cells and cytokine levels. There was a trend of weak-to-moderate associations between serial blood cytokine levels and MACE, albeit this was non-significant after adjustment for multiple testing (FDR): r2 = 0.28 for PON3 (p = 0.00075, FDR = 0.28), SIGLEC1 (p = 0.00077, FDR = 0.28), and IL-6 (p = 0.00086, FDR = 0.31). Conclusions: Peripheral blood cytokine levels were not reliable biomarkers for the myocardial presence of inflammatory cells. PON3, SIGLEC1, and IL-6 demonstrated a statistically non-significant trend of a weak-to-moderate association with MACE in cardiac amyloidosis. Since we recently demonstrated that amyloidosis with an inflammatory component is associated with poor outcomes, these additional findings underscore the need for alternative approaches to identify and manage inflammation in this patient population.