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A retrospective magnetic resonance imaging (MRI) study on a large cohort of children with thalassemia major (TM) showed cardiac involvement by early childhood; 21% of children presented with abnormal cardiac T2* and 16% with cardiac fibrosis. Moreover, moderate and/or severe liver iron overload (IO

The present paper investigates the role of urban stress, local identity and sustainable worldviews in the prediction of a set of urban pro-environmental behaviors: recycling, domestic water saving, non-littering, sustainable transport, support for environmental associations, and willingness to pay for green energy. Using self-report measures, a correlational field study was carried out (N = 242). Results show that both urban stress and endorsement of sustainable worldviews are significant positive predictors of pro-environmental behavior in general, and of non-littering and supporting environmental organizations in particular. City identity moderates the relationship between urban stress and, respectively, willingness to pay for green energy and non-littering: a high level of stress predicts these pro-environmental patterns only for those who strongly identify with their city. The theoretical and practical implications of these results are discussed.

Background: Classification of phenotype severity in patients with beta-thalassaemia has so far relied mainly on expert opinion using parameters of genotype, clinical features at diagnosis, and transfusion requirement. The aim of this study was to use a large dataset of patients with beta-thalassaemia and evaluate a classification system based on onset variables agreed on by an international expert group, including age at diagnosis, at first transfusion, and at first iron chelation. Methods: A retrospective dataset of 7910 patients with homozygous or compound heterozygous beta-thalassaemia was used and subjected to cluster and classification analysis starting with the onset variables. Results: Cluster analysis suggested that three clusters with minimal overlapping exist. Three phenotype severity classes (mild, moderate, severe) were accordingly assigned which showed statistically significant descending variation of age at diagnosis and start of transfusion and iron chelation. The estimated classification error rate was only 3.07% with an accuracy of 96.93%. It was evident that severe patients had higher blood requirement and iron overload levels and showed a younger age for mortality especially from heart disease. Although mild and moderate patients showed the opposite in gradual severity, they still showed evidence of high morbidity rate for complications that require longer time to manifest (eg liver damage and hepatocellular carcinoma). Conclusion: Age of diagnosis and start of transfusion and iron chelation distinguish three classes of phenotype severity in beta-thalassaemia that carry unique clinical profiles. Further prospective studies are recommended to validate these findings. Funding Statement: The authors state: "None" Declaration of Interests: The authors state: " None to disclose." Ethics Approval Statement: An International Health Repository (IHR) protocol, approved on May 25th, 2017 by the Italian Ethical Committee (EudraCT and Sponsor's Protocol Code Numbers were 2017-004457-17 and 143AOR2017) was established to allow collection of relevant data.

Summary APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility., Graphical Abstract, Highlights • Each AIRE-deficient patient has a private repertoire of autoantibody reactivities • Loss of B cell tolerance occurs during T cell-dependent somatic hypermutation • Patient autoantibodies have unprecedented affinities for conformational epitopes • Patient autoantibodies can display disease-ameliorating properties in vivo, Self-reactive antibodies specific for type I interferons are associated with protection against type I diabetes in patients with an autoimmune syndrome caused by mutations in AIRE.

Background & Aims Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autoimmune disorder characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency, but patients also develop intestinal disorders. APECED is an autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE, which regulates immune tolerance) that allow self-reactive T cells to enter the periphery. Enteric α-defensins are antimicrobial peptides secreted by Paneth cells. Patients with APECED frequently have gastrointestinal symptoms and seroreactivity against secretory granules of Paneth cells. We investigated whether enteric α-defensins are autoantigens in humans and mice with AIRE deficiency. Methods We analyzed clinical data, along with serum and stool samples and available duodenal biopsies from 50 patients with APECED collected from multiple centers in Europe. Samples were assessed for expression of defensins and other molecules by quantitative reverse transcription polymerase chain reaction and flow cytometry; levels of antibodies and other proteins were measured by immunohistochemical and immunoblot analyses. Histologic analyses were performed on biopsy samples. We used Aire −/− mice as a model of APECED, and studied the effects of transferring immune cells from these mice to athymic mice. Results Enteric defensins were detected in extraintestinal tissues of patients with APECED, especially in medullary thymic epithelial cells. Some patients with APECED lacked Paneth cells and were seropositive for defensin-specific autoantibodies; the presence of autoantibodies correlated with frequent diarrhea. Aire −/− mice developed defensin-specific T cells. Adoptive transfer of these T cells to athymic mice resulted in T-cell infiltration of the gut, loss of Paneth cells, microbial dysbiosis, and the induction of T-helper 17 cell-mediated autoimmune responses resembling those observed in patients with APECED. Conclusions In patients with APECED, loss of AIRE appears to cause an autoimmune response against enteric defensins and loss of Paneth cells. Aire −/− mice developed defensin-specific T cells that cause intestinal defects similar to those observed in patients with APECED. These findings provide a mechanism by which loss of AIRE-mediated immune tolerance leads to intestinal disorders in patients with APECED.

Allan–Herndon–Dudley syndrome (AHDS), an X linked condition, is characterized by severe intellectual disability, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia in combination with altered TH levels, in particular, high serum T3 levels. Mutations in the MCT8 gene coding for the monocarboxylate thyroid hormone transporter 8 have been associated with AHDS. Here we describe a family with the presence of a MCT8 gene mutation, p.A224T, in three consecutive generations. In two generations its presence was detected in the hemizygous state in two males with neurological abnormalities including mental retardation, axial hypotonia, hypertonia of arms and legs and athetoid movements. One of them presented normal thyroid hormone levels. Mutation was also detected, although in the heterozygous state, in three females showing thyroid hormone levels in the normal range. Our results show the difficulty of distinguishing AHDS from patients with X-linked intellectual disability solely on the basis of clinical features and biochemical tests, and we advise screening for MCT8 mutations in either young or older patients with severe intellectual disability, axial hypotonia/dystonia, poor head control, spastic paraplegia, and athetoid movements even when they have normal thyroid hormone profiles.

Purpose To build and evaluate a national network able to improve the care of thalassemia, a genetic disorder in haemoglobin synthesis often associated with iron accumulation in a variety of organs, due to the continuous blood transfusions. Methods The MIOT (Myocardial Iron Overload in Thalassemia) network is constituted by thalassemia and magnetic resonance imaging (MRI) centers. Thalassemia centers are responsible for patient recruitment and collection of anamnestic and clinical data. MRI centers have been equipped with a standardized acquisition technique and an affordable workstation for image analysis. They are able to perform feasible and reproducible heart and liver iron overload assessments for a consistent number of thalassemia patients in a robust manner. All centers are linked by a web-based network, configured to collect and share patient data. Results On 30th March 2008, 695 thalassemia patients were involved in the network. The completion percentage of the patient records in the database was 85 ± 6.5%. Six hundred and thirteen patients (88%) successfully underwent MRI examination. Each MRI center had a specific absorption capacity that remained constant over time, but the network was capable of sustaining an increasing number of patients due to continuous enrollment of new centers. The patient's comfort, assessed as the mean distance from the patient home locations to the MRI centers, significantly increased during the network's evolution. Conclusion The MIOT network seems to be a robust and scalable system in which T2* MRI-based cardiac and liver iron overload assessment is available, accessible and reachable for a significant and increasing number of thalassemia patients in Italy (about 420 per year), reducing the mean distance from the patient locations to the MRI sites from 951 km to 387 km. A solid, wide and homogeneous database will constitute an important scientific resource, shortening the time scale for diagnostic, prognostic and therapeutical evidence-based research on the management of thalassemia disease.

Background & Aims: Liver disease has been described in 10%–15% of patients with autoimmune polyglandular syndrome type 1 (APS-1). After the discovery of cytochrome P450 1A2 (CYP1A2) as a hepatocellular autoantigen in liver-kidney microsomal autoantibody (LKM)-positive patients with APS-1, the investigation of antiliver antibodies was extended to 11 Sardinian patients with APS-1. Methods: Indirect immunofluorescence and Western blotting analysis were performed to study the antiliver antibodies. Results: Immunofluorescence revealed LKM antibodies in 3 patients with APS-1, 1 of whom died of fulminant hepatitis. Western blotting showed a liver microsomal protein band of approximately 51 kilodaltons in the LKM-positive sera of these 3 patients. Western blotting performed with recombinant cytochrome P450 enzymes allowed the identification of CYP2A6 as a specific target antigen. Conclusions: LKM antibodies in APS-1 sera are specifically directed against CYP1A2 or CYP2A6, but their diagnostic and prognostic significance for liver disease remain to be determined. GASTROENTEROLOGY 1998;114:324-328