A novel homozygous mutation of the AIRE gene in an APECED patient from Pakistan: case report and review of the literature

Autoimmune-poly-endocrinopathy-candidiasis-ectodermal-dystrophy syndrome (APECED) is a rare monogenic recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Criteria for the diagnosis of APECED are the presence of two of the following disorders: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CHP), and Addison's disease. APECED develops at high incidence in Finns, Sardinians, and Iranian Jews and presents with a wide range of clinical phenotypes and genotypes. In this manuscript, we report the clinical, endocrinological, and molecular features of a 16-year-old female patient from Pakistan living in Italy and presenting the major APECED clinical manifestations CMC, CHP, and primary adrenal insufficiency. Premature ovarian failure, chronic bronchopneumopathy, vitiligo, Hashimoto's thyroiditis emerged as associated diseases. In our patient, AIRE gene screening revealed the novel c.396G > C (p. Arg132Ser; p. R132S) mutation in homozygosity thus confirming APECED diagnosis. This is the first reported mutation within the nuclear localization signal (NLS) that is associated with APECED. The NLS mutation affects the nuclear import of classical transcription factors through nuclear pore by recognition of nuclear import receptors, the importin a molecules. By displaying crystal structures of the peptide containing the KRK basic residue cluster bound to a importins, we show that p. R132S replacement in 131-KRK-133 does not reproduce these interactions. Thus, we propose that the novel mutation exerts its pathogenetic effect by impairing the nuclear import of the Aire protein. The present case report is added to a limited series of Pakistani APECED patients who we reviewed from the scientific literature, mostly diagnosed on clinical findings

Helicobacter, gamma-glutamyltransferase and cancer: further intriguing connections

Virulence of Helicobacter pylori , H. Suis and other bacteria appears to be partly mediated through a release of gamma-glutamyltransferase (GGT), an enzyme activity capable of promoting biochemical reactions ultimately resulting in damage to gastric epithelium and suppression of immune response. Recently published studies show that secretion of bacterial GGT occurs in the form of exosome-like vescicles. Very similar GGT-rich exosomes have been described to originate from human cancer cells, and the hypothesis is thus forwarded that in the resistant and invasive phenotype of malignant cells such vescicular/exosomal GGT may play roles akin to those described for Helicobacter infection, thus providing a significant contribution to the establishment of cancer metastases

Evoluzione dell'ipotiroidismo subclinico e sua correlazione con le concentrazioni sieriche di glucosio e trigliceridi in soggetti affetti da obesità morbigena dopo intervento di chirurgia bariatrica di gastrectomia a manica

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Le alterazioni dell'attività cerebrale nelle donne con obesità grave può migliorare dopo intervento di bypass gastrico

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Comparative study on the preventing effects of oral vanadyl sulfate and dietary restriction on the age-related glucose intolerance in rats.

BACKGROUND AND AIMS: Aging is associated with a progressive impairment of glucose tolerance. The aim of this study was to explore the protective effects of the chronic oral administration of the insulino-mimetic agent vanadyl sulfate (VOSO4) as compared with those exerted by a long-lasting dietary restriction. METHODS: Male Sprague-Dawley rats, either fed ad libitum (AL) or subjected to 40% dietary restriction (DR), were used. VOSO4 (0.5 mg/mL drinking water) was administered to a subgroup of AL rats for two months, starting at 16 months of age. Rats were subjected to an intravenous glucose tolerance test (IVGTT) at 16 and 18 months of age. Finally, the beta-cell responsiveness to glucose was evaluated in vitro by the isolated perfused pancreas preparation. RESULTS: The IVGTT performed in 16-month-old rats showed that DR prevented the development of the moderate glucose intolerance observed in AL rats. The IVGTT performed at 18 months of age confirmed the beneficial effect of DR and showed that VOSO4 was able to prevent the further age-related progression of glucose intolerance observed in AL rats. Pancreas perfusion studies showed that no increase in insulin secretion occurred in both VOSO4-treated and DR rats with respect to the age-matched AL controls, consistently with the in vivo observation of post-loading insulinaemic changes. CONCLUSIONS: On the basis of these results, we conclude that the beneficial effect of both treatments is mostly related to an improvement of tissue sensitivity to insulin rather than to an insulinotropic effect

Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression

Regulatory T (Treg) cells represent a subpopulation of suppressor CD4+ T cells critically involved in the establishment of peripheral tolerance through the inhibition of effector T (Teff) cells and the suppression of the immune-mediated tissue destruction toward self-antigens. Treg generation, their suppressive properties and also Treg-Teff cell interactions could be modulated at least in part by programmed cell death-1 (PD-1) expression on their surface and through binding between PD-1 and programmed cell death ligand-1 (PD-L1). Defects involving PD-1 and Tregs can lead to the development of pathological conditions, including autoimmune disorders or promote cancer progression by favoring tumor evasion from the host immune response. At the same time, PD-1 and Tregs could represent attractive targets for treatment, as demonstrated by the therapeutic blockade of PD-L1 applied for the management of different cancer conditions in humans. In the present Review, we focus specifically the role of PD-1/PD-L1 on Treg development and activity

Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers

Letter to the edito

The Impact of Specific Viruses on Clinical Outcome in Children Presenting with Acute Heart Failure

Abstract: The presence and type of viral genomes have been suggested as the main etiology for inflammatory dilated cardiomyopathy. Information on the clinical implication of this finding in a large population of children is lacking. We evaluated the prevalence, type, and clinical impact of specific viral genomes in endomyocardial biopsies (EMB) collected between 2001 and 2013 among 63 children admitted to our hospital for acute heart failure (median age 2.8 years). Viral genome was searched by polymerase chain reaction (PCR). Patients underwent a complete two-dimensional echocardiographic examination at hospital admission and at discharge and were followed-up for 10 years. Twenty-seven adverse events (7 deaths and 20 cardiac transplantations) occurred during the follow-up. Viral genome was amplified in 19/63 biopsies (35%); PVB19 was the most commonly isolated virus. Presence of specific viral genome was associated with a significant recovery in ejection fraction, compared to patients without viral evidence (p < 0.05). In Cox-regression analysis, higher survival rate was related to virus-positive biopsies (p < 0.05). When comparing long-term prognosis among different viral groups, a trend towards better prognosis was observed in the presence of isolated Parvovirus B19 (PVB19) (p = 0.07). In our series, presence of a virus-positive EMB (mainly PVB19) was associated with improvement over time in cardiac function and better long-term prognosis

Detection of GAD65 Autoreactive T-Cells by HLA Class I Tetramers in Type 1 Diabetic Patients

Type 1 diabetes (T1D) is an autoimmune disease, in which pancreatic β cells are destroyed in genetically predisposed individuals. While the direct contribution of autoantibodies to the disease pathogenesis is controversial, it is generally recognised that the mechanism of β cell destruction is mediated by autoreactive T cells that had escaped the thymic selection. We aimed to design a method to detect circulating CD8+ T cells autoreactive against an epitope of the glutamic acid decarboxylase autoantigen, isoform 65 (GAD65) ex vivo in T1D patients by using HLA class I tetramers. Low frequencies of GAD65 peptide-specific CD8+ cytotoxic T lymphocytes were detected in peripheral blood lymphocytes (PBMC) of normal controls after GAD65 peptide-specific stimulation. Conversely, their frequencies were significantly higher than in controls in PBMC of T1D patients after GAD65 peptide stimulation. These preliminary data are encouraging in order to develop a reliable assay to be employed in large-scale screening studies