The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Choice of pharmaceutical form as a key factor during ketogenic diet: a case report.

West syndrome is a severe epilepsy syndrome characterised by the appearance of drug-resistant epileptic disorders associated with hypsarrhythmia and intellectual disability. Among non-pharmacological treatments, the ketogenic diet, which consists of low carbohydrate intake and a rich lipid intake, stands out. This treatment induces a state of ketosis, which has been related to a decrease in the number of seizures. It is essential to control the carbohydrate intake within drug treatment for these patients since many pharmaceutical forms, specifically liquid oral medication, may contain carbohydrates in the form of mono/polysaccharides or polyols. We describe the case report of an infant with drug-resistant West syndrome, treated with a ketogenic diet, whose antiseizure liquid medication impeded a proper response to the diet. After the substitution of these medications, the patient showed a remarkable decrease in the number of seizures.

Intrahepatic Cholestasis Is a Clinically Significant Feature Associated with Natural History of X-Linked Myotubular Myopathy (XLMTM): A Case Series and Biopsy Report.

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy characterized by profound skeletal muscle weakness, respiratory distress, and motor dysfunction. However, pathology is not limited to muscle and can be associated with life-threatening hepatic peliosis. Hepatobiliary disease has been reported in up to 17% of XLMTM patients but has not been extensively characterized. We report on five XLMTM patients who experienced intrahepatic cholestasis in their disease natural history, illustrating the need to further investigate these manifestations. These patients shared presentations that included pruritus, hypertransaminemia, and hyperbilirubinemia with normal gamma-glutamyl transferase, following infection or vaccination. Three patients who had genetic testing showed no evidence of genetic mutations associated with familial cholestasis. In one patient, progression to cirrhotic, decompensated liver disease occurred. Further investigations into the molecular pathomechanism underpinning these clinical observations in XLMTM patients will be important for informing patient care.

Eructos supragástricos. Una entidad a conocer / Supragastric belches. An entity to know

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Data Mining Techniques Applied to Hydrogen Lactose Breath Test.

OBJECTIVES: Analyze a set of data of hydrogen breath tests by use of data mining tools. Identify new patterns of H2 production. METHODS: Hydrogen breath tests data sets as well as k-means clustering as the data mining technique to a dataset of 2571 patients. RESULTS: Six different patterns have been extracted upon analysis of the hydrogen breath test data. We have also shown the relevance of each of the samples taken throughout the test. CONCLUSIONS: Analysis of the hydrogen breath test data sets using data mining techniques has identified new patterns of hydrogen generation upon lactose absorption. We can see the potential of application of data mining techniques to clinical data sets. These results offer promising data for future research on the relations between gut microbiota produced hydrogen and its link to clinical symptoms.