Case report: Neonatal-onset inflammatory bowel disease due to novel compound heterozygous mutations in DUOX2

Very Early Onset Inflammatory Bowel Disease (VEO-IBD) is potentially associated with genetic disorders of the intestinal epithelial barrier or inborn errors of immunity (IEI). Dual oxidase 2 (DUOX2), an H2O2-producing NADPH oxidase expressed at apical enterocyte membranes, plays a crucial role in innate defense response. Biallelic DUOX2 mutations have been described only in two patients with VEO-IBD to date. We report the case of a 1-month-old female infant who presented persistent high C-reactive protein (CRP) levels from birth and anemia. Positive occult blood and very high calprotectin in the stool were detected and abdominal ultrasound showed thickened last ileal loop. Full endoscopy evaluation revealed important colon stenosis with multiple pseudo-polyploidy formations that resulted refractory to steroid therapy, requiring a partial colic resection. Histological examination of biopsy samples showed morphological features of IBD. Whole Exome Sequencing (WES) disclosed compound heterozygous variants in the DUOX2 gene: the pathogenic c.2524C>T; p.Arg842Ter and the variant of uncertain significance (VUS) c.3175C>T; p.Arg1059Cys. Molecular and functional studies showed the presence of mutant DUOX2 in the intestinal epithelium of the patient, albeit with at least 50% decreased catalytic activity. In conclusion, we describe the third patient to date with compound heterozygous variants of DUOX2, responsible for monogenic neonatal-IBD. This case expands the knowledge about Mendelian causes of VEO-IBD and DUOX2 deficiency. We suggest that DUOX2 should be part of the diagnostic evaluation of patients with suspected monogenic VEO-IBD

Long-term vitamin E supplementation fails to reduce lipid peroxidation in people at cardiovascular risk: analysis of underlying factors

BACKGROUND: Antioxidant supplementation with vitamin E had no effect in the prevention of cardiovascular diseases (CVD) in three recent large, randomized clinical trials. In order to reassess critically the role of vitamin E in CVD prevention, it is important to establish whether these results are related to a lack of antioxidant action. METHODS: We examined the in vivo antioxidant effect of vitamin E (300 mg/day for about three years) in 144 participants in the Primary Prevention Project (females and males, aged ≥ 50 y, with at least one major CV risk factor, but no history of CVD). Urinary 8-epi-PGF(2α) (isoprostane F(2α)-III or 15-F(2t)-isoP), a validated biomarker of lipid peroxidation, was measured by mass spectrometry. RESULTS: Urinary excretion of 8-epi-PGF(2α) [pg/mg creatinine, median (range)] was 141 (67–498) in treated and 148 (76–561) in untreated subjects (p = 0.10). Taking into account possible confounding variables, multiple regression analysis confirmed that vitamin E had no significant effect on this biomarker. Levels of 8-epi-PGF(2α) were in the normal range for most subjects, except smokers and those with uncontrolled blood pressure or hyperglycemia. CONCLUSIONS: Prolonged vitamin E supplementation did not reduce lipid peroxidation in subjects with major cardiovascular risk factors. The observation that the rate of lipid peroxidation was near normal in a large proportion of subjects may help explain why vitamin E was not effective as an antioxidant in the PPP study and was ineffective for CVD prevention in large scale trials

HIPOTIREOIDISMO: UMA REVISÃO BIBLIOGRÁFICA SOBRE AS ETIOLOGIAS, DIAGNÓSTICO E CONDUTAS TERAPÊUTICAS

Introduction: Hypothyroidism is a common endocrine condition characterized by insufficient production of thyroid hormones. This dysfunction affects approximately 4.6% of the world population, with a higher prevalence in women and the elderly. Objective: Review the etiologies, diagnosis and treatment of hypothyroidism. Methodology: This is a bibliographic review, using articles present in the following databases: PubMed, Web of Science and Scopus. Original articles and systematic reviews in English and Portuguese published between 2013 and 2024, which addressed hypothyroidism, were included. After analysis, 31 articles were selected to prepare this bibliographic review. Results and Discussion: Among the main etiologies discussed are autoimmune disorders, such as Hashimoto's thyroiditis, treatment with radioactive iodine, nutritional deficiencies and the effects of medications. Laboratory tests, such as measuring TSH (thyroid-stimulating hormone), free T4 and antithyroid antibodies, are essential for diagnosing hypothyroidism. Hormone replacement therapy with levothyroxine, a synthetic thyroxine (T4) hormone, is the main therapeutic approach for primary hypothyroidism. Conclusion: Hypothyroidism is a common endocrine condition that significantly affects patients' quality of life.Introducción: El hipotiroidismo es una afección endocrina común caracterizada por una producción insuficiente de hormonas tiroideas. Esta disfunción afecta aproximadamente al 4,6% de la población mundial, con mayor prevalencia en mujeres y personas mayores. Objetivo: Revisar las etiologías, diagnóstico y tratamiento del hipotiroidismo. Metodología: Se trata de una revisión bibliográfica, utilizando artículos presentes en las siguientes bases de datos: PubMed, Web of Science y Scopus, se incluyeron artículos originales y revisiones sistemáticas en inglés y portugués publicados entre 2013 y 2024, que abordaron el hipotiroidismo. Luego del análisis, se seleccionaron 31 artículos para elaborar esta revisión bibliográfica. Resultados y Discusión: Entre las principales etiologías discutidas se encuentran los trastornos autoinmunes, como la tiroiditis de Hashimoto, el tratamiento con yodo radiactivo, las deficiencias nutricionales y los efectos de los medicamentos. Las pruebas de laboratorio, como la medición de TSH (hormona estimulante de la tiroides), T4 libre y anticuerpos antitiroideos, son fundamentales para diagnosticar el hipotiroidismo. La terapia de reemplazo hormonal con levotiroxina, una hormona tiroxina (T4) sintética, es el principal enfoque terapéutico para el hipotiroidismo primario. Conclusión: El hipotiroidismo es una condición endocrina común que afecta significativamente la calidad de vida de los pacientes.O hipotireoidismo é uma condição endócrina comum, caracterizada pela produção insuficiente de hormônios tireoidianos. Essa disfunção afeta aproximadamente 4,6% da população mundial, com prevalência maior em mulheres e idosos. Objetivo: Revisar as etiologias, diagnóstico e o tratamento do hipotireoidismo. Metodologia: Trata-se de uma revisão bibliográfica, utilizando artigos presentes nas seguintes bases de dados: PubMed, Web of Science e Scopus Foram incluídos artigos originais e revisões sistemáticas em inglês e português publicadas entre 2013 e 2024, que abordassem sobre o hipotireoidismo. Após a análise, foram selecionados 31 artigos para a confecção dessa revisão bibliográfica.  Resultados e Discussão: Entre as principais etiologias discutidas estão os distúrbios autoimunes, como a tireoidite de Hashimoto, o tratamento com iodo radioativo, deficiências nutricionais e os efeitos de medicamentos. Os exames laboratoriais, como a dosagem de TSH (hormônio estimulante da tireoide), T4 livre e anticorpos antitireoidianos, são fundamentais para o diagnóstico do hipotireoidismo. A terapia de reposição hormonal com levotiroxina, um hormônio sintético de tiroxina (T4), é a principal abordagem terapêutica para o hipotireoidismo primário.  Conclusão: O hipotireoidismo é uma condição endócrina comum que afeta significativamente a qualidade de vida dos pacientes.Introdução: O hipotireoidismo é uma condição endócrina comum, caracterizada pela produção insuficiente de hormônios tireoidianos. Essa disfunção afeta aproximadamente 4,6% da população mundial, com prevalência maior em mulheres e idosos. Objetivo: Revisar as etiologias, diagnóstico e o tratamento do hipotireoidismo. Metodologia: Trata-se de uma revisão bibliográfica, utilizando artigos presentes nas seguintes bases de dados: PubMed, Web of Science e Scopus Foram incluídos artigos originais e revisões sistemáticas em inglês e português publicadas entre 2013 e 2024, que abordassem sobre o hipotireoidismo. Após a análise, foram selecionados 31 artigos para a confecção dessa revisão bibliográfica.  Resultados e Discussão: Entre as principais etiologias discutidas estão os distúrbios autoimunes, como a tireoidite de Hashimoto, o tratamento com iodo radioativo, deficiências nutricionais e os efeitos de medicamentos. Os exames laboratoriais, como a dosagem de TSH (hormônio estimulante da tireoide), T4 livre e anticorpos antitireoidianos, são fundamentais para o diagnóstico do hipotireoidismo. A terapia de reposição hormonal com levotiroxina, um hormônio sintético de tiroxina (T4), é a principal abordagem terapêutica para o hipotireoidismo primário.  Conclusão: O hipotireoidismo é uma condição endócrina comum que afeta significativamente a qualidade de vida dos pacientes

Radiosensitivity in patients affected by ARPC1B deficiency: a new disease trait?

Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is a recently described inborn error of immunity (IEI) presenting with combined immunodeficiency and characterized by recurrent infections and thrombocytopenia. Manifestations of immune dysregulation, including colitis, vasculitis, and severe dermatitis, associated with eosinophilia, hyper-IgA, and hyper-IgE are also described in ARPC1B-deficient patients. To date, hematopoietic stem cell transplantation seems to be the only curative option for patients. ARPC1B is part of the actin-related protein 2/3 complex (Arp2/3) and cooperates with the Wiskott–Aldrich syndrome protein (WASp) in the regulation of the actin cytoskeleton remodeling and in driving double-strand break clustering for homology-directed repair. In this study, we aimed to investigate radiosensitivity (RS) in ARPC1B-deficient patients to assess whether it can be considered an additional disease trait. First, we performed trio-based next-generation-sequencing studies to obtain the ARPC1B molecular diagnosis in our index case characterized by increased RS, and then we confirmed, using three different methods, an increment of radiosensitivity in all enrolled ARPC1B-deficient patients. In particular, higher levels of chromatid-type aberrations and γH2AX foci, with an increased number of cells arrested in the G2/M-phase of the cell cycle, were found in patients’ cells after ionizing radiation exposition and radiomimetic bleomycin treatment. Overall, our data suggest increased radiosensitivity as an additional trait in ARPC1B deficiency and support the necessity to investigate this feature in ARPC1B patients as well as in other IEI with cytoskeleton defects to address specific clinical follow-up and optimize therapeutic interventions

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Background: Activated phosphoinositide-3-kinase d syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain of-function (GOF) disease; and identify predictors of severity in APDS. Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients. (J Allergy Clin Immunol 2023;152:984-96.

La nouvelle organisation administrative italienne.

Rivalta Maria. La nouvelle organisation administrative italienne.. In: Revue internationale de droit comparé. Vol. 3 N°4, Octobre-décembre 1951. pp. 606-615

Two State Reactivity Paradigm in Catalysis. The Example of X-H (X = O, N, C) and C-C Bonds Activation Mediated by Transition Metal Compounds

A brief review of the theoretical work carried out on the activation of O-H, N-H, C-H and C-C bonds of small prototypical molecules mediated by \u201cbare\u201d transition metal atoms and cations in gas-phase is reported. Potential energy surfaces are examined in light of the role that spin changes can play in determining the final outcome of this kind of reactions and the results are analyzed in terms of two state reactivity paradigm. The performance of Density Functional Theory, in its B3LYP formulation, in this field is discussed along with comparison with experimental findings and high level ab initio computations

Acetylene cyclotrimerization by early second-row transition metals in the gas phase. A theoretical study

The acetylene cyclotrimerization reaction mediated by the left-hand-side bare transition metal atoms Y, Zr, Nb, and Mo has been studied theoretically, employing DFT in its B3LYP formulation. The complete reaction mechanism has been analyzed, identifying intermediates and transition states. Both the ground spin state and at least one low-lying excited state have been considered to establish whether possible spin crossings between surfaces of different multiplicity can occur. Our results show that the overall reaction is highly favorable from a thermodynamic point of view and ground state transition states lie always below the energy limit represented by ground state reactants. After the activation of two acetylene molecules and formation of a bis-ligated complex, the reaction proceeds to give a metallacycle intermediate, as the alternative formation of a cyclobutadiene complex is energetically disfavored. All the examined reaction paths involve formation of a metallacycloheptatriene intermediate that in turn generates a metal-benzene adduct from which finally benzene is released. Similarities and differences in the behaviors of the considered four metal atoms have been examined. \ua9 2005 American Chemical Society

Potential effectiveness of pelvic floor rehabilitation treatment for postradical prostatectomy incontinence, climacturia, and erectile dysfunction: a case series

INTRODUCTION: Radical prostatectomy is the treatment of choice for prostate cancer; although novel techniques have significantly reduced its side effects, the procedure can provoke urinary incontinence of various degrees and/or erectile dysfunction. AIM: We evaluate the effect of a complete pelvic floor rehabilitation program on both incontinence and erectile dysfunction, including climacturia, in a preliminary case series. MAIN OUTCOMES MEASURES: Pad usage and International Index of Erectile Function (IIEF-15) Questionnaire. METHODS: Three male patients, previously submitted to nerve and bladder neck sparing radical prostatectomy, presented with urinary incontinence, climacturia and erectile dysfunction of new onset. We decided to manage those subjects with a pelvic-floor rehabilitation program consisting of active pelvic-floor muscle exercises, electromyography biofeedback for strength and endurance, electrical stimulation. The whole program lasted 4 months, with weekly sessions, including general advices on lifestyle changes. Pad usage for incontinence and IIEF-15 were used to assess symptoms before and after the procedure. RESULTS: Before a complete rehabilitation program, pad usage was 1 per day in all the subjects, and the score for erectile function was set at 17 (range 15-20). After the procedure, all the patients experienced a satisfying urinary continence and an improvement in erectile function (mean IIEF score: 22, range 19-24). Similarly, climacturia seems to be subjectively reduced in all the subjects. CONCLUSION: Pelvic floor muscles exercises seem to result in an improved urinary continence and erectile function after radical prostatectomy. Since this is the first clinical case series dealing with this topic, our outcomes are encouraging and suggest the potential usefulness of such noninvasive treatment modalit