Pregnancy Outcome in Women With APECED (APS-1) : A Multicenter Study on 43 Females With 83 Pregnancies

Context: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also known as autoimmune polyendocrine syndrome type 1) has a severe, unpredictable course. Autoimmunity and disease components may affect fertility and predispose to maternal and fetal complications, but pregnancy outcomes remain unknown. Objective: To assess fetal and maternal outcomes and course of clinical APECED manifestations during pregnancy in women with APECED. Design and Setting: A multicenter registry-based study including 5 national patient cohorts. Patients: 321 females with APECED. Main Outcome Measure: Number of pregnancies, miscarriages, and deliveries. Results: Forty-three patients had altogether 83 pregnancies at median age of 27 years (range, 17-39). Sixty (72%) pregnancies led to a delivery, including 2 stillbirths (2.4%) and 5 (6.0%) preterm livebirths. Miscarriages, induced abortions, and ectopic pregnancies were observed in 14 (17%), 8 (10%), and 1 (1.2%) pregnancies, respectively. Ovum donation resulted in 5 (6.0%) pregnancies. High maternal age, premature ovarian insufficiency, primary adrenal insufficiency, or hypoparathyroidism did not associate with miscarriages. Women with livebirth had, on average, 4 APECED manifestations (range 0-10); 78% had hypoparathyroidism, and 36% had primary adrenal insufficiency. APECED manifestations remained mostly stable during pregnancy, but in 1 case, development of primary adrenal insufficiency led to adrenal crisis and stillbirth. Birth weights were normal in >80% and apart from 1 neonatal death of a preterm baby, no serious perinatal complications occurred. Conclusions. Outcome of pregnancy in women with APECED was generally favorable. However, APECED warrants careful maternal multidisciplinary follow-up from preconceptual care until puerperium.Peer reviewe

Comparative assessment of energy metabolism, body composition and metabolic features in children with hypothalamic and simple obesity

Background: Hypothalamic obesity often develops after surgical treatment of craniopharyngioma and is characterized by rapid weight gain, high frequency of metabolic disorders, body composition specificity and resistance to standard lifestyle modification approaches and medication therapy of obesity. Recent studies show that one of the mechanisms, explaining weight gain in these children is decrease in resting energy expenditure (REE).Aims: To compare REE, body composition parameters, and the frequency of metabolic disorders in children with hypothalamic and simple obesity.Materials and methods: The study included 60 obese children aged 7 to 17 years, divided into two groups. The study group included 20 children with hypothalamic obesity, developed after craniopharyngioma treatment. The control group consisted of 40 children with simple obesity. Body composition, REE, and metabolic disorders were associated in all children.Results: Children with hypothalamic obesity showed a significant decrease of resting energy expenditure. The average decrease in REE was 13.1%, but in single patients it reached 33.4%. The percentage of fat mass in hypothalamic and simple obesity does not differ significantly (39.7% [36.2; 42.6] vs 38.8 % [35.9; 43.2]; p=0.69). Screening for metabolic disorders revealed a high prevalence of metabolic disorders in hypothalamic obesity: impaired glucose tolerance - in 10%; dyslipidemia - 55%, insulin resistance-50%, non-alcoholic fatty liver disease - 60 %.Conclusions: Children with hypothalamic obesity showed a significant decrease of resting energy expenditure. When planning a diet in this group of patients it is preferable to use indirect calorimetry. Hypothalamic obesity even at an early age is associated with a high frequency of metabolic disturbance. Hypothalamic obesity in children is not associated with more pronounced hyperinsulinemia and insulin resistance compared to the simple obesity

Insulinoma in childhood: a retrospective review of 22 patients from one referral centre

BackgroundInsulinomas are very rare in childhood with sparse knowledge on the clinical aspects and the presence of Multiple Endocrine Neoplasia type 1 (MEN1).MethodsWe conducted a retrospective review of patients diagnosed with insulinoma between 1995 and 2021, presenting to one referral centre in Russia. Clinical, biochemical, genetic, imaging and histological data were collected. In addition, follow-up and family data were obtained.ResultsA total of twenty-two children aged 5 to 16 years were identified. The median (range) gap between the first hypoglycaemia symptoms and diagnosis was 10 (1–46) months. Twelve children (55%) were misdiagnosed to have epilepsy and were treated with anticonvulsants before hypoglycemia was revealed. Contrast enhanced MRI and/or CT were accurate to localize the lesion in 82% (n=18). Five patients (23%) had multiple pancreatic lesions. All children underwent surgical treatment. The median (range) diameter of removed tumors was 1.5 (0.3-6) cm. Histopathological studies confirmed the presence of insulinoma in all cases. Immunohistochemical studies revealed G2 differentiation grade in 10 out of 17 cases. Two patients were diagnosed with metastatic insulinoma. One of them had metastases at the time of insulinoma diagnosis, while the other was diagnosed with liver metastases eight years after the surgery. Eight children (36%) were found to carry MEN1 mutations, inherited n=5, de novo n=1, no data, n=2. Children with MEN1 had significantly higher number of pancreatic tumors compared to sporadic cases. All of them developed additional MEN1 symptoms during the following 2-13 years. In the five patients with inherited MEN1, seven family members had hitherto undiscovered MEN1 manifestations.ConclusionsIn this large cohort of children with rare pediatric insulinomas, MEN1 syndrome and G2 tumors were frequent, as well as hitherto undiscovered MEN1 manifestations in family members. Our data emphasize the need of genetic testing in all children with insulinoma and their relatives, even in the absence of any other features, as well as the importance of a prolonged follow-up observation

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.publishedVersio

Phase Equilibria of the In–Pd–Sn System at 500 °C and 800 °C: Experimental Study and CALPHAD Modeling

Phase equilibria in the In–Pd–Sn system were investigated by a combination of key experiments and thermodynamic modeling. Partial isothermal sections at 500 °C and 800 °C of the In–Pd–Sn system for Pd contents above 66 at.% have been plotted experimentally using scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM/EDX) and X-ray diffraction (XRD). The solubility of the third component in binary compounds InPd3 and Pd3Sn was determined. The new ternary compound τ1 was found in Pd contents ranging from 20 to 25 at.% and at Sn contents varying from 5 to approximately 17 at.% Sn. This compound crystallizes in an Al3Ti-type tetragonal structure. Isostructural InPd2 and Pd2Sn phases from the In–Pd and Pd–Sn binary compositions form a continuous phase field in the ternary system at both temperatures. The temperatures of the solidus, liquidus, and phase transitions of the alloys along the Pd–In50Sn50 line were measured using DTA/DSC. Thermodynamic calculation of the In–Pd–Sn ternary system is performed using the CALPHAD method using the Thermo-Calc® software. The thermodynamic properties of the disordered fcc and liquid phases were described by the Redlich–Kister–Muggianu model. To describe intermetallic phases, namely, InPd3, Pd3Sn, τ1 and Pd2(InxSn1−x), a two-sublattice models was used. Thermodynamic description of the In–Pd–Sn system obtained in this study is in good agreement both with our results and the published experimental dat

Phenotype of bone-marrow mononuclear cells before and after short-time precondition with erythropoietin from patients with ischemic heart failure

Aim ― To reveal the results of the condition of the bone marrow mononuclear cells (BM-MNCs) with erythropoietin (Epo). Material and Methods ― There were 30-ty patients with coronary artery disease (CAD) enrolled in this study during 2016-2017 years. 95% were men. All were in angina NYHA class II-III. Hypertension presented in 90%, peripheral atherosclerosis in 60%. BM-MNCs were obtained by centrifugation of bone marrow aspirate on Ficoll-Paque, washed, and then preconditioned with Epo. Phenotype, cell cycle, cell death, proliferation, migration, and tube formation before, and after precondition BM-MNCs with Epo were done. Results ― In this study, we observed the presence in cellular graft of the hematopoietic stem cells (HSCs), and endothelial progenitor cells (EPCs) at the different stage of maturation/differentiation, and mesenchymal stem cells (MSCs). Precondition BM-MNCs with Epo increased number of HSCs carrying erythropoietin receptor (EpoR), and EPCs carrying CD184. Also, Epo detained СВ34+ cells in a rest phase of cell cycle (G0G1). Condition media from BM-MNCs treated with Epo augment tube formation and wound healing by EA.hy 929. Conclusion ― Epo in vitro increased number of the stem cells carrying EpoR and CD184, and increased accumulation of CD34+ cell in G0G1 phase of cell cycle, and induced production of proangiogenic factor by BM-MNCs. Further investigation is needed to assess the type of cytokines produced by BM-MNCs after condition with Epo

Pregnancy Outcome in Women With APECED (APS-1): A Multicenter Study on 43 Females With 83 Pregnancies

Context Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also known as autoimmune polyendocrine syndrome type 1) has a severe, unpredictable course. Autoimmunity and disease components may affect fertility and predispose to maternal and fetal complications, but pregnancy outcomes remain unknown. Objective To assess fetal and maternal outcomes and course of clinical APECED manifestations during pregnancy in women with APECED. Design and Setting A multicenter registry-based study including 5 national patient cohorts. Patients 321 females with APECED. Main Outcome Measure Number of pregnancies, miscarriages, and deliveries. Results Forty-three patients had altogether 83 pregnancies at median age of 27 years (range, 17–39). Sixty (72%) pregnancies led to a delivery, including 2 stillbirths (2.4%) and 5 (6.0%) preterm livebirths. Miscarriages, induced abortions, and ectopic pregnancies were observed in 14 (17%), 8 (10%), and 1 (1.2%) pregnancies, respectively. Ovum donation resulted in 5 (6.0%) pregnancies. High maternal age, premature ovarian insufficiency, primary adrenal insufficiency, or hypoparathyroidism did not associate with miscarriages. Women with livebirth had, on average, 4 APECED manifestations (range 0-10); 78% had hypoparathyroidism, and 36% had primary adrenal insufficiency. APECED manifestations remained mostly stable during pregnancy, but in 1 case, development of primary adrenal insufficiency led to adrenal crisis and stillbirth. Birth weights were normal in >80% and apart from 1 neonatal death of a preterm baby, no serious perinatal complications occurred. Conclusions Outcome of pregnancy in women with APECED was generally favorable. However, APECED warrants careful maternal multidisciplinary follow-up from preconceptual care until puerperium

Clinical and immunological characteristics of diabetes mellitus in patients with autoimmune polyglandular syndrome type 1 in Russia

Background. Autoimmune polyglandular syndrome type 1 (APS type 1) is a rare inherited autoimmune disease caused by mutations in AIRE gene (autoimmune regulator) and characterized by list of components. Diabetes mellitus (DM) can be one of components of this disease. Aims. To show frequency of DM in patients with APS type 1 in Russia, to describe clinical and immunological aspects of DM in patients with APS type 1 Materials and methods. 113 patients have been enrolled in the study, 16 of them had DM (15/16) or impaired glucose tolerance (1/16). Antibodies against glutamate decarboxylase, tyrosine phosphatase, zinc transporter-8, insulin and -cells of pancreas were investigated in 30 patients with APS type 1 without DM and in 11 patients with APS type 1 and DM. ELISA test was used for detection autoantibodies. Results. Frequency of DM in patients with APS type 1 in Russia is 14.1% (16/113). Some patients had slow-progressive DM 19%(3/16). Antibodies against insulin and -cells were not specific and also were not sensitive markers for DM in APS type 1. Antibodies against tyrosine phosphatase and zinc transporter-8 test showed high specificity (100% и 97%), but low sensitivity (42% и 33,3%). Antibodies against glutamate decarboxylase were less specific (70%) and had very low sensitivity (58,3%). Conclusions. Frequency of DM in patients with APS type 1 in Russia is high to compare to other countries. 20% of Russian patients had slow-progressive course of DM. Antibodies against tyrosine phosphatase and zinc transporter-8 were the most specific for DM in patients with APS type 1, but sensitivity of these antibodies was low