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ABSTRACT: In physiological conditions, few circulating hematopoietic stem/progenitor cells (cHSPCs) are present in the peripheral blood, but their contribution to human hematopoiesis remain unsolved. By integrating advanced immunophenotyping, single-cell transcriptional and functional profiling, and integration site (IS) clonal tracking, we unveiled the biological properties and the transcriptional features of human cHSPC subpopulations in relationship to their bone marrow (BM) counterpart. We found that cHSPCs reduced in cell count over aging and are enriched for primitive, lymphoid, and erythroid subpopulations, showing preactivated transcriptional and functional state. Moreover, cHSPCs have low expression of multiple BM-retention molecules but maintain their homing potential after xenotransplantation. By generating a comprehensive human organ-resident HSPC data set based on single-cell RNA sequencing data, we detected organ-specific seeding properties of the distinct trafficking HSPC subpopulations. Notably, circulating multi-lymphoid progenitors are primed for seeding the thymus and actively contribute to T-cell production. Human clonal tracking data from patients receiving gene therapy (GT) also showed that cHSPCs connect distant BM niches and participate in steady-state hematopoietic production, with primitive cHSPCs having the highest recirculation capability to travel in and out of the BM. Finally, in case of hematopoietic impairment, cHSPCs composition reflects the BM-HSPC content and might represent a biomarker of the BM state for clinical and research purposes. Overall, our comprehensive work unveiled fundamental insights into the in vivo dynamics of human HSPC trafficking and its role in sustaining hematopoietic homeostasis. GT patients' clinical trials were registered at ClinicalTrials.gov (NCT01515462 and NCT03837483) and EudraCT (2009-017346-32 and 2018-003842-18).
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Hematopoese , Células-Tronco Hematopoéticas , Homeostase , Animais , Humanos , Camundongos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Análise de Célula ÚnicaRESUMO
Celiac Disease (CD) is a T-cell mediated disorder caused by immune response to gluten, although the mechanisms underlying CD progression are still elusive. We analyzed immune cell composition, plasma cytokines, and gliadin-specific T-cell responses in patients with positive serology and normal intestinal mucosa (potential-CD) or villous atrophy (acute-CD), and after gluten-free diet (GFD). We found: an inflammatory signature and the presence of circulating gliadin-specific IFN-γ+ T cells in CD patients regardless of mucosal damage; an increased frequency of IL-10-secreting dendritic cells (DC-10) in the gut and of circulating gliadin-specific IL-10-secreting T cells in potential-CD; IL-10 inhibition increased IFN-γ secretion by gliadin-specific intestinal T cells from acute- and potential-CD. On GFD, inflammatory cytokines normalized, while IL-10-producing T cells accumulated in the gut. We show that IL-10-producing cells are fundamental in controlling pathological T-cell responses to gluten: DC-10 protect the intestinal mucosa from damage and represent a marker of potential-CD.
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Doença Celíaca , Humanos , Gliadina , Interleucina-10 , Glutens , Citocinas , Mucosa IntestinalRESUMO
AIMS/HYPOTHESIS: Islet autoantibodies (AAbs) are detected in >90% of individuals with clinically suspected type 1 diabetes at disease onset. A single AAb, sometimes at low titre, is often detected in some individuals, making their diagnosis uncertain. Type 1 diabetes genetic risk scores (GRS) are a useful tool for discriminating polygenic autoimmune type 1 diabetes from other types of diabetes, particularly the monogenic forms, but testing is not routinely performed in the clinic. Here, we used a type 1 diabetes GRS to screen for monogenic diabetes in individuals with weak evidence of autoimmunity, i.e. with a single AAb at disease onset. METHODS: In a pilot study, we genetically screened 142 individuals with suspected type 1 diabetes, 42 of whom were AAb-negative, 27 of whom had a single AAb (single AAb-positive) and 73 of whom had multiple AAbs (multiple AAb-positive) at disease onset. Next-generation sequencing (NGS) was performed in 41 AAb-negative participants, 26 single AAb-positive participants and 60 multiple AAb-positive participants using an analysis pipeline of more than 200 diabetes-associated genes. RESULTS: The type 1 diabetes GRS was significantly lower in AAb-negative individuals than in those with a single and multiple AAbs. Pathogenetic class 4/5 variants in MODY or monogenic diabetes genes were identified in 15/41 (36.6%) AAb-negative individuals, while class 3 variants of unknown significance were identified in 17/41 (41.5%). Residual C-peptide levels at diagnosis were higher in individuals with mutations compared to those without pathogenetic variants. Class 3 variants of unknown significance were found in 11/26 (42.3%) single AAb-positive individuals, and pathogenetic class 4/5 variants were present in 2/26 (7.7%) single AAb-positive individuals. No pathogenetic class 4/5 variants were identified in multiple AAb-positive individuals, but class 3 variants of unknown significance were identified in 19/60 (31.7%) patients. Several patients across the three groups had more than one class 3 variant. CONCLUSIONS/INTERPRETATION: These findings provide insights into the genetic makeup of patients who show weak evidence of autoimmunity at disease onset. Absence of islet AAbs or the presence of a single AAb together with a low type 1 diabetes GRS may be indicative of a monogenic form of diabetes, and use of NGS may improve the accuracy of diagnosis.
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Diabetes Mellitus Tipo 1 , Humanos , Autoimunidade/genética , Projetos Piloto , Autoanticorpos , Fatores de RiscoRESUMO
A link between maternal anxiety during pregnancy and adverse socio-emotional outcomes in childhood has been consistently sustained on the very early neurodevelopmental alteration of structural pathways between fetal limbic and cortical brain regions. In this study, we provide follow-up evidence for a feed-forward model linking (i) maternal anxiety, (ii) fetal functional neurodevelopment, (iii) neonatal functional network organization with (iv) socio-emotional neurobehavioral development in early childhood. Namely, we investigate a sample of 16 mother-fetus dyads and show how a maternal state-trait anxiety profile with pregnancy-specific worries can significantly influence functional synchronization patterns between regions of the fetal limbic system (i.e., hippocampus and amygdala) and the neocortex, as assessed through resting-state functional magnetic resonance imaging. Generalization of the findings was supported by leave-one-out cross-validation. We further show how this maternal-fetal cross-talk propagates to functional network topology in the neonate, specifically targeting connector hubs, and further maps onto socio-emotional profiles, assessed through Bayley-III socio-emotional scale in early childhood (i.e., in the 12-24 months range). Based on this evidence, we put forward the hypothesis of a "Maternal-Fetal-Neonatal Anxiety Backbone", through which neurobiological changes driven by maternal anxiety could trigger a divergence in the establishment of a cognitive-emotional development blueprint, in terms of the nascent functional homeostasis between bottom-up limbic and top-down higher-order neuronal circuitry.
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Encéfalo , Imageamento por Ressonância Magnética , Recém-Nascido , Feminino , Gravidez , Humanos , Pré-Escolar , Encéfalo/patologia , Emoções , Feto , AnsiedadeRESUMO
Tolerogenic dendritic cells play a critical role in promoting antigen-specific tolerance via dampening of T cell responses, induction of pathogenic T cell exhaustion and antigen-specific regulatory T cells. Here we efficiently generate tolerogenic dendritic cells by genetic engineering of monocytes with lentiviral vectors co-encoding for immunodominant antigen-derived peptides and IL-10. These transduced dendritic cells (designated DCIL-10/Ag) secrete IL-10 and efficiently downregulate antigen-specific CD4+ and CD8+ T cell responses from healthy subjects and celiac disease patients in vitro. In addition, DCIL-10/Ag induce antigen-specific CD49b+LAG-3+ T cells, which display the T regulatory type 1 (Tr1) cell gene signature. Administration of DCIL-10/Ag resulted in the induction of antigen-specific Tr1 cells in chimeric transplanted mice and the prevention of type 1 diabetes in pre-clinical disease models. Subsequent transfer of these antigen-specific T cells completely prevented type 1 diabetes development. Collectively these data indicate that DCIL-10/Ag represent a platform to induce stable antigen-specific tolerance to control T-cell mediated diseases.
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Diabetes Mellitus Tipo 1 , Interleucina-10 , Animais , Camundongos , Antígenos , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/metabolismo , Tolerância Imunológica , Interleucina-10/genética , Interleucina-10/metabolismo , Linfócitos T Reguladores/metabolismo , Humanos , Doença CelíacaRESUMO
Preterm birth can affect cognitive functions, such as attention or more generally executive control mechanisms, with severity in impairments proportional to prematurity. The functional cross-talk between the Default Mode (DMN) and Executive Control (ECN) networks mirrors the integrity of cognitive processing and is directly related to brain development. In this study, a cohort of 20 preterm-born infants was investigated using rs-fMRI. First, we addressed biological maturity of the DMN per se and its interplay with the ECN in terms of patterns of increased functional connectivity. Second, we assessed the impact of the degree of prematurity on the DMN-ECN functional interplay development in relation to cognitive outcome at six months. Our results highlighted the emergence of DMN in preterm neonates, with connectivity strength and synchronization between the anterior DMN hub and frontal areas increasing as a function of biological maturity. Further, cognitive scores at 6 months were predicted by mPFC-ECN connectivity strength with degree of prematurity impacting on mPFC-ECN connectivity and triggering differential patterns of functional maturation of the ECN for very early/early and moderate/late preterm neonates. Our findings suggest that the prematurity window allows to observe precursors of functional plasticity that may underlie different developmental trajectories in preterm children.
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Função Executiva , Nascimento Prematuro , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Criança , Cognição , Feminino , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , GravidezRESUMO
BACKGROUND: Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear. OBJECTIVE: We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations. METHODS: Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. RESULTS: Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor-related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor-related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. CONCLUSIONS: Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.
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Diabetes Mellitus Tipo 1/congênito , Diarreia/imunologia , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças do Sistema Imunitário/congênito , Imunossupressores/uso terapêutico , Mutação/genética , Sirolimo/uso terapêutico , Linfócitos T Reguladores/imunologia , Movimento Celular , Células Cultivadas , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diarreia/tratamento farmacológico , Diarreia/genética , Regulação da Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Tolerância Imunológica , Interleucinas/genética , Interleucinas/metabolismo , Ativação Linfocitária , Masculino , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismoRESUMO
Autoantibodies (AAbs) are a hallmark of Type 1 diabetes (T1D). Alterations in the frequency and phenotype of follicular helper (Tfh) T cells have been previously documented in patients with type 1 diabetes (T1D), but the contribution of follicular regulatory T (Treg) cells, which are responsible for suppressing AAb development, is less clear. Here, we investigated the frequency and activation status of follicular (CXCR5+) and conventional (CXCR5-) Treg cells in the blood of children with new-onset T1D, and children with risk for developing T1D (AAb-positive) and compared them to AAb-negative controls. Blood follicular and conventional Treg cells were higher in frequency in children with new onset T1D, but expressed reduced amounts of PD-1 as compared to AAb-negative children. Interestingly, the proportion of circulating FOXP3+ Tregs expressing PD-1 was also reduced in AAb-positive at-risk children as compared to AAb-negative controls, suggesting its potential use as a biomarker of disease progression. Follicular Treg cells were reduced in frequency in the spleens of prediabetic NOD mice as they became older and turned diabetic. Interestingly, PD-1 expression declined also on circulating follicular and conventional Treg cells in prediabetic NOD mice as they aged. Together, these findings show that the frequency of circulating follicular and conventional Treg cells and their levels of PD-1 change with disease progression in children at-risk for developing T1D and in NOD mice.
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Diabetes Mellitus Tipo 1/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Animais , Autoanticorpos/imunologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead , Cabelo/imunologia , Humanos , Ilhotas Pancreáticas/imunologia , Masculino , Camundongos Endogâmicos NOD , Receptores CXCR5RESUMO
Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are used in pregnant patients with rheumatic diseases. Long-term follow-up data about newborns exposed to bDMARDs during pregnancy are however scarce. Here we summarize the published evidence and available recommendations for use of bDMARDs during pregnancy. We analyse clinical features at birth and at follow-up of 84 children, including: 16 consecutive children born to mothers with autoimmune diseases exposed to bDMARDs in utero; 32 children born to mothers with autoimmune diseases who did not receive bDMARDs; 36 children born to healthy mothers. In our monocentric cohort, children born to mothers with autoimmune diseases had lower gestational age at birth compared to those born to healthy mothers, independently of exposure to bDMARDs. At multivariate analysis, prematurity was an independent predictor of the need for antibiotic treatment, but not for hospitalisation or neonatal intensive care unit (ICU) stay during the neonatal period. Exposure to bDMARDs during pregnancy does not seem to interfere with post-natal development up to infancy. Prospective studies are needed in larger cohorts of pregnant patients to confirm that bDMARDs do not have a negative impact on psychomotor achievements in newborns.
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Antirreumáticos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Feminino , Humanos , Recém-Nascido , Masculino , Mães , Gravidez , Resultado da GravidezRESUMO
BACKGROUND: The relationship between the risk of celiac disease and both the age at which gluten is introduced to a child's diet and a child's early dietary pattern is unclear. METHODS: We randomly assigned 832 newborns who had a first-degree relative with celiac disease to the introduction of dietary gluten at 6 months (group A) or 12 months (group B). The HLA genotype was determined at 15 months of age, and serologic screening for celiac disease was evaluated at 15, 24, and 36 months and at 5, 8, and 10 years. Patients with positive serologic findings underwent intestinal biopsies. The primary outcome was the prevalence of celiac disease autoimmunity and of overt celiac disease among the children at 5 years of age. RESULTS: Of the 707 participants who remained in the trial at 36 months, 553 had a standard-risk or high-risk HLA genotype and completed the study. At 2 years of age, significantly higher proportions of children in group A than in group B had celiac disease autoimmunity (16% vs. 7%, P=0.002) and overt celiac disease (12% vs. 5%, P=0.01). At 5 years of age, the between-group differences were no longer significant for autoimmunity (21% in group A and 20% in group B, P=0.59) or overt disease (16% and 16%, P=0.78 by the log-rank test). At 10 years, the risk of celiac disease autoimmunity was far higher among children with high-risk HLA than among those with standard-risk HLA (38% vs. 19%, P=0.001), as was the risk of overt celiac disease (26% vs. 16%, P=0.05). Other variables, including breast-feeding, were not associated with the development of celiac disease. CONCLUSIONS: Neither the delayed introduction of gluten nor breast-feeding modified the risk of celiac disease among at-risk infants, although the later introduction of gluten was associated with a delayed onset of disease. A high-risk HLA genotype was an important predictor of disease. (Funded by the Fondazione Celiachia of the Italian Society for Celiac Disease; CELIPREV ClinicalTrials.gov number, NCT00639444.).
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Doença Celíaca/prevenção & controle , Dieta , Proteínas Alimentares/administração & dosagem , Glutens , Antígenos HLA/genética , Fatores Etários , Idade de Início , Autoanticorpos/sangue , Aleitamento Materno , Doença Celíaca/diagnóstico , Doença Celíaca/genética , Criança , Pré-Escolar , Feminino , Proteínas de Ligação ao GTP/imunologia , Genótipo , Gliadina/imunologia , Glutens/administração & dosagem , Humanos , Lactente , Recém-Nascido , Intestino Delgado/patologia , Estimativa de Kaplan-Meier , Masculino , Estudos Prospectivos , Proteína 2 Glutamina gama-Glutamiltransferase , Risco , Transglutaminases/imunologiaRESUMO
Aims: Wolfram Syndrome Spectrum Disorder (WFS1-SD), in its "classic" form, is a rare autosomal recessive disease with poor prognosis and wide phenotypic spectrum. Insulin dependent diabetes mellitus (DM), optic atrophy (OA) diabetes insipidus (DI) and sensorineural deafness (D) are the main features of WFS1-SD. Gonadal dysfunction (GD) has been described mainly in adults with variable prevalence and referred to as a minor clinical feature. This is the first case series investigating gonadal function in a small cohort of paediatric patients affected by WFS1-SD. Methods: Gonadal function was investigated in eight patients (3 male and 5 female) between 3 and 16 years of age. Seven patients have been diagnosed with classic WFS1-SD and one with non-classic WFS1-SD. Gonadotropin and sex hormone levels were monitored, as well as markers of gonadal reserve (inhibin-B and anti-Mullerian hormone). Pubertal progression was assessed according to Tanner staging. Results: Primary hypogonadism was diagnosed in 50% of patients (n=4), more specifically 67% (n=2) of males and 40% of females (n=2). Pubertal delay was observed in one female patient. These data confirm that gonadal dysfunction may be a frequent and underdiagnosed clinical feature in WFS1-SD. Conclusions: GD may represent a frequent and earlier than previously described feature in WFS1-SD with repercussions on morbidity and quality of life. Consequently, we suggest that GD should be included amongst clinical diagnostic criteria for WFS1-SD, as has already been proposed for urinary dysfunction. Considering the heterogeneous and elusive presentation of WFS1-SD, this clinical feature may assist in an earlier diagnosis and timely follow-up and care of treatable associated diseases (i.e. insulin and sex hormone replacement) in these young patients.
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Diabetes Mellitus Tipo 1 , Transtornos Gonadais , Síndrome de Wolfram , Adulto , Humanos , Feminino , Masculino , Criança , Síndrome de Wolfram/complicações , Síndrome de Wolfram/diagnóstico , Qualidade de Vida , GônadasRESUMO
We report the case of a paediatric female patient affected by Bannayan-Riley-Ruvalcaba syndrome (BRRS) and congenital hypothyroidism (CH) with homozygous mutation of the TPO gene. She underwent total thyroidectomy at the age of seven years because of the development of a multinodular goiter. BRRS patients present an increased risk of benign and malignant thyroid disease since childhood because of inactivating mutation of PTEN, an onco-suppressor gene. Instead, homozygous mutations in the TPO gene can be associated with severe forms of hypothyroidism with goiter; previous studies have described cases of follicular and papillary thyroid cancer in CH patients with TPO mutation despite a perfectly controlled thyroid function with Levothyroxine therapy. To our knowledge, this is the first case that describes the possible synergic role of coexisting mutation of both TPO and PTEN in the development of multinodular goiter underlining the importance of a tailored surveillance program in these patients, especially during childhood.
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Hipotireoidismo Congênito , Bócio , Síndrome do Hamartoma Múltiplo , Neoplasias da Glândula Tireoide , Humanos , Criança , Feminino , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/genética , Mutação , Bócio/complicações , Bócio/genética , Bócio/cirurgia , PTEN Fosfo-Hidrolase/genéticaRESUMO
AIMS: The target of metabolic control (HbA1c < 7% or 53 mmol/mol) recommended by the ADA and ISPAD is attained by 30% of children with Type 1 Diabetes (T1D). Advances in technologies for T1D aim to improve metabolic outcomes and reduce complications. This observational study assesses the long-term outcomes of advanced technologies for treatment of T1D compared to conventional approach started at onset in a group of very young children with T1D. METHODS: 54 patients with less 4 years old at onset of T1D were enrolled and followed for up to 9 years after diagnosis. 24 subjects started continuous subcutaneous insulin (CSII) treatment and 30 subjects received MDI therapy from onset. Auxological data, HbA1c and total daily insulin dose (TDD/kg) have been collected at admission and every 4 months. HbA1cAUC>6%, rates of acute complications, glycemic variability indices and glucometrics were also recorded. RESULTS: Patients with CSII therapy had significantly lower mean HbA1c values compared to subjects receiving MDI treatment. CSII approach also recorded lower mean HbA1cAUC>6% and TDD/kg than MDI therapy. At the last download data, the time in range (TIR) was higher in patients with CSII and hyperglycemia events were lower. Better glycemic variability indices have been described during CSII therapy, including mean glycemia, standard deviation, coefficient of variation (CV), glycemia risk index (GRI) and high blood glucose index (HBGI). There was no statistically significant difference between frequency of severe hypoglycemia and ketoacidosis episodes between groups. CONCLUSIONS: Early initiation of diabetes technologies is safe and able to determine a better long term glycemic control in young children with T1D. It also allows to flatten the trajectory of HbA1c, probably reducing microvascular, macrovascular and neurological complications of diabetes in this very peculiar age group.
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Diabetes Mellitus Tipo 1 , Humanos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Glicemia/metabolismo , Hemoglobinas Glicadas , Automonitorização da Glicemia , Insulina/uso terapêutico , Sistemas de Infusão de InsulinaRESUMO
OBJECTIVES: Pathogenic variants in AIFM1 have been associated with a wide spectrum of disorders, spanning from CMT4X to mitochondrial encephalopathy. Here we present a novel phenotype and review the existing literature on AIFM1-related disorders. METHODS: We performed EEG recordings, brain MRI and MR Spectroscopy, metabolic screening, echocardiogram, clinical exome sequencing (CES) and family study. Effects of the variant were established on cultured fibroblasts from skin punch biopsy. RESULTS: The patient presented with drug-resistant, electro-clinical, multifocal seizures 6 h after birth. Brain MRI revealed prominent brain swelling of both hemispheres and widespread signal alteration in large part of the cortex and of the thalami, with sparing of the basal nuclei. CES analysis revealed the likely pathogenic variant c.5T>C; p.(Phe2Ser) in the AIFM1 gene. The affected amino acid residue is located in the mitochondrial targeting sequence. Functional studies on cultured fibroblast showed a clear reduction in AIFM1 protein amount and defective activities of respiratory chain complexes I, III and IV. No evidence of protein mislocalization or accumulation of precursor protein was observed. Riboflavin, Coenzyme Q10 and thiamine supplementation was therefore given. At 6 months of age, the patient exhibited microcephaly but did not experience any further deterioration. He is still fed orally and there is no evidence of muscle weakness or atrophy. INTERPRETATION: This is the first AIFM1 case associated with neonatal seizures and diffuse white matter involvement with relative sparing of basal ganglia, in the absence of clinical signs suggestive of myopathy or motor neuron disease.
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Encefalomiopatias Mitocondriais , Doença dos Neurônios Motores , Masculino , Recém-Nascido , Humanos , Mitocôndrias/genética , Tiamina , Convulsões , Fator de Indução de ApoptoseRESUMO
Subcutaneous fat necrosis of the newborn (SCFN) is a panniculitis that develops in fatty areas after fetal or perinatal distress. Prognosis is generally good with complete regression, but it can be complicated by metabolic abnormalities like hypoglycemia, hypertriglyceridemia, thrombocytopenia, and also potentially life-threatening hypercalcemia. Treatments have included hydration, furosemide and corticosteroids. These treatments can be prolonged for several days and can have complications such as nephrocalcinosis. Use of bisphosphonates has been rarely reported in newborn. We describe a case of severe hypercalcemia complicating subcutaneous fat necrosis in a newborn successfully treated by a single dose of pamidronate after having obtained partial response by therapy with hyperhydration, furosemide and hydrocortisone. When high levels of calcium do not respond to first line therapy with hyperhydration and diuretic therapy, bisphosphonates treatment could be considered a valid choice to treat hypercalcemia and to avoid corticosteroids. Further studies are needed to understand if pamidronate and other bisphosphonates can be considered the first choice in hypercalcemia due to SCFN.
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Chronic urticaria (CU) is defined by the presence of itchy wheals, sometimes accompanied by angioedema, lasting for at least 6 weeks. CU is treated with second-generation antihistamines, increased up to four times the normal doses for second-line treatment. Omalizumab (a monoclonal antibody anti-IgE) may be recommended as third-line therapy in children aged over 12 years. Few reports have suggested that glucose homeostasis is impaired in some type 2 diabetic patients receiving omalizumab, and even in non-diabetic patients, fasting blood glucose and HOMA-IR values appeared to be significantly increased. We report the case of a 13-year-old girl with diabetes mellitus type 1 and chronic spontaneous urticaria (CSU) refractory to standard recommended therapy that we treated with omalizumab at a standard recommended dose of 300 mg every 4 weeks. We observed a rapid and complete remission of CSU after treatment with this humanized monoclonal antibody without detrimental effects on the patient's glucose control especially in terms of HbA1c (glycated hemoglobin), time in glycemic range (TIR), and daily insulin needs.
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Antialérgicos , Urticária Crônica , Diabetes Mellitus Tipo 1 , Adolescente , Antialérgicos/efeitos adversos , Criança , Doença Crônica , Urticária Crônica/diagnóstico , Urticária Crônica/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Humanos , Omalizumab/efeitos adversosRESUMO
Introduction: Despite the use of technology, recurrent diabetic ketoacidosis (DKA) prevention remains an unmet need in children and adolescents with T1D and may be accompanied by life-threatening acute complications. We present a rare case of non-occlusive mesenteric ischemia (NOMI) with overt manifestation after DKA resolution and a discussion of recent literature addressing DKA-associated NOMI epidemiology and pathogenesis in children and adolescents. Case Presentation: A 13-year-old female with previously diagnosed T1D, was admitted at our emergency department with hypovolemic shock, DKA, hyperosmolar state and acute kidney injury (AKI). Mildly progressive abdominal pain persisted after DKA correction and after repeated ultrasound evaluations ultimately suspect for intestinal perforation, an intraoperative diagnosis of NOMI was made. Conclusion: The diagnosis of DKA-associated NOMI must be suspected in pediatric patients with DKA, persistent abdominal pain, and severe dehydration even after DKA resolution.
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Diabetes Mellitus Tipo 1 , Cetoacidose Diabética , Isquemia Mesentérica , Dor Abdominal/complicações , Adolescente , Criança , Diabetes Mellitus Tipo 1/complicações , Cetoacidose Diabética/complicações , Cetoacidose Diabética/diagnóstico , Feminino , Humanos , Isquemia Mesentérica/complicações , Isquemia Mesentérica/etiologiaRESUMO
Beckwith-Wiedemann Syndrome (BWS) is a rare genetic disorder characterized by overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycemia, predisposition to embryonal tumor, lateralized overgrowth, and leg length discrepancy (LLD), which can affect normal posture and gait. Aim of this study was to evaluate the effects of guided growth (temporary epiphysiodesis technique) as LLD management in BWS patients. Between 2007 and 2021, 22 BWS patients (15 F, 7 M) with a mean age of 7.9 years (2.9-14.4) and a mean LLD at first surgery of 3.65 cm (2-10), underwent temporary proximal tibial (PTE) and distal femur epiphysiodesis (DFE). In 18 patients the first surgical procedure was PTE, in one, DFE, and in 3 cases, PTE and DFE at the same time, respectively. Eleven patients reached equality of leg length after a mean follow-up of 7.7 years (3.7-13.0) and mean age of 13.3 years (12.7-27.5); 10 patients underwent 3 surgical procedures, one 7 procedures. Fifteen patients had no complications. No severe complications, infection, articular stiffness, or neuro-vascular lesions occurred in remaining patients; complications included secondary varus or valgus axial deviation in a total of 6 patients, and two screw breakages in two patients. Guided growth as a minimally invasive procedure seems efficient for LLD treatment with low complication rate in BWS patients.
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Use of antiretrovirals is associated to body fat accumulation. We measured body composition in adolescents living with HIV switched to a dolutegravir-containing regimen. Trunk fat and trunk/body fat ratio markedly increased after 12 months. Total and low density lipoprotein cholesterol decreased after 3 months. Increase in trunk fat may put at risk of future cardiovascular problems, despite improvement in the lipid profile.
Assuntos
Antirretrovirais/uso terapêutico , Distribuição da Gordura Corporal , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Gordura Abdominal/efeitos dos fármacos , Adolescente , Antirretrovirais/metabolismo , Estudos de Coortes , Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/metabolismo , Compostos Heterocíclicos com 3 Anéis/metabolismo , Humanos , Lipoproteínas/metabolismo , Lipoproteínas LDL/metabolismo , Estudos Longitudinais , Oxazinas/metabolismo , Piperazinas/metabolismo , Piridonas/metabolismo , Adulto JovemRESUMO
CONTEXT: Analysis of a 2-screen program for congenital hypothyroidism (CH) was performed using differential dried-blood spot thyrotropin (bTSH) cutoffs of 10 mU/L at first screening (all infants) and 5 mU/L at second screening (selected infants). OBJECTIVES: This work aimed to characterize CH infants identified by the second screening and compare infants with bTSH of 5.0 to 9.9 and 10 mU/L or greater on second screening. DESIGN AND PATIENTS: Maternal and neonatal clinical features were retrospectively analyzed for 119 CH babies detected on the second screen in the Lombardy region of Italy, 2007 to 2014. RESULTS: Fifty-two (43.7%) of the 119 CH neonates showed bTSH values ranging from 5.0 to 9.9 mU/L at the second screening (low bTSH group) and 67 (56.3%) bTSH of 10.0 mU/L or greater (high bTSH group). The frequency of thyroid dysgenesis and eutopic gland was similar in both groups, as was the frequency of permanent and transient CH. Moreover, a high frequency of extrathyroidal malformations was found in both groups. The percentage of preterm infants (57.7% vs 23.9%, Pâ <â .001) and infants admitted to the neonatal intensive care unit (50.0% vs 17.9%, Pâ <â .001) was significantly higher in the low vs the high bTSH group. In addition, maternal treatment with glucocorticoids in pregnancy was significantly more frequent in the low bTSH group than in the high bTSH group (11.5% vs 1.5%, Pâ =â .042), as well as maternal hypothyroidism and/or goiter (26.9% vs 10.4%, Pâ =â .036). CONCLUSIONS: This study has demonstrated that a lower TSH cutoff at the second screening can detect additional cases of CH and that a second bTSH cutoff of 5.0 mU/L is appropriate for identifying preterm newborns and babies with associated risk factors.