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1.
Clin Infect Dis ; 72(2): 319-322, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33501967

RESUMO

A time series analysis of 871 543 pediatric emergency visits revealed that the coronavirus disease 2019 (COVID-19) lockdown and school closures were associated with a significant decrease in infectious diseases disseminated through airborne or fecal-oral transmission: common cold, gastroenteritis, bronchiolitis, and acute otitis. No change was found for urinary tract infections.


Assuntos
Pandemias , Criança , Controle de Doenças Transmissíveis , Humanos , Instituições Acadêmicas
2.
Front Immunol ; 11: 595478, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250898

RESUMO

Primary infection with varicella-zoster virus (VZV) causes chickenpox, a benign and self-limited disease in healthy children. In patients with primary or acquired immunodeficiencies, primary infection can be life-threatening, due to rapid dissemination of the virus to various organs [lung, gastrointestinal tract, liver, eye, central nervous system (CNS)]. We retrospectively described and compared the clinical presentations and outcomes of disseminated varicella infection (DV) in patients with acquired (AID) (n= 7) and primary (PID) (n= 12) immunodeficiencies. Patients with AID were on immunosuppression (mostly steroids) for nephrotic syndrome, solid organ transplantation or the treatment of hemopathies, whereas those with PID had combined immunodeficiency (CID) or severe CID (SCID). The course of the disease was severe and fulminant in patients with AID, with multiple organ failure, no rash or a delayed rash, whereas patients with CID and SICD presented typical signs of chickenpox, including a rash, with dissemination to other organs, including the lungs and CNS. In the PID group, antiviral treatment was prolonged until immune reconstitution after bone marrow transplantation, which was performed in 10/12 patients. Four patients died, and three experienced neurological sequelae. SCID patients had the worst outcome. Our findings highlight substantial differences in the clinical presentation and course of DV between children with AID and PID, suggesting differences in pathophysiology. Prevention, early diagnosis and treatment are required to improve outcome.

3.
Clin Infect Dis ; 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32492117

RESUMO

A time series analysis of 871,543 pediatric emergency visits revealed that the COVID-19 lockdown and school closure were associated with a significant decrease in infectious diseases disseminated through airborne or fecal-oral transmissions: common cold, gastro-enteritis, bronchiolitis, acute otitis. No change was found for urinary tract infections.

5.
Int Health ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31990348

RESUMO

BACKGROUND: To identify deprivation indicators usable in everyday practice and included in medico-administrative databases, particularly with infectious diseases, which represent the greatest proportion of hospitalizations. Our objective was to compare ecological indicators to individual questionnaires and apply both types to the study of the impact of deprivation on hospital efficiency. METHODS: We conducted an epidemiological observational prospective multicentre study in two French public hospitals between 20 October 2016 and 20 March 2017. Children hospitalized for one of the four most common infectious diseases were included and their parents were asked to answer the Evaluation of Precarity and Inequalities in Health Examination Centers (EPICES) questionnaire. The ecological indicator French DEPrivation index (FDep) was derived from patients' address, both at the zip code and at a smaller geographical area (IRIS [ilôts de regroupement pour l'information statistique]) level. Correlation and concordance between the three indicators were assessed. The endpoint used to assess the impact on hospital efficiency was the ratio between patients' length of stay (LOS) and the national LOS of their disease-related group. RESULTS: Data were available for 540 patients with a mean age of 9 mo. A total of 56.1% of patients were considered deprived with EPICES, 50.4% with zip code FDep and 45.7% with IRIS FDep. Concordance between EPICES and either type of FDep was <0.1. There was no increase in LOS compared with national LOS with any of the indicators. CONCLUSIONS: Individual and ecological indicators do not measure the same aspects of deprivation. The decision to use one or the other must be carefully weighed when studying the impact of deprivation on the healthcare system.

6.
Proc Natl Acad Sci U S A ; 116(33): 16463-16472, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31346092

RESUMO

Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients' primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.


Assuntos
Proteínas de Ligação a DNA/genética , Síndrome de Job/genética , Sítios de Splice de RNA/genética , Fator de Transcrição STAT3/genética , Adulto , Alelos , Linfócitos B/metabolismo , Linfócitos B/patologia , Pré-Escolar , Éxons/genética , Feminino , Regulação da Expressão Gênica/genética , Heterozigoto , Humanos , Síndrome de Job/patologia , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismo , Linfócitos T/patologia
7.
J Exp Med ; 216(9): 2057-2070, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31270247

RESUMO

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients' fibroblast phenotypes are rescued with WT IFNAR1 Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.


Assuntos
Padrões de Herança/genética , Vacina contra Sarampo/efeitos adversos , Receptor de Interferon alfa e beta/deficiência , Vacina contra Febre Amarela/efeitos adversos , Adolescente , Alelos , Criança , Feminino , Humanos , Imunidade , Lactente , Interferon Tipo I/metabolismo , Masculino , Vacina contra Sarampo/imunologia , Proteínas Mutantes/metabolismo , Mutação/genética , Linhagem , Receptor de Interferon alfa e beta/genética , Transdução de Sinais , Vacina contra Febre Amarela/imunologia
8.
Proc Natl Acad Sci U S A ; 115(34): E8007-E8016, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30072435

RESUMO

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5'-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5'-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.


Assuntos
Éxons , Síndromes de Imunodeficiência/genética , Mutação , Penetrância , Biossíntese de Proteínas/genética , Processamento de RNA/genética , Receptores de Laminina/genética , Proteínas Ribossômicas/genética , Baço/anormalidades , Regiões 5' não Traduzidas , Feminino , Efeito Fundador , Heterozigoto , Humanos , Síndromes de Imunodeficiência/metabolismo , Masculino , Doenças da Imunodeficiência Primária , Receptores de Laminina/biossíntese , Proteínas Ribossômicas/biossíntese , Baço/metabolismo
9.
Am J Med Genet A ; 173(7): 1858-1865, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28488400

RESUMO

Chromosome 7 germline macrodeletions have been implicated in human congenital malformations and developmental delays. We herein report a novel heterozygous macrodeletion of 7q34-q36.3 in a 16-year-old girl originally from West Indies. Similar to previously reported cases of germline chromosome 7q terminal deletions, our patient has dental malposition, and developmental (growth and intellectual) delay. Novel phenotypic features include endemic Kaposi sarcoma (KS), furrowed tongue, thoracolumbar scoliosis, and mild mitral valve dysplasia. The occurrence of human herpes virus 8-driven KS, in a child otherwise normally resistant to other infectious agents and without any other tumoral lesion, points to a very selective immunodeficiency. While defects in organogenesis have been described with such macrodeletions, this is the first report of immunodeficiency and cancer predisposition.

10.
Br J Haematol ; 178(3): 457-467, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28444728

RESUMO

The BRAFV600E mutation is reported in half of patients with Langerhans cell histiocytosis (LCH). This study investigated the detection of the BRAFV600E allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAFV600E -mutated LCH were investigated to detect ccf BRAFV600E at diagnosis (n = 48) and during follow-up (n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAFV600E was positive in 15/15 (100%) patients with risk-organ positive multisystem (RO+ MS) LCH, 5/12 (42%) of patients with RO- MS LCH and 3/21 (14%) patients with single-system (SS) LCH (P < 0·001, Fisher's exact test). The positive BRAFV600E load was higher for RO+ patients (mean, 2·90%; range, 0·04-11·4%) than for RO- patients (mean, 0·16%; range, 0·01-0·39) (P = 0·003, Mann-Whitney U test). After first-line vinblastine-steroid induction therapy, 7/7 (100%) of the non-responders remained positive for ccf BRAFV600E compared to 2/4 (50%) of the partial-responders and 0/4 of the complete responders (P = 0·002, Fisher's exact test). Six children treated with vemurafenib showed a clinical response that was associated with a decrease in the ccf BRAFV600E load at day 15. Thus, ccf BRAFV600E is a promising biomarker for monitoring the response to therapy for children with RO+ MS LCH or RO- LCH resistant to first-line chemotherapy.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Proteínas Proto-Oncogênicas B-raf/sangue , Adolescente , Alelos , Biomarcadores/sangue , Sistema Livre de Células/metabolismo , Criança , Pré-Escolar , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada , Feminino , Seguimentos , Glucocorticoides/uso terapêutico , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/genética , Humanos , Indóis/uso terapêutico , Lactente , Masculino , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/uso terapêutico , Vemurafenib , Vimblastina/uso terapêutico
11.
J Allergy Clin Immunol ; 139(5): 1641-1649.e6, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27702670

RESUMO

BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective production of reactive oxygen species in phagocytic cells that results in life-threatening infections and severe inflammatory manifestations. The treatment of inflammatory manifestations remains challenging because it can be associated with an increased risk of infections. Previous studies have shown that phagocytes from patients with CGD display a defect in autophagy and a reactive oxygen species-independent activation of the inflammasome. OBJECTIVE: Because the intersections between autophagy and the inflammasome have been observed in patients with various diseases and microbial infections, we investigated the possible benefit of restoring the autophagy defect through rapamycin, a potent autophagy inducer, in the setting of CGD. METHODS: We studied 15 patients given a diagnosis of CGD and followed in our institution. All patients were free of any active infection at the time of the study. RESULTS: We show that patients with CGD present a consistent inflammatory phenotype defined by (1) increased nonclassical and intermediate monocytes, (2) a proinflammatory state of mononuclear phagocytes with increased IL-1ß and TNF-α content, (3) a TH17 bias of CD4+ T cells, (4) and an increase in IL-17A-secreting neutrophil numbers. We document the reversion of CGD inflammatory status by the mammalian target of rapamycin inhibitor rapamycin on the different immune cell subsets. We also provide evidence for the enhancement of rapamycin's inhibitory effect on IL-1ß secretion by the IL-1 receptor antagonist anakinra in phagocytes of patients with CGD. CONCLUSION: Altogether, these data open new therapeutic approaches for CGD-related inflammatory manifestations.


Assuntos
Doença Granulomatosa Crônica/imunologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Humanos , Imunossupressores/farmacologia , Lactente , Inflamação/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Fagócitos/efeitos dos fármacos , Fagócitos/imunologia , Sirolimo/farmacologia , Adulto Jovem
12.
Joint Bone Spine ; 81(3): 257-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24793086

RESUMO

Still's disease (Systemic-onset Juvenile Idiopathic Arthritis: SoJIA) is characterised by high-spiking daily fevers, arthritis and evanescent rashes. Diagnosis of Still's disease is often challenging. Infectious diseases and other inflammatory conditions, especially in young children, Kawasaki disease may look similar. Clinicians often rely on echocardiographic evidence of coronary artery abnormalities to differentiate between Kawasaki disease and Still's disease. Coronary artery dilation would typically favour the diagnosis of Kawasaki disease. We present four children with Still's disease and coronary artery abnormalities who were initially misdiagnosed as Kawasaki disease. The first patient had pericarditis and an irregular wall of the left coronary artery, without dilation on echocardiography. The second patient had a left coronary artery dilatation and a pericarditis. The third patient had thickened left coronary artery walls, and the fourth patient had a hyperechogenicity of the left and right coronary arteries. They received IVIG without success. The diagnosis of Still's disease was made secondary with evidence of persistent arthritis. All but one patient finally needed biologic treatments. Coronary abnormalities may be observed during various febrile conditions and do not exclude the diagnosis of Still's disease.


Assuntos
Artrite Juvenil/diagnóstico , Doença da Artéria Coronariana/diagnóstico por imagem , Adolescente , Artrite Juvenil/complicações , Artrite Juvenil/terapia , Pré-Escolar , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/terapia , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Estudos Retrospectivos , Ultrassonografia
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