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1.
BMJ Open ; 7(6): e016031, 2017 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-28637741

RESUMO

INTRODUCTION: Sedation is an essential part of paediatric critical care. Midazolam, often in combination with opioids, is the current gold standard drug. However, as it is a far-from-ideal agent, clonidine is increasingly being used in children. This drug is prescribed off-label for this indication, as many drugs in paediatrics are. Therefore, the CLOSED trial aims to provide data on the pharmacokinetics, safety and efficacy of clonidine for the sedation of mechanically ventilated patients in order to obtain a paediatric-use marketing authorisation. METHODS AND ANALYSIS: The CLOSED study is a multicentre, double-blind, randomised, active-controlled non-inferiority trial with a 1:1 randomisation between clonidine and midazolam. Both treatment groups are stratified according to age in three groups with the same size: <28 days (n=100), 28 days to <2 years (n=100) and 2-18 years (n=100). The primary end point is defined as the occurrence of sedation failure within the study period. Secondary end points include a pharmacokinetic/pharmacodynamic relationship, pharmacogenetics, occurrence of delirium and withdrawal syndrome, opioid consumption and neurodevelopment in the neonatal age group. Logistic regression will be used for the primary end point, appropriate statistics will be used for the secondary end points. ETHICS: Written informed consent will be obtained from the parents/caregivers. Verbal or deferred consent will be used in the sites where national legislation allows. The study has institutional review board approval at recruiting sites. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION: EudraCT: 2014-003582-24; Clinicaltrials.gov: NCT02509273; pre-results.


Assuntos
Clonidina/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Midazolam/uso terapêutico , Projetos de Pesquisa , Adolescente , Analgésicos Opioides/administração & dosagem , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Clonidina/efeitos adversos , Clonidina/farmacocinética , Delírio/induzido quimicamente , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacocinética , Lactente , Recém-Nascido , Unidades de Terapia Intensiva , Midazolam/efeitos adversos , Midazolam/farmacocinética , Respiração Artificial , Síndrome de Abstinência a Substâncias , Falha de Tratamento
2.
BMC Infect Dis ; 17(1): 302, 2017 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-28438138

RESUMO

BACKGROUND: A number of biomarkers have been studied for the diagnosis of sepsis in paediatrics, but no gold standard has been identified. Procalcitonin (PCT) was demonstrated to be an accurate biomarker for the diagnosis of sepsis in adults and showed to be promising in paediatrics. Our study reviewed the diagnostic accuracy of PCT as an early biomarker of sepsis in neonates and children with suspected sepsis. METHODS: A comprehensive literature search was carried out in Medline/Pubmed, Embase, ISI Web of Science, CINAHL and Cochrane Library, for studies assessing PCT accuracy in the diagnosis of sepsis in children and neonates with suspected sepsis. Studies in which the presence of infection had been confirmed microbiologically or classified as "probable" by chart review were included. Studies comparing patients to healthy subjects were excluded. We analysed data on neonates and children separately. Our primary outcome was the diagnostic accuracy of PCT at the cut-off of 2-2.5 ng/ml, while as secondary outcomes we analysed PCT cut-offs <2 ng/ml and >2.5 ng/ml. Pooled sensitivities and specificities were calculated by a bivariate meta-analysis and heterogeneity was graphically evaluated. RESULTS: We included 17 studies, with a total of 1408 patients (1086 neonates and 322 children). Studies on neonates with early onset sepsis (EOS) and late onset sepsis (LOS) were grouped together. In the neonatal group, we calculated a sensitivity of 0.85, confidence interval (CI) (0.76; 0.90) and specificity of 0.54, CI (0.38; 0.70) at the PCT cut-off of 2.0-2.5 ng/ml. In the paediatric group it was not possible to undertake a pooled analysis at the PCT cut-off of 2.0-2.5 ng/ml, due to the paucity of the studies. CONCLUSIONS: PCT shows a moderate accuracy for the diagnosis of sepsis in neonates with suspected sepsis at the cut-off of 2.0-2.5 ng/ml. More studies with high methodological quality are warranted, particularly in neonates, studies considering EOS and LOS separately are needed to improve specificity. TRIAL REGISTRATION: PROSPERO Identifier: CRD42016033809 . Registered 30 Jan 2016.


Assuntos
Calcitonina/sangue , Sepse/diagnóstico , Biomarcadores/sangue , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sepse/microbiologia
3.
Ital J Pediatr ; 42: 44, 2016 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-27116911

RESUMO

BACKGROUND: Differential diagnosis between sepsis and non-infectious inflammatory disorders demands improved biomarkers. Soluble Triggering Receptor Expression on Myeloid cells (sTREM-1) is an activating receptor whose role has been studied throughout the last decade. We performed a systematic review to evaluate the accuracy of plasma sTREM-1 levels in the diagnosis of sepsis in children with Systemic Inflammatory Response Syndrome (SIRS). METHODS: A literature search of PubMed, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and ISI Web of Knowledge databases was performed using specific search terms. Studies were included if they assessed the diagnostic accuracy of plasma sTREM-1 for sepsis in paediatric patients with SIRS. Data on sensitivity, specificity, positive predictive value, negative predictive value, area under receiver operating characteristic curve were extracted. The methodological quality of each study was assessed using a checklist based on the Quality Assessment Tool for Diagnostic Accuracy Studies. RESULTS: Nine studies comprising 961 patients were included, four of which were in newborns, three in children and two in children with febrile neutropenia. Some data from single studies support a role of sTREM-1 as a diagnostic tool in pediatric sepsis, but cannot be considered conclusive, because a quantitative synthesis was not possible, due to heterogeneity in studies design. CONCLUSIONS: This systematic review suggests that available data are insufficient to support a role for sTREM in the diagnosis and follow-up of paediatric sepsis.


Assuntos
Glicoproteínas de Membrana/sangue , Células Mieloides , Receptores Imunológicos/sangue , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Biomarcadores/sangue , Criança , Diagnóstico Diferencial , Humanos , Síndrome de Resposta Inflamatória Sistêmica/sangue , Receptor Gatilho 1 Expresso em Células Mieloides
4.
Am J Health Syst Pharm ; 73(8): 556-61, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27045067

RESUMO

PURPOSE: The development, analysis, and first clinical use of a novel eye drop formulation of plasminogen and hyaluronate sodium for the treatment of a patient with ligneous conjunctivitis (LC) are described. SUMMARY: LC is a chronic inflammatory disorder of the eye that can in rare cases lead to corneal involvement and subsequent blindness. Topically administered plasminogen is an effective treatment for LC; however, the lack of a specific and validated formulation of plasminogen for topical treatment can constitute a gap in the quality of care. A novel formulation of plasminogen and hyaluronate sodium for the treatment of LC was developed by combining commercially available products. Through a series of tests, including microbiological, viscosity, and pH analyses, the novel eye drop formulation was demonstrated to have constant activity (3.3 IU/mL or greater), to be microbiologically stable (i.e., sterile), and to be safe enough for daily administration. The first clinical application of the novel eye drop formulation was in the case of a nine-year-old girl with LC affecting both eyes. Initially, the girl's parents administered two drops every three hours to the left eye each day while the girl was awake. On examination after 30 days of daily use of the eye drop formulation, the patient was found to have a clear cornea and no membrane development on the conjunctiva; the formulation was subsequently administered in both eyes, with positive results. CONCLUSION: A new formulation of plasminogen plus hyaluronate sodium was developed, tested, and used successfully in a girl with LC.


Assuntos
Conjuntivite/tratamento farmacológico , Ácido Hialurônico/administração & dosagem , Plasminogênio/administração & dosagem , Plasminogênio/deficiência , Dermatopatias Genéticas/tratamento farmacológico , Administração Oftálmica , Química Farmacêutica , Criança , Combinação de Medicamentos , Feminino , Humanos , Soluções Oftálmicas , Resultado do Tratamento
5.
J Clin Immunol ; 35(4): 373-83, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25875698

RESUMO

PURPOSE: Hematopoietic cell transplantation (HCT) provides a curative therapy for severe forms of primary immunodeficiencies (PID). While the timing and extent of T-cell reconstitution following transplant for PID has been studied in depth, less is known about the kinetics of B-cell development and long-term restoration of humoral functions, which been often reported to be suboptimal after HCT. METHODS: We studied longitudinally B-cell development and function in a cohort of 13 PID patients transplanted between 1997 and 2010, with a follow-up ranging from 0.7 to 15 years. Flow cytometric analysis of naïve and antigen-experienced B-cell subsets and in vitro functional responses to CpG were compared with data from healthy children and correlated with the degree of B-cell chimerism and in vivo antibody production. RESULTS: We found that total memory B-cells count remained below normal levels for the first 2 years of follow up and progressively normalized. Switched memory B-cells (CD19+CD27+IgD-IgM-) were restored early and better than IgM memory B-cells (CD19+CD27+IgD+IgM+), which remained significantly reduced long-term. The recovery of memory B-cells correlated with good in vivo humoral function and normalization of CpG-response. A complete B-cell reconstitution was usually associated with donor B-cells chimerism and pre-transplant conditioning. Donor source and the underlying genetic defect represented also important variables. CONCLUSION: Monitoring of phenotypic and functional changes on B-cells following HCT may prove clinically relevant to tailor patients' care. In particular the analysis of IgM memory and switched memory B-cells in addition to in vitro B-cells stimulation are recommended before Ig replacement therapy (IgRT) discontinuation.


Assuntos
Linfócitos B/imunologia , Imunidade , Síndromes de Imunodeficiência/imunologia , Adolescente , Formação de Anticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Criança , Pré-Escolar , Feminino , Seguimentos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Isotipos de Imunoglobulinas/sangue , Isotipos de Imunoglobulinas/imunologia , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Imunofenotipagem , Lactente , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Linfócitos T/imunologia , Linfócitos T/metabolismo , Quimeras de Transplante , Transplante Homólogo , Resultado do Tratamento
6.
J Allergy Clin Immunol ; 126(1): 127-32.e7, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20542322

RESUMO

BACKGROUND: Nuclear factor-kappaB (NF-kappaB) is a key transcription factor that regulates both innate and adaptive immunity as well as ectodermal development. Mutations in the coding region of the IkappaB kinase gamma/NF-kappaB essential modifier (NEMO) gene cause X-linked ectodermal dysplasia with immunodeficiency. OBJECTIVE: To determine the genetic cause of recurrent sinopulmonary infections and dysgammaglobulinemia in a patient with a normal NEMO coding sequence and his affected brother. METHODS: TNF-alpha and IFN-alpha production in response to Toll-like receptor (TLR) stimulation was analyzed by ELISA, NEMO mRNA levels were measured by quantitative PCR, and NEMO protein expression was measured by Western blotting. NF-kappaB activation was assessed by nuclear translocation of p65 and luciferase reporter gene assays. RESULTS: TLR-induced TNF-alpha and IFN-alpha production by PBMCs was impaired in the patient and his brother. Sequencing of the patient's NEMO gene revealed a novel mutation in the 5' untranslated region, which was also present in the brother, resulting in abnormally spliced transcripts and a 4-fold reduction in mRNA levels. NEMO protein levels in EBV transformed B cells and fibroblasts from the index patient were 8-fold lower than normal controls. NF-kappaB p65 nuclear translocation in the patient's EBV B cells after TLR7 ligation was defective. NF-kappaB-dependent luciferase gene expression in IL-1-stimulated fibroblasts from the patient was impaired. CONCLUSION: This is the first description of immune deficiency resulting from low expression of a normal NEMO protein.


Assuntos
Regiões 5' não Traduzidas/genética , Quinase I-kappa B/genética , Síndromes de Imunodeficiência/etiologia , Mutação , Criança , Citocinas/biossíntese , Humanos , Quinase I-kappa B/análise , Proteínas I-kappa B/metabolismo , Síndromes de Imunodeficiência/genética , Interleucina-1beta/farmacologia , Masculino , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Fosforilação , Sítios de Splice de RNA , RNA Mensageiro/análise , Receptores Toll-Like/fisiologia
7.
Int J Pediatr Otorhinolaryngol ; 73 Suppl 1: S42-8, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20114155

RESUMO

Many adults and children with an underlying immunodeficiency can frequently present to ear, nose and throat (ENT) surgeons. This work deals with the presentation, investigation and management of immuno-compromised children in ENT practise. Both primary immunodeficiencies (PID) and secondary or acquired immunodeficiencies such as human immunodeficiency virus (HIV) infection are here discussed. The aim of this work is to give a complete and exhaustive description of ENT manifestations in immunodeficiency, and to outline basic principles to guide clinical practice.


Assuntos
Síndrome de Imunodeficiência Adquirida/complicações , Fibrose Cística/complicações , Otorrinolaringopatias/diagnóstico , Otorrinolaringopatias/virologia , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Criança , Fibrose Cística/diagnóstico , Diagnóstico Diferencial , Humanos , Otorrinolaringopatias/etiologia , Peroxidase/deficiência
8.
Radiology ; 232(2): 461-5, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15215545

RESUMO

PURPOSE: To evaluate the water diffusivity of normal-appearing white matter (NAWM) in patients with tuberous sclerosis complex compared with that in control subjects. MATERIALS AND METHODS: Diffusion and conventional magnetic resonance (MR) imaging examinations were performed in 18 patients with clinically established tuberous sclerosis complex (10 male and eight female patients; mean age, 20.1 years; range, 12-30 years), as well as in 18 age-matched control subjects (nine male and nine female; mean age, 20.2 years; range, 11-28 years). Apparent diffusion coefficients (ADCs) were generated, and small elliptic regions of interest were manually placed both in perilesional NAWM and in six anatomic locations of NAWM remote from hamartomatous lesions. Perilesional ADCs were compared with those at the same anatomic site on the contralateral side of the brain (generalized linear regression analysis). ADCs from the predetermined sites in patients were compared with those in control subjects (generalized linear regression analysis). RESULTS: Supratentorial ADCs were higher in patients with tuberous sclerosis complex than in control subjects, and statistically significant differences were observed in the occipital white matter, frontal white matter, centrum semiovale, parietal white matter, and corona radiata (for each location, P <.001). Significant increases were also seen in the perilesional NAWM compared with NAWM at the same anatomic locations on the contralateral side (P <.001). Infratentorial ADCs were normal. CONCLUSION: Significant ADC increases were measured in the supratentorial NAWM.


Assuntos
Edema Encefálico/diagnóstico , Imagem de Difusão por Ressonância Magnética , Aumento da Imagem , Processamento de Imagem Assistida por Computador , Esclerose Tuberosa/diagnóstico , Adolescente , Adulto , Barreira Hematoencefálica/fisiologia , Encéfalo/patologia , Mapeamento Encefálico , Criança , Diagnóstico Diferencial , Dominância Cerebral/fisiologia , Feminino , Humanos , Modelos Lineares , Masculino , Valores de Referência
9.
Pediatr Radiol ; 34(7): 547-51, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15114413

RESUMO

BACKGROUND: Three-dimensional MRI (3D-MRI) is a reliable tool for the evaluation of anatomical volumes. Volumetric measurement of the normal anterior pituitary gland in childhood has been performed in the past by 2D-MRI calculations, but has inherent inaccuracies. OBJECTIVE: To obtain accurate normal anterior pituitary gland volume in childhood using 3D-MRI coronal sections. MATERIALS AND METHODS: The anterior pituitary gland was measured using coronal T1-weighted 3D-gradient-echo sequences (section thickness 0.75 mm). The study group was composed of 95 prepubertal children (age range 2 months-10 years) with clinically normal pituitary function and no pituitary or brain abnormalities. RESULTS: A measurement error of 0.2-0.4% was assessed by using a phantom study. Volumetric evaluation of the anterior pituitary gland showed progressive growth of the gland from a mean 131+/-24 mm(3) at 2-12 months, to 249+/-25 mm(3) at 1-4 years and 271+/-29 mm(3) at 5-10 years. CONCLUSIONS: These data may be useful for paediatricians in the evaluation of patients with neuroendocrine diseases, in particular growth hormone deficiency.


Assuntos
Imagem Tridimensional , Imagem por Ressonância Magnética , Adeno-Hipófise/crescimento & desenvolvimento , Análise de Variância , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Imagens de Fantasmas , Valores de Referência , Estatísticas não Paramétricas
10.
Eur Radiol ; 13(7): 1571-6, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12835969

RESUMO

Diffusion-weighted imaging (DWI) has been shown to be highly sensitive in detecting acute cerebral infarction, but its use in detecting hypoxic-ischemic encephalopathy (HIE) in neonates is still controversial. Moreover, few reports concern pre-term infants with possible periventricular leukomalacia (PVL). We examined the ability of this technique to detect cerebral changes in the acute phase of PVL. Fifteen MR examinations were performed in 11 pre-term infants (mean age 3.4 days, range 2-6 days). Conventional DWI sequences, apparent diffusion coefficient (ADC) maps, and US obtained in the acute phase were compared. All the neonates underwent US follow-up up to 4 months after delivery; those with suspected PVL also underwent MRI follow-up for up to 2 months. Qualitative and quantitative evaluations were performed to assess the presence of DW changes compatible with PVL. Diffusion-weighted MRI showed signal hyperintensity associated with decreased ADC values in 3 subjects (27%). In these patients conventional MRI sequences were interpreted as normal and US (performed at the same time) as doubtful in 2 and compatible with PVL in 1 subject. The MRI and US follow-up confirmed severe damage in all these patients. In 1 neonate hemorrhages involving the germinative matrix were identified. In 8 neonates MRI was considered normal. In these subjects US follow-up (up to 4 months) confirmed no signs of PVL. Diffusion-weighted imaging may have a higher correlation with later evidence of PVL than does conventional MR imaging and US when performed in the acute phase of the disease.


Assuntos
Encéfalo/patologia , Imagem de Difusão por Ressonância Magnética , Leucomalácia Periventricular/diagnóstico , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Estudos Prospectivos
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