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Neurologic morbidity is highly prevalent in pediatric critical illness, and the use of benzodiazepines and/or opioids is a risk factor for delirium and post-discharge sequelae. However, little is known about how multidrug sedation with these medications interacts with inflammation in the developing brain, a frequent condition during childhood critical illness that has not been extensively studied. In weanling rats, mild-moderate inflammation was induced with lipopolysaccharide (LPS) on postnatal day (P)18 and combined with 3 days repeated opioid and benzodiazepine sedation using morphine and midazolam (MorMdz) between P19-21. Delirium-like behaviors including abnormal response to whisker stimulation, wet dog shakes, and delay in finding buried food were induced in male and female rat pups treated with LPS, MorMdz, or LPS/MorMdz (n ≥ 17/group) and were compared using a z-score composite. Composite behavior scores were significantly increased in LPS, MorMdz, and LPS/MorMdz groups compared to saline control (F3,78 = 38.1, p < 0.0001). Additionally, expression of glial-associated neuroinflammatory markers ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) in western blots of P22 brain homogenate were significantly higher after LPS than after LPS/MorMdz (Iba1, p < 0.0001; GFAP, p < 0.001). Likewise, proinflammatory cytokines were increased in brains of LPS-treated pups versus Saline (p = 0.002), but not LPS/MorMdz-treated pups (p = 0.16). These results are of potential interest during pediatric critical illness, as inflammation is ubiquitous and the effects of multidrug sedation on homeostatic neuroimmune responses need to be considered along with neurodevelopmental effects.
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Delírio , Doenças Neuroinflamatórias , Humanos , Ratos , Animais , Masculino , Feminino , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/metabolismo , Assistência ao Convalescente , Estado Terminal , Alta do Paciente , Encéfalo/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Benzodiazepinas/farmacologia , Analgésicos Opioides/efeitos adversos , Delírio/metabolismo , Lipopolissacarídeos/toxicidadeRESUMO
OBJECTIVES: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. DESIGN: Retrospective study. SETTING: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. PATIENTS: Children (< 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25-14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index (n = 817) was 19.4 kg/m2 (16-25.8 kg/m2), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU (n = 379) and hospital (n = 857) stay were 3.9 days (2-7.7 d) and 4 days (1.9-7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. CONCLUSIONS: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.
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COVID-19/complicações , COVID-19/epidemiologia , COVID-19/fisiopatologia , Criança Hospitalizada/estatística & dados numéricos , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Adolescente , Fatores Etários , Índice de Massa Corporal , COVID-19/mortalidade , Criança , Pré-Escolar , Comorbidade , Feminino , Mortalidade Hospitalar/tendências , Humanos , Lactente , Unidades de Terapia Intensiva/estatística & dados numéricos , Modelos Logísticos , Masculino , Estudos Retrospectivos , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/mortalidadeRESUMO
In the midst of concerns for potential neurodevelopmental effects after surgical anesthesia, there is a growing awareness that children who require sedation during critical illness are susceptible to neurologic dysfunctions collectively termed pediatric post-intensive care syndrome, or PICS-p. In contrast to healthy children undergoing elective surgery, critically ill children are subject to inordinate neurologic stress or injury and need to be considered separately. Despite recognition of PICS-p, inconsistency in techniques and timing of post-discharge assessments continues to be a significant barrier to understanding the specific role of sedation in later cognitive dysfunction. Nonetheless, available pediatric studies that account for analgesia and sedation consistently identify sedative and opioid analgesic exposures as risk factors for both in-hospital delirium and post-discharge neurologic sequelae. Clinical observations are supported by animal models showing neuroinflammation, increased neuronal death, dysmyelination, and altered synaptic plasticity and neurotransmission. Additionally, intensive care sedation also contributes to sleep disruption, an important and overlooked variable during acute illness and post-discharge recovery. Because analgesia and sedation are potentially modifiable, understanding the underlying mechanisms could transform sedation strategies to improve outcomes. To move the needle on this, prospective clinical studies would benefit from cohesion with regard to datasets and core outcome assessments, including sleep quality. Analyses should also account for the wide range of diagnoses, heterogeneity of this population, and the dynamic nature of neurodevelopment in age cohorts. Much of the related preclinical evidence has been studied in comparatively brief anesthetic exposures in healthy animals during infancy and is not generalizable to critically ill children. Thus, complementary animal models that more accurately "reverse translate" critical illness paradigms and the effect of analgesia and sedation on neuropathology and functional outcomes are needed. This review explores the interactive role of sedatives and the neurologic vulnerability of critically ill children as it pertains to survivorship and functional outcomes, which is the next frontier in pediatric intensive care.
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Objective: To describe light and sound characteristics in the rooms of critically ill children. Design: Prospective observational cohort study, with continuously measured light and sound levels. Setting: Tertiary care pediatric intensive care unit (PICU), with a newly constructed expansion and an older, pre-existing section. Patients: Critically ill patients 0-18 years old, requiring respiratory or cardiovascular support. Patients with severe cognitive pre-conditions were excluded. Measurements and Main Results: One hundred patients were enrolled, totaling 602 patient-days. The twenty-four hour median illuminance was 16 (IQR 5-53) lux (lx). Daytime (07:00-21:00) median light level was 27 lx (IQR 13-82), compared with 4 lx (IQR 1-10) overnight (22:00-06:00). Peak light levels occurred midday between 11:00 and 14:00, with a median of 48 lx (IQR 24-119). Daytime median illuminance trended higher over the course of admission, whereas light levels overnight were consistent. Midday light levels were higher in newly constructed rooms: 78 lx (IQR 30-143) vs. 26 lx (IQR 20-40) in existing rooms. The twenty-four hour median equivalent sound level (LAeq) was 60 (IQR 55-64) decibels (dB). Median daytime LAeq was 62 dB (IQR 58-65) and 56 dB (IQR 52-61) overnight. On average, 35% of patients experienced at least one sound peak >80 dB every hour from 22:00 to 06:00. Overnight peaks, but not median sound levels nor daytime peaks, decreased over the course of admission. There was no difference in sound between new and pre-existing rooms. Conclusions: This study describes continuously measured light and sound in PICU rooms. Light levels were low even during daytime hours, while sound levels were consistently higher than World Health Organization hospital room recommendations of <35 dB. Given the relevance of light and sound to sleep/wake patterns, and evidence of post-intensive care syndromes, the clinical effects of light and sound on critically ill children should be further explored as potentially modifiable environmental factors.
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Abusive head trauma (AHT) is broadly defined as injury of the skull and intracranial contents as a result of perpetrator-inflicted force and represents a persistent and significant disease burden in children under the age of 4 years. When compared to age-matched controls with typically single occurrence accidental traumatic brain injury (TBI), mortality after AHT is disproportionately high and likely attributable to key differences between injury phenotypes. This article aims to review the epidemiology of AHT, summarize the current state of AHT diagnosis, treatment, and prevention as well as areas for future directions of study. Despite neuroimaging advances and an evolved understanding of AHT, early identification remains a challenge for contemporary clinicians. As such, the reported incidence of 10-30 per 100,000 infants per year may be a considerable underestimate that has not significantly decreased over the past several decades despite social campaigns for public education such as "Never Shake a Baby." This may reflect caregivers in crisis for whom education is not sufficient without support and intervention, or dangerous environments in which other family members are at risk in addition to the child. Acute management specific to AHT has not advanced beyond usual supportive care for childhood TBI, and prevention and early recognition remain crucial. Moreover, AHT is frequently excluded from studies of childhood TBI, which limits the precise translation of important brain injury research to this population. Repeated injury, antecedent abuse or neglect, delayed medical attention, and high rates of apnea and seizures on presentation are important variables to be considered. More research, including AHT inclusion in childhood TBI studies with comparisons to age-matched controls, and translational models with clinical fidelity are needed to better elucidate the pathophysiology of AHT and inform both clinical care and the development of targeted therapies. Clinical prediction rules, biomarkers, and imaging modalities hold promise, though these have largely been developed and validated in patients after clinically evident AHT has already occurred. Nevertheless, recognition of warning signs and intervention before irreversible harm occurs remains the current best strategy for medical professionals to protect vulnerable infants and toddlers.
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BACKGROUND: Although small series have suggested that younger age is associated with less favorable outcome after severe traumatic brain injury (TBI), confounders and biases have limited our understanding of this relationship. We hypothesized that there would be an association between age and mortality in children within an ongoing observational, cohort study. METHODS: The first 200 subjects from the Approaches and Decisions for Acute Pediatric TBI trial were eligible for this analysis (inclusion criteria: severe TBI (Glasgow Coma Scale [GCS] score ≤ 8], age 18 years, and intracranial pressure (ICP) monitor placed; exclusion: pregnancy). Children with suspected abusive head trauma (AHT) were excluded to avoid bias related to the association between AHT and mortality. Demographics, and prehospital and resuscitation events were collected/analyzed, and children were stratified based on age at time of injury (< 5, 5-< 11, 11-18 years) and presented as mean ± standard error of the mean (SEM). Analyses of variance were used to test the equality of the means across the group for continuous variable, and Chi-square tests were used to compare percentages for discrete variables (post hoc comparisons were made using t test and Bonferroni corrections, as needed). Kaplan-Meier curves were generated for each age subgroup describing the time of death, and log-rank was used to compare the curves. Cox proportional hazards regression models were used to assess the effect of age on time to death while controlling for covariates. RESULTS: In the final cohort (n = 155, 45 excluded for AHT), overall age was 9.2 years ± 0.4 and GCS was 5.3 ± 0.1. Mortality was similar between strata (14.0, 20.0, 20.9%, respectively, p = 0.58). Motor vehicle accidents were the most common mechanism across all strata, while falls tended to be more common in the youngest stratum (p = 0.08). The youngest stratum demonstrated increased incidence of spontaneous hypothermia at presentation and decreased hemoglobin concentrations and coagulopathies, while the oldest demonstrated lower platelet counts. CONCLUSIONS: In contrast to previous reports, we failed to detect mortality differences across age strata in children with severe TBI. We have discerned novel associations between age and various markers of injury-unrelated to AHT-that may lead to testable hypotheses in the future.
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Fatores Etários , Lesões Encefálicas Traumáticas/mortalidade , Índice de Gravidade de Doença , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Pesquisa Comparativa da Efetividade , Feminino , Humanos , MasculinoRESUMO
OBJECTIVES: To determine prevalence of delirium in critically ill children and explore associated risk factors. DESIGN: Multi-institutional point prevalence study. SETTING: Twenty-five pediatric critical care units in the United States, the Netherlands, New Zealand, Australia, and Saudi Arabia. PATIENTS: All children admitted to the pediatric critical care units on designated study days (n = 994). INTERVENTION: Children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the bedside nurse. Demographic and treatment-related variables were collected. MEASUREMENTS AND MAIN RESULTS: Primary study outcome measure was prevalence of delirium. In 159 children, a final determination of mental status could not be ascertained. Of the 835 remaining subjects, 25% screened positive for delirium, 13% were classified as comatose, and 62% were delirium-free and coma-free. Delirium prevalence rates varied significantly with reason for ICU admission, with highest delirium rates found in children admitted with an infectious or inflammatory disorder. For children who were in the PICU for 6 or more days, delirium prevalence rate was 38%. In a multivariate model, risk factors independently associated with development of delirium included age less than 2 years, mechanical ventilation, benzodiazepines, narcotics, use of physical restraints, and exposure to vasopressors and antiepileptics. CONCLUSIONS: Delirium is a prevalent complication of critical illness in children, with identifiable risk factors. Further multi-institutional, longitudinal studies are required to investigate effect of delirium on long-term outcomes and possible preventive and treatment measures. Universal delirium screening is practical and can be implemented in pediatric critical care units.
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Estado Terminal/psicologia , Delírio/epidemiologia , Adolescente , Austrália/epidemiologia , Criança , Pré-Escolar , Coma/epidemiologia , Delírio/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Masculino , Países Baixos/epidemiologia , Nova Zelândia/epidemiologia , Prevalência , Fatores de Risco , Arábia Saudita/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Neuroblastoma is the most common extra-cranial solid tumour in children. Natural killer (NK) cells are innate lymphocytes that are known to mediate the direct cytotoxicity of neuroblastoma tumour cells. Natural variation in the highly polymorphic killer immunoglobulin-like receptors (KIR) and their cognate human leukocyte antigen (HLA) class I ligands results in considerable diversity in NK cell function. As the early onset of neuroblastoma suggests the contribution of genetic factors, we investigated if individual KIR genes, combined KIR gene haplotypes or compound KIR-HLA ligand genotypes could influence susceptibility to neuroblastoma. Genotype analysis of the KIR genes as well as their three major HLA class I ligand groups, HLA-C1, HLA-C2 and HLA-Bw4, was carried out in a cohort of 201 neuroblastoma patients compared with 240 healthy control subjects using polymerase chain reaction with sequence-specific primers. We found a significant increase in the frequency of KIR2DL2 (P = 0.019) as well as KIR2DS2 (P = 0.008) in patients with neuroblastoma compared with the healthy control group. While the incidence of the least inhibitory compound KIR-HLA-C genotype, KIR2DL3 in the presence of HLA-C1 was slightly reduced in neuroblastoma patients, this did not reach statistical significance (P = 0.069). In summary, while KIR-HLA compound genotypes have previously been implicated in predicting treatment outcomes in neuroblastoma, here we show that the presence of the individual KIR genes, KIR2DL2 and KIR2DS2, irrespective of HLA-C genotype is associated with the onset of this embryonal malignancy.
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Predisposição Genética para Doença , Neuroblastoma/genética , Receptores KIR2DL2/genética , Receptores KIR/genética , Alelos , Estudos de Casos e Controles , Centrômero/genética , Estudos de Coortes , Sequência Conservada/genética , Antígenos HLA-C/genética , Haplótipos , Humanos , Ligantes , Telômero/genéticaRESUMO
In a previous study, the fecal biomarkers calprotectin and α1-antitrypsin (α1-AT) at symptom onset were reported to be significantly associated with the response to steroids in gastrointestinal GvHD (GI-GvHD). The purpose of this trial was to evaluate the dynamics of the fecal biomarkers calprotectin and α1-AT throughout the course of GvHD. Patients who were refractory to steroids had initially higher biomarker levels and in the course of GvHD demonstrated a continuous increase in fecal biomarkers. In contrast, the dynamics of calprotectin and α1-AT demonstrated low and decreasing levels in cortico-sensitive GvHD. In steroid-refractory patients who received a second line of treatment, the biomarker levels at the beginning of second-line treatment did not predict the subsequent response. Nevertheless, calprotectin levels progressively decreased in subsequent responders, whereas non-responders demonstrated continuously high levels of calprotectin. α1-AT values correlated to a lesser extent with the response to second-line treatment and remained elevated in both non-responders and responders. In conclusion, calprotectin monitoring can be of use in the management of immunosuppressive treatment in GI-GvHD.
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Fezes , Gastroenteropatias/metabolismo , Doença Enxerto-Hospedeiro/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , alfa 1-Antitripsina/metabolismo , Biomarcadores/metabolismo , Feminino , Gastroenteropatias/tratamento farmacológico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND AND OBJECTIVES: We describe the recognition and pattern of care of voluntary blood donors with early-uncomplicated genetic haemochromatosis in our blood donation centre. MATERIALS AND METHODS: Asymptomatic volunteers with suspicion of hereditary haemochromatosis (HH) due to an elevated ferritin level on routine screening were referred for further investigation. Alternatively, we accepted subjects with prediagnosed HH on referral. In the case of early-uncomplicated genetic haemochromatosis, either standard whole blood donation (WBD) or double-erythrocytapheresis (DEC) was offered. RESULTS: A median of six procedures was needed to achieve a ferritin value below 100 ng/ml in the WBD group and of four in the DEC group (P = 0·5). The rate of donation side-effects was higher in the DEC group, while the costs it generated were equivalent to WBD. CONCLUSION: Compared with WBD, DEC had no beneficial effect on treatment number, length of treatment, side-effects or treatment budget in early-uncomplicated HH. Integrating donors with uncomplicated genetic haemochromatosis to blood donation programmes can supplement blood stores and provide the donors with a cost-effective and altruistic purpose of treatment.
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Doadores de Sangue , Hemocromatose/terapia , Adulto , Idoso , Remoção de Componentes Sanguíneos , Feminino , Ferritinas/sangue , Hemocromatose/diagnóstico , Hemocromatose/genética , Humanos , Masculino , Pessoa de Meia-Idade , Suíça , Adulto JovemRESUMO
Niemann Pick Type C2 (NPC2) is a rare autosomal recessive disease caused by mutations in the NPC2 gene (OMIM 601015). Clinically, NPC2 presents in most cases in the neonatal period with inflammatory lung disease, which may lead to death in the first year. If patients survive the neonatal period, they may develop a severe neurological disease. Here we present the developmental and neurological follow up at 5 years of age of a child with NPC2 successfully treated with allogenic bone marrow transplantation (BMT) at the age of 16 months. A homozygous p.E20X sequence variation previously associated with a severe phenotype was identified. In contrast to the previously reported patients with the same mutations, our patient has no respiratory compromise and has made some developmental progress (especially gross motor), though is significantly delayed (particularly in speech and language). Haematopoietic stem cell transplantation (HSCT) could be considered for patients with this mutation as long as performed early in the course of the disease.
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Transplante de Medula Óssea , Doença de Niemann-Pick Tipo C/cirurgia , Evolução Fatal , Humanos , Lactente , Recém-Nascido , Doença de Niemann-Pick Tipo C/fisiopatologia , Transplante HomólogoRESUMO
BACKGROUND: Fibre-optic bronchoscopy with bronchoalveolar lavage (BAL) is a safe procedure and is associated with low morbidity and mortality in immunocompromised children. Although many studies have highlighted the advantages of positive BAL results in the diagnosis of pulmonary infections, there have been few reports examining the impact of a negative BAL result on clinical management in immunocompromised children on empiric broad-spectrum antimicrobial therapy. AIM: The aim of this study was to evaluate BAL in the diagnosis of pulmonary infections in children with haematological malignancies who develop pneumonia unresponsive to empiric antimicrobial therapy, and also to determine whether a negative BAL result contributed to the clinical management of these patients. MATERIALS AND METHODS: A retrospective review of 44 BAL procedures performed in 33 children with haematological malignancy diagnosed and treated at Our Lady's Children Hospital, Crumlin, Dublin 12, Ireland, over a 10-year period was carried out. RESULTS: We identified a pathogen causing pneumonia in 24 of 44 BAL procedures (54.5 %). The BAL procedure resulted in modification of antimicrobial treatment after 20 of 24 procedures with positive results (83.3 %) in 16 of 20 patients (80 %). Management was changed after 8 of 20 procedures with negative results (40 %) in 8 of 18 patients (44.4 %). The procedure was well tolerated in all patients. CONCLUSIONS: Our study supports the use of bronchoscopy with BAL as a diagnostic intervention in this patient population. We consider BAL a safe procedure from which both positive and negative results contribute to the patient's clinical management.
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Líquido da Lavagem Broncoalveolar/microbiologia , Neoplasias Hematológicas/complicações , Pneumonia/diagnóstico , Adolescente , Anti-Infecciosos/uso terapêutico , Broncoscopia , Criança , Pré-Escolar , Feminino , Hospitais Pediátricos , Humanos , Hospedeiro Imunocomprometido , Lactente , Irlanda , Leucemia/complicações , Linfoma/complicações , Masculino , Pneumonia/tratamento farmacológico , Pneumonia/etiologia , Estudos RetrospectivosRESUMO
Umbilical cord blood is being used increasingly as a source of haematopoietic stem cells for transplantation because of rapid availability, and the unavailability of a HLA matched adult donor for some patients. This study reports the characteristics and outcomes of 15 patients who have undergone umbilical cord blood transplantation (UCBT) in Ireland between 1998 and 2009. The median total nucleated cell and CD34+ doses post-processing were 6.5 x 107cells/kg and 1.8 x 105 cells/kg, respectively. Median neutrophil recovery time was 30 days (range, 14-44). Median platelet recovery time was 46.5 days (range, 35-148). 33.3% of patients developed acute cutaneous graft-versus-host disease (GVHD) grade I-II. Three patients died of transplant-related toxicity and two died of leukaemic relapse. We conclude that, with a satisfactory stem cell dose, UCBT offers a high chance of engraftment with acceptable toxicity, and should be regarded as a favourable option in selected patients when satisfactory bone marrow or peripheral blood stem cell donors are not available.
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Transplante de Células-Tronco de Sangue do Cordão Umbilical , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Contagem de Leucócitos , Masculino , Neutrófilos , Contagem de PlaquetasRESUMO
BACKGROUND: Neuroblastoma remains a major cause of cancer-linked mortality in children. miR-204 has been used in microRNA expression signatures predictive of neuroblastoma patient survival. The aim of this study was to explore the independent association of miR-204 with survival in a neuroblastoma cohort, and to investigate the phenotypic effects mediated by miR-204 expression in neuroblastoma. METHODS: Neuroblastoma cell lines were transiently transfected with miR-204 mimics and assessed for cell viability using MTS assays. Apoptosis levels in cell lines were evaluated by FACS analysis of Annexin V-/propidium iodide-stained cells transfected with miR-204 mimics and treated with chemotherapy drug or vehicle control. Potential targets of miR-204 were validated using luciferase reporter assays. RESULTS: miR-204 expression in primary neuroblastoma tumours was predictive of patient event-free and overall survival, independent of established known risk factors. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro. miR-204 direct targeting of the 3' UTR of BCL2 and NTRK2 (TrkB) was confirmed. CONCLUSION: miR-204 is a novel predictor of outcome in neuroblastoma, functioning, at least in part, through increasing sensitivity to cisplatin by direct targeting and downregulation of anti-apoptotic BCL2. miR-204 also targets full-length NTRK2, a potent oncogene involved with chemotherapy drug resistance in neuroblastoma.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , MicroRNAs/farmacologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Receptor trkB/efeitos dos fármacos , Análise de Variância , Animais , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Modelos Animais de Doenças , Intervalo Livre de Doença , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Etoposídeo/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Glicoproteínas de Membrana/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos , Camundongos SCID , Neuroblastoma/mortalidade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Proteínas Tirosina Quinases/efeitos dos fármacos , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , Reação em Cadeia da Polimerase em Tempo Real , Receptor trkB/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
Records (years 2005-2007) were analyzed from a Thoroughbred stud farm in central Kentucky. Data from all breeding cycles of foaling mares were tabulated (3184 cycles of 2003 foaling mares bred between 7 and 163 days postpartum). A multiple logistic regression model employing Bayesian statistics was used to adjust for factors that significantly affected outcome; odds ratios (ORs) for pregnancy rate, pregnancy loss rate, and foaling rate were determined to examine the influence of day of postpartum breeding on these parameters. Mares bred before Day 22 (Day 0 = day of foaling) postpartum had a decreased OR for becoming pregnant (P < 0.05); the median OR for becoming pregnant (1.00) was not reached until Day 46 postpartum. Mares bred before Day 13 postpartum had an increased OR for pregnancy loss (P < 0.05). The median OR for pregnancy loss did not decline below 1.00 until Day 78 postpartum. Mares bred before Day 20 postpartum had a decreased OR for producing a foal (P < 0.05). The median OR for producing a foal (1.00) was not reached until Day 75 postpartum. We concluded that fertility (in terms of a higher OR for becoming pregnant and a lower OR for pregnancy loss, resulting in a higher OR for producing a foal) continued to improve in Thoroughbred mares for approximately 2.5 mo postpartum. These findings are of importance to management strategies directed at early postpartum breeding, and explain some of the reported drift in subsequent foaling dates of Thoroughbred mares, despite management practices that employ early postpartum breeding.
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Aborto Animal/epidemiologia , Cruzamento/métodos , Cavalos/fisiologia , Período Pós-Parto , Taxa de Gravidez , Animais , Teorema de Bayes , Feminino , Modelos Logísticos , Masculino , Razão de Chances , Gravidez , Resultado da Gravidez/veterinária , Fatores de TempoRESUMO
BACKGROUND: Overall survival in paediatric cancer has improved significantly over the past 20 years. Treatment strategies have been intensified, and supportive care has made substantial advances. Historically, paediatric oncology patients admitted to an intensive care unit (ICU) have had extremely poor outcomes. METHODS: We conducted a retrospective cohort study over a 3-year period in a single centre to evaluate the outcomes for this particularly vulnerable group of patients admitted to a paediatric ICU. RESULTS: Fifty-five patients were admitted a total of 66 times to the ICU during the study period. The mortality rate of this group was 23% compared with an overall ICU mortality rate of 5%. 11/15 patients who died had an underlying haematological malignancy. Twenty-eight percent of children with organism-identified sepsis died. CONCLUSIONS: While mortality rates for paediatric oncology patients admitted to a ICU have improved, they are still substantial. Those with a haematological malignancy or admitted with sepsis are most at risk.
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Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Neoplasias/mortalidade , Neoplasias/terapia , Adolescente , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Irlanda/epidemiologia , Masculino , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Treatment strategies for relapsed/refractory AML are limited and disappointing. Recently, high-dose melphalan (HDM) chemotherapy and autologous hematopoietic SCT (HSCT) has been proposed for AML re-induction. We investigated the impact of HDM remission induction in highly advanced relapsed/refractory AML patients planned for allogeneic HSCT. A total of 23 patients with relapsed/refractory AML were prospectively scheduled for HDM with or without stem cell support followed by myeloablative allogeneic HSCT. Patients included nine individuals with a history of previous HSCT (seven allogeneic, two autologous). A total of 18 patients (78%) achieved a leukemia-free state and an additional four had substantial reduction of the initial leukemia burden warranting treatment continuation. There were no differences between patients with or without immediate stem cell support regarding mucositis or other organ toxicity. A total of 20 patients proceeded to myeloablative allogeneic HSCT. Outcome of allogeneic HSCT was poor: 11 patients (55%) relapsed, 7 patients (35%) died from TRM and only 2 patients (10%) were alive at the last follow-up. Our study shows that HDM is effective in inducing a leukemia-free state in patients with highly advanced relapsed/refractory AML. Leukemia burden reduction with HDM, however, did not translate into improved OS.
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Leucemia Mieloide Aguda/terapia , Melfalan/administração & dosagem , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Recidiva , Indução de Remissão/métodos , Transplante Autólogo , Resultado do TratamentoRESUMO
Overcoming childhood cancers is critically dependent on the state of research. Understanding how, with whom and what the research community is doing with childhood cancers is essential for ensuring the evidence-based policies at national and European level to support children, their families and researchers. As part of the European Union funded EUROCANCERCOMS project to study and integrate cancer communications across Europe, we have carried out new research into the state of research in childhood cancers. We are very grateful for all the support we have received from colleagues in the European paediatric oncology community, and in particular from Edel Fitzgerald and Samira Essiaf from the SIOP Europe office. This report and the evidence-based policies that arise from it come at a important junction for Europe and its Member States. They provide a timely reminder that research into childhood cancers is critical and needs sustainable long-term support.
RESUMO
High-dose chemotherapy (HDT) and hematopoietic SCT are effective in patients with relapsing or refractory malignant lymphoma. Collection of sufficient numbers of stem cells is a prerequisite for such a therapy. In a pilot trial, we evaluated the feasibility of stem cell mobilization with vinorelbine/G-CSF in patients with lymphoma, a regimen allowing precise timing and harvesting of sufficient stem cells in myeloma patients. Forty-five patients with lymphoma received vinorelbine 35 mg/m(2) i.v. on day 1 and G-CSF 10 microg/kg/day s.c., divided in two daily doses from day 4 until collection. Stem cell collection was successfully performed in 43 patients (96%) with a median of 3.6 x 10(6) CD34(+) cells/kg (range: 1.4-16) in the collected product. In 28 patients (62%), the first stem cell apheresis was performed on day 8, and for 28 patients a sufficient stem cell yield was reached with one apheresis only. All 43 patients underwent high-dose chemotherapy with BEAM and auto-SCT with hematological recovery on time and without unexpected toxicity. In conclusion, vinorelbine/G-CSF allows accurate timing and safe harvesting of sufficient stem cells in patients with malignant lymphoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Linfoma não Hodgkin/terapia , Vimblastina/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Custos de Medicamentos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Transplante Autólogo , Vimblastina/administração & dosagem , Vimblastina/uso terapêutico , VinorelbinaRESUMO
Mucopolysaccharidosis type 1 (MPS1) is an autosomal recessive disorder with severe, moderate and mild phenotypes: Hurler, Hurler-Scheie and Scheie syndromes. We estimated incidence (2001-2006) and prevalence (2002 census) of MPS1 in the Irish Republic (ROI) using population data, database and chart review of all live MPS1 patients attending two specialised centres. Patient genotypes, ethnicity, province of origin, age at diagnosis and presenting features were recorded. Thirty-one patients (14 females, 17 males) were alive, 27 of whom were <15 years. Twenty-six patients had Hurler syndrome, four had Hurler-Scheie and one had Scheie syndrome. The birth incidence was 1 in 26 206 births with a carrier frequency of 1 in 81. Of note, 19/26 (73%) Hurler patients were Irish Travellers. Amongst Irish Travellers the incidence was 1 in 371 with a carrier frequency of 1 in 10. This is the highest recorded incidence worldwide. Given the morbidity and mortality associated with delayed treatment we recommend targeted newborn screening for this population.