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1.
Pediatr Crit Care Med ; 21(6): e316-e324, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32343108

RESUMO

OBJECTIVES: Extracorporeal cardiopulmonary resuscitation in children with refractory cardiac arrest has been shown to improve survival, however, risk factors associated with mortality and neurologic impairments are not well defined. We analyzed our recent institutional experience with pediatric extracorporeal cardiopulmonary resuscitation to identify variables associated with survival and neurocognitive outcome. DESIGN: Retrospective observational study. SETTING: Pediatric cardiology and congenital heart surgery departments of a tertiary referral heart center. PATIENTS: Seventy-two consecutive children (median age, 0.3 yr [0.0-1.9 yr]) who underwent extracorporeal cardiopulmonary resuscitation at our institution during the study period from 2005 to 2016. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Median duration of resuscitation was 60 minutes (42-80 min) and median extracorporeal support duration was 5.4 days (2.2-7.9 d). Forty-three (59.7%) extracorporeal cardiopulmonary resuscitation events occurred during off-hours, however, neither duration of resuscitation (65 min [49-89 min] vs 51 min [35-80 min]; p = 0.16) nor survival (34.9% vs 37.9%; p = 0.81) differed significantly compared to working hours. Congenital heart disease was present in 84.7% of the patients. Survival to hospital discharge was 36.1%; younger age, higher lactate levels after resuscitation, acute kidney injury, renal replacement therapy, hepatic injury, and complexity of prior cardiothoracic surgical procedures were significantly associated with mortality. At mid-term follow-up (median, 4.1 yr [3.7-6.1 yr]), 22 patients (84.6% of discharge survivors) were still alive with 77.3% having a favorable neurologic outcome. High lactate levels, arrest location other than ICU, and requirement for renal replacement therapy were associated with unfavorable neurologic outcome. Interestingly, longer duration of resuscitation did not negatively impact survival or neurologic outcome. CONCLUSIONS: Extracorporeal cardiopulmonary resuscitation is a valuable tool for the treatment of children with refractory cardiac arrest and a favorable neurologic outcome can be achieved in the majority of survivors even after prolonged resuscitation. Mortality after extracorporeal cardiopulmonary resuscitation in postcardiac surgery children is associated with procedural complexity.

2.
Mediators Inflamm ; 2019: 6431957, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871429

RESUMO

Introduction: Fever is frequently observed after acute ischemic events and is associated with poor outcome and higher mortality. Targeted temperature management (TTM) is recommended for neuroprotection in comatose cardiac arrest survivors, but pyrexia after rewarming is proven to be detrimental in clinical trials. However, the cellular mechanisms and kinetics of post-TTM rebound pyrexia remain to be elucidated. Therefore, we investigated the effects of cooling and post-TTM pyrexia on the inflammatory response and apoptosis in a cardiomyocyte ischemia-reperfusion (IR) injury model. Methods: HL-1 cardiomyocytes were divided into the following groups to investigate the effect of oxygen-glucose deprivation/reperfusion (OGD/R), hypothermia (33.5°C), and pyrexia (40°C): normoxia controls maintained at 37°C and warmed to 40°C, OGD/R groups maintained at 37°C and cooled to 33.5°C for 24 h with rewarming to 37°C, and OGD/R pyrexia groups further warmed from 37 to 40°C. Caspase-3 and RBM3 were assessed by Western blot and TNF-α, IL-6, IL-1ß, SOCS3, iNOS, and RBM3 transcriptions by RT-qPCR. Results: OGD-induced oxidative stress (iNOS) in cardiomyocytes was attenuated post-TTM by cooling. Cytokine transcriptions were suppressed by OGD, while reperfusion induced significant TNF-α transcription that was exacerbated by cooling. Significant inductions of TNF-α, IL-6, IL-1ß, and SOCS3 were observed in noncooled, but not in cooled and rewarmed, OGD/R-injured cardiomyocytes. Further warming to pyrexia induced a sterile inflammatory response in OGD/R-injured groups that was attenuated by previous cooling, but no inflammation was observed in pyrexic normoxia groups. Moreover, cytoprotective RBM3 expression was induced by cooling but suppressed by pyrexia, correlating with apoptotic caspase-3 activation. Conclusion: Our findings show that maintaining a period of post-TTM "therapeutic normothermia" is effective in preventing secondary apoptosis-driven myocardial cell death, thus minimizing the infarct area and further release of mediators of the innate sterile inflammatory response after acute IR injury.


Assuntos
Apoptose/fisiologia , Febre/metabolismo , Hipotermia Induzida/métodos , Inflamação/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Linhagem Celular , Febre/imunologia , Inflamação/imunologia , Camundongos , Miocárdio/metabolismo , Miócitos Cardíacos/imunologia , Traumatismo por Reperfusão/imunologia , Fator de Necrose Tumoral alfa/metabolismo
3.
Front Cell Neurosci ; 13: 273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293389

RESUMO

Introduction: Hypothermia attenuates cerebral ischemia-induced neuronal cell death associated with neuroinflammation. The calcineurin inhibitor cyclosporin A (CsA) has been shown to be neuroprotective by minimizing activation of inflammatory pathways. Therefore, we investigated whether the combination of hypothermia and treatment with CsA has neuroprotective effects in an oxygen-glucose deprivation/reperfusion (OGD/R) injury model in neuronal and BV-2 microglia monocultures, as well as in an organotypic hippocampal slice culture (OHSC). Methods: Murine primary neurons, BV-2 microglia, and OHSC were pretreated with CsA and exposed to 1 h OGD (0.2% O2) followed by reperfusion at normothermia (37°C) or hypothermia (33.5°C). Cytotoxicity was measured by lactate dehydrogenase and glutamate releases. Damage-associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1), heat shock protein 70 (Hsp70), and cold-inducible RNA-binding protein (CIRBP) were detected in cultured supernatant by western blot analysis. Interleukin-6 (IL-6), Interleukin-1α and -1ß (IL-1α/IL1-ß), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein 1 (MCP1), inducible nitric oxide synthase (iNOS), glia activation factors ionized calcium-binding adapter molecule 1 (Iba1), and transforming growth factor ß1 (TGF-ß1) gene expressions were analyzed by RT-qPCR. Results: Exposure to OGD plus 10 µM CsA was sufficient to induce necrotic cell death and subsequent release of DAMPs in neurons but not BV-2 microglia. Moreover, OGD/R-induced secondary injury was also observed only in the neurons, which was not attenuated by cooling and no increased toxicity by CsA was observed. BV-2 microglia were not sensitive to OGD/R-induced injury but were susceptible to CsA-induced toxicity in a dose dependent manner, which was minimized by hypothermia. CsA attenuated IL-1ß and Iba1 expressions in BV-2 microglia exposed to OGD/R. Hypothermia reduced IL-1ß and iNOS expressions but induced TNF-α and Iba1 expressions in the microglia. However, these observations did not translate to the ex vivo OHCS model, as general high expressions of most cytokines investigated were observed. Conclusion: Treatment with CsA has neurotoxic effects on primary neurons exposed to OGD but could inhibit BV-2 microglia activation. However, CsA and hypothermia treatment after ischemia/reperfusion injury results in cytotoxic neuroinflammation in the complex ex vivo OHSC.

4.
Cardiol Young ; 29(5): 672-678, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31097048

RESUMO

OBJECTIVE: We developed the Long-term Early Development Research (LEADER) project to investigate the development of children with CHD and/or after cardiopulmonary resuscitation. Both populations are at risk for delays in motor, cognitive, and language development. However, few studies to date have investigated the longitudinal development in these children. METHODS: To establish a clinical research unit, we planned three studies: a cross-sectional study in children after cardiopulmonary resuscitation (LEADER-REA Pilot Study), a longitudinal study in children after cardiopulmonary resuscitation, with a focus on evaluating various biomarkers as predictors for developmental outcome (LEADER-CPR study), and a longitudinal study in children with ventricular septal defect, tetralogy of Fallot, or transposition of the great arteries after cardiac surgery (LEADER-CHD study). RESULTS: Implementation of all three LEADER studies was successful and study protocols were conducted as planned. Findings from the LEADER-REA Pilot study have been recently published and data collection for both prospective trials is ongoing. Descriptive analysis of the first 20 assessments of the LEADER-CHD study showed no severe deficits in overall cognitive, motor, and language developments in the children. CONCLUSIONS: Children with CHD and/or after cardiopulmonary resuscitation are at risk for developmental delay. Therefore, a detailed developmental assessment is necessary as a pre-requisite for individual developmental support. Our LEADER project has been shown to be feasible in a clinical setting and is the first step towards the establishment of a clinical research unit in our clinic with a focus on longitudinal research.


Assuntos
Desenvolvimento Infantil , Deficiências do Desenvolvimento/etiologia , Cardiopatias Congênitas/psicologia , Cardiopatias Congênitas/cirurgia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Deficiências do Desenvolvimento/diagnóstico , Feminino , Alemanha , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Projetos Piloto , Estudos Prospectivos , Fatores de Risco
5.
J Clin Psychol Med Settings ; 26(4): 575-583, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30850900

RESUMO

Unfavorable neurological outcome in children after cardiopulmonary resuscitation in infancy is frequent. However, few studies have investigated the development of these patients using comprehensive developmental tests and the feasibility of the Bayley Scales of Infant Development, 3rd Edition (BSID-III) has not been reported for this population. In this cross-sectional pilot study, we assessed the cognitive, language, and motor development in infants after cardiopulmonary resuscitation of ≥ 5 min with the BSID-III at the age of 12 or 24 months, depending on recruitment age. For analysis, 11 patients with in-hospital (n = 8) and out-of-hospital (n = 3) cardiac arrest were included. BSID-III results could not be quantified in three patients because of visual/hearing and/or motor impairment. In patients with quantifiable scores, 50.0% scored average in composite BSID-III scores, while the other 50.0% showed developmental delays, scoring distinctly below average. We conclude that the BSID-III is feasible for developmental assessment in the majority of the study population, but the use of instruments suitable for hearing/visually impaired and/or severely disabled infants is crucial to avoid biased results. Accurate characterization of developmental deficits is important to facilitate early identification and therapy of deficits.

6.
Early Hum Dev ; 128: 27-34, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30448707

RESUMO

BACKGROUND: Survival rates of children with congenital heart disease (CHD) have increased significantly in the decade. There is now increased interest in the long-term outcome and quality of life of these children. AIMS: To assess the educational achievement of patients with CHD in Germany. STUDY DESIGN: Cross-sectional study using an online survey. The recruitment of study participants was carried out via the database of the German National Register for Congenital Heart Defects (NRCHD). SUBJECTS: Patients born between 1992 and 2011 were enrolled in the study. For 2609 study participants (female = 1870 (71.7%); 1072 (41.1%) patients; 1537 (58.9%) parents), who participated in the survey, detailed information regarding the underlying CHD diagnosis and clinical data was available. OUTCOME MEASURES: Age at enrollment, secondary school form, school year repetition, school degree. RESULTS: The large majority of study participants were enrolled at a conventional elementary school (83.4%) and started school at the age of 6 years or below (73.3%). In total 45.7% of graduated study participants graduated with the qualification necessary to study at any university. In terms of analysis of the different CHD severity subgroups 57.3% of patients with a mild CHD, 47.5% with a moderate CHD and only 35.1% suffering from a severe CHD attained a high school diploma. CONCLUSIONS: In our study, the majority of participating CHD patients had a standard school career. These initial results are of great importance to affected families and treating physicians as they show that, in general, a normal school career is possible for all CHD patients.


Assuntos
Desempenho Acadêmico , Cardiopatias Congênitas/epidemiologia , Adolescente , Adulto , Feminino , Alemanha , Humanos , Masculino , Sistema de Registros
7.
Interact Cardiovasc Thorac Surg ; 28(5): 789-796, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590597

RESUMO

OBJECTIVES: We analysed our 29-year experience of surgical repair of atrioventricular septal defect (AVSD) to define risk factors for mortality and reoperation. METHODS: Between 1988 and 2017, 508 patients received AVSD repair in our institution; 359 patients underwent surgery for complete AVSD, 76 for intermediate AVSD and 73 for partial AVSD. The median age of the patients was 6.1 months (interquartile range 10.3 months), and the median weight was 5.6 kg (interquartile range 3.2 kg). The standard AVSD repair was performed using 2-patch technique (n = 347) and complete cleft closure (n = 496). The results were divided into 2 surgical eras (early era 1986-2004 and late era 2004-2017). Risk factors were analysed to determine the impact of patient age, weight, the presence of trisomy 21 and complex AVSD on mortality and reoperation rate. RESULTS: In-hospital mortality decreased from 10.2% (n = 26) in early surgical era to 1.6% (n = 4) in late surgical era (P < 0.001). Seventy-seven patients required reoperation. Freedom from reoperation was 84.4% after 25 years. The main indication for reoperation was left atrioventricular valve regurgitation (13.8%). The multivariable Cox regression analysis revealed reoperation of the left AV valve, early surgical era, patient age <3.0 months and complex AVSD to be independent risk factors for mortality. Age <3.0 months, complex AVSD and moderate/severe left AV valve regurgitation at discharge predicted reoperation. CONCLUSIONS: AVSD repair can be performed with low mortality and reoperation rate. Age <3 months, complex AVSD and moderate/severe regurgitation of the left AV valve at discharge were predictors for reoperation. Reoperation of the left AV valve was the strongest risk factor for mortality.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Previsões , Defeitos dos Septos Cardíacos/cirurgia , Feminino , Seguimentos , Alemanha/epidemiologia , Defeitos dos Septos Cardíacos/diagnóstico , Defeitos dos Septos Cardíacos/mortalidade , Mortalidade Hospitalar/tendências , Humanos , Lactente , Masculino , Alta do Paciente , Reoperação , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Resultado do Tratamento
8.
J Heart Lung Transplant ; 37(12): 1459-1466, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30292432

RESUMO

BACKGROUND: The majority of children supported with ventricular assist devices (VADs) are bridged to heart transplantation. Although bridge to recovery has been reported, low recovery patient numbers has precluded systematic analysis. The aim of this study was to delineate recovery rates and predictors of recovery and to report on long-term follow-up after VAD explantation in children. METHODS: Children bridged to recovery at our institution from January 1990 to May 2016 were compared with a non-recovery cohort. Clinical and echocardiographic data before and at pump stoppages and after VAD explantation were analyzed. Kaplan‒Meier estimates of event-free survival, defined as freedom from death or transplantation after VAD removal, were determined. RESULTS: One hundred forty-nine children (median age 5.8 years) were identified. Of these, 65.2% had cardiomyopathy, 9.4% had myocarditis, and 24.8% had congenital heart disease. The overall recovery rate was 14.2%, and was 7.1% in patients with dilated cardiomyopathy. Predictors of recovery were age <2 years (recovery rate 27.8%, odds ratio [OR] 5.64, 95% confidence interval [CI] 2.0 to 16.6) and diagnosis of myocarditis (rate 57.1%; OR 17.56, 95% CI 4.6 to 67.4). After a median follow-up of 10.8 years, 15 patients (83.3%) were in Functional Class I and 3 (16.7%) in were in Class II. Mean left ventricular ejection fraction was 53% (range 28% to 64%). Ten- and 15-year event-free survival rates were both 84.1 ± 8.4%. CONCLUSIONS: Children <2 years of age and those diagnosed with myocarditis have the highest probability of recovery. Long-term survival after weaning from the VAD was better than after heart transplantation, as demonstrated in the excellent long-term stability of ejection fraction and functional class.


Assuntos
Transplante de Coração , Coração Auxiliar , Complicações Pós-Operatórias/etiologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Transplante de Coração/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Complicações Pós-Operatórias/mortalidade , Intervalo Livre de Progressão , Fatores de Risco
9.
Cardiol Young ; 28(1): 32-38, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28899436

RESUMO

Purpose Through this study we aimed to assess the educational level and employment status of adults with CHD in Germany. METHODS: Data were acquired from an online survey carried out in 2015 by the German National Register for Congenital Heart Defects. A total of 1458 adults with CHD participated in the survey (response rate: 37.6%). For 1198 participants, detailed medical information, such as main cardiac diagnosis and information from medical reports, was available. RESULTS: Of the participants surveyed (n=1198), 54.5% (n=653) were female, and the mean age was 30 years. The majority of respondents (59.4%) stated that they had high education levels and that they were currently employed (51.1%). Patients with simple CHD had significantly higher levels of education (p<0.001) and were more likely to be employed (p=0.01) than were patients with complex CHD. CONCLUSIONS: More than half of the participants had high education levels and the majority were employed. The association between CHD and its severity and individuals' educational attainment should be investigated more closely in future studies.


Assuntos
Escolaridade , Emprego , Cardiopatias Congênitas/epidemiologia , Adulto , Feminino , Alemanha , Humanos , Masculino , Qualidade de Vida , Sistema de Registros , Inquéritos e Questionários , Adulto Jovem
10.
BMJ Open ; 7(12): e018966, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29288186

RESUMO

INTRODUCTION: Congenital heart disease (CHD) is the most common birth defect. Studies on the development of children with CHD point towards deficits in motoric, cognitive and language development. However, most studies are cross-sectional and there is a gap in the knowledge concerning developmental trajectories, risk and protective factors and a lack of research concerning environmental predictors. Specifically, no studies have so far considered the importance of early caregiving experiences and child temperament for the development of children with CHD. METHODS: In a single-centre prospective cohort study, cognitive, motoric and language development of 180 children after corrective surgery for a simple transposition of the great arteries (TGA), tetralogy of Fallot (TOF) or ventricular septal defect (VSD) will be assessed at ages 12, 24 and 36 months with the Bayley Scales of Infant Development 3rd Edition (BSID-III). At age 12 months, a free-play video observation will be conducted to investigate the relationship between primary caregiver and child, and child temperament will be assessed with the Infant Behavior Questionnaire-Revised Short Version. Medical information will be obtained from patient records and demographic information via questionnaires. ANALYSIS: Frequency and severity of developmental delays will be reported descriptively. Differences between groups (TGA, TOF, VSD) will be subjected to repeated-measures analysis across time points. Multiple regressions will be applied for the analysis of predictors at each time point. For the analysis of differential developmental trajectories, mixed-model analysis will be applied. ETHICS AND DISSEMINATION: The study has been approved by the local medical ethics committee. Written informed consent will be obtained from all participants. Parents have the option to be debriefed about BSID-III results after each assessment and about the study results after project completion. Results will be disseminated in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: DRKS00011006; Pre-results.


Assuntos
Desenvolvimento Infantil , Cardiopatias Congênitas/psicologia , Cardiopatias Congênitas/cirurgia , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Testes Neuropsicológicos , Estudos Prospectivos , Projetos de Pesquisa , Fatores de Risco , Índice de Gravidade de Doença , Inquéritos e Questionários
11.
Congenit Heart Dis ; 12(6): 787-793, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28719142

RESUMO

OBJECTIVE: To assess the prevalence of congenital heart disease (CHD) in Germany in relation to phenotypes, severity and gender. DESIGN: Cross-sectional registry study. SETTING: We analyzed data from patients with CHD born between 1996 and 2015. PATIENTS: A total of 26 630 patients, registered with the NRCHD, were born between 1996 and 2015. 10 927 patients were excluded from the current analysis due to prior registration with the NRCHD under the German PAN Prevalence Study, which showed a potential bias in the inclusion of this patient population (proportion of mild cardiac lesions was comparatively high due to improved diagnostic capability for earlier identifying minor lesions). At least 15 703 patients with demographic data and detailed medical information were included in the current study. INTERVENTIONS: None. OUTCOME MEASURES: Prevalence of CHD in Germany differentiated into gender, severity, and phenotype. RESULTS: In total, 15 703 patients with CHD (47.1% female) were included in this study. The five most common phenotypes were found to be ventricular septal defect (19.2%), atrial septal defect (13.0%), Tetralogy of Fallot (9.3%), univentricular heart (9.4%), and coractation of the aortae (7.0%). The prevalence of CHD in regard to severity changed over the duration of the observation period. From 1996 to 2007, the number of simple CHD rose steadily (P < .001), whereas the number of severe CHD has grown significantly since 2008/2009 (P < .001). In regard to gender, the prevalence of simple CHD was higher in females, whereas complex lesions were more common in males (P < .001). CONCLUSIONS: Our study shows a growing number of registered severe CHD in the recent decade in Germany. This development is noteworthy as it implicates a growing demand for first intensive hospital care, expert pediatric cardiologic aftercare, and consequently higher economic impact for this patient population.


Assuntos
Cardiopatias Congênitas/epidemiologia , Vigilância da População , Sistema de Registros , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Feminino , Alemanha/epidemiologia , Cardiopatias Congênitas/diagnóstico , Humanos , Lactente , Masculino , Fenótipo , Prevalência , Estudos Retrospectivos , Índice de Gravidade de Doença , Distribuição por Sexo , Adulto Jovem
13.
Int Immunopharmacol ; 30: 9-17, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26613512

RESUMO

Post-transplant lymphoproliferative disorder is a severe complication in solid organ transplant recipients, which is highly associated with Epstein-Barr virus infection in pediatric patients and occasionally presents as Burkitt- or Burkitt-like lymphoma. The mammalian target of rapamycin (mTOR) pathway has been described as a possible antitumor target whose inhibition may influence lymphoma development and proliferation after pediatric transplantation. We treated Epstein-Barr virus positive (Raji and Daudi) and negative (Ramos) human Burkitt lymphoma derived cells with mTOR inhibitor everolimus alone and in combination with clinically relevant immunosuppressive calcineurin inhibitors (tacrolimus or cyclosporin A). Cell proliferation, toxicity, and mitochondrial metabolic activity were analyzed. The effect on mTOR Complex 1 downstream targets p70 S6 kinase, eukaryotic initiation factor 4G, and S6 ribosomal protein activation was also investigated. We observed that treatment with everolimus alone significantly decreased Burkitt lymphoma cell proliferation and mitochondrial metabolic activity. Everolimus in combination with cyclosporin A had a stronger suppressive effect in Epstein-Barr virus negative but not in Epstein-Barr virus positive cells. In contrast, tacrolimus completely abolished the everolimus-mediated suppressive effects. Moreover, we showed a significant decrease in activation of mTOR Complex 1 downstream targets after treatment with everolimus that was attenuated when combined with tacrolimus, but not with cyclosporin A. For the first time we showed the competitive effect between everolimus and tacrolimus when used as combination therapy on Burkitt lymphoma derived cells. Thus, according to our in vitro data, the combination of calcineurin inhibitor cyclosporin A with everolimus is preferred to the combination of tacrolimus and everolimus.


Assuntos
Antineoplásicos/farmacologia , Linfoma de Burkitt/tratamento farmacológico , Ciclosporina/farmacologia , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Everolimo/farmacologia , Herpesvirus Humano 4/imunologia , Imunossupressores/farmacologia , Mitocôndrias/efeitos dos fármacos , Tacrolimo/farmacologia , Linfoma de Burkitt/complicações , Linfoma de Burkitt/imunologia , Calcineurina/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Combinada , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Humanos , Mitocôndrias/fisiologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Células Tumorais Cultivadas
14.
Am J Physiol Heart Circ Physiol ; 309(1): H45-52, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25888512

RESUMO

Beta-blockers contribute to treatment of heart failure. Their mechanism of action, however, is incompletely understood. Gradients in beta-blocker sensitivity of helically aligned cardiomyocytes compared with counteracting transversely intruding cardiomyocytes seem crucial. We hypothesize that selective blockade of transversely intruding cardiomyocytes by low-dose beta-blockade unloads ventricular performance. Cardiac magnetic resonance imaging (MRI) 3D tagging delivers parameters of myocardial performance. We studied 13 healthy volunteers by MRI 3D tagging during escalated intravenous administration of esmolol. The circumferential, longitudinal, and radial myocardial shortening was determined for each dose. The curves were analyzed for peak value, time-to-peak, upslope, and area-under-the-curve. At low doses, from 5 to 25 µg·kg(-1)·min(-1), peak contraction increased while time-to-peak decreased yielding a steeper upslope. Combining the values revealed a left shift of the curves at low doses compared with baseline without esmolol. At doses of 50 to 150 µg·kg(-1)·min(-1), a right shift with flattening occurred. In healthy volunteers we found more pronounced myocardial shortening at low compared with clinical dosage of beta-blockers. In patients with ventricular hypertrophy and higher prevalence of transversely intruding cardiomyocytes selective low-dose beta-blockade could be even more effective. MRI 3D tagging could help to determine optimal individual beta-blocker dosing avoiding undesirable side effects.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Propanolaminas/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Antagonistas Adrenérgicos beta/administração & dosagem , Adulto , Feminino , Coração/efeitos dos fármacos , Humanos , Imageamento Tridimensional , Imagem por Ressonância Magnética , Masculino , Propanolaminas/administração & dosagem
15.
J Heart Lung Transplant ; 33(8): 816-21, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24836553

RESUMO

BACKGROUND: The pediatric Berlin Heart (BH) EXCOR device provides mechanical circulatory support as a bridge to transplantation or recovery in children. Despite the availability of various pump sizes, information on the impact of pump size on clinical outcome is still lacking. We aimed to evaluate whether pump size in relation to body surface area (BSA) has an impact on clinical outcome. METHODS: Children requiring implantation of a BH between 2000 and 2013 were included in this retrospective study. Primary end-points were events leading to BH explantation (transplantation, recovery or death) and the secondary end-point was occurrence of thromboembolic events. Patients were categorized into three groups according to BH stroke volume per BSA: optimal (30 to 50 ml/m(2)); small (<30 ml/m(2)); and large (>50 ml/m(2)). RESULTS: Eighty children (median age 2.2 years, median BSA 0.50 m(2)) underwent BH implantation. Fifty-five (69%) children had an optimally sized pump implanted, whereas 8 children (10%) had small pump and 17 (21%) large pump implantation. Overall survival rate was 69%. Weaning was possible in 15 children (19%), and 39 children (49%) were transplanted. Mortality, myocardial recovery and transplantation were not related to age, BSA or pump size. Thromboembolic events occurred significantly more frequently in children treated with large pumps. CONCLUSIONS: The broad range of body sizes in children from newborns to adolescents requires a wide choice of appropriately sized devices. Large pump size in relation to BSA is an independent risk factor for occurrence of thromboembolic events.


Assuntos
Tamanho Corporal , Desenho de Equipamento/efeitos adversos , Insuficiência Cardíaca/terapia , Coração Auxiliar/efeitos adversos , Tromboembolia/epidemiologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento
16.
Artif Organs ; 35(4): E91-100, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21375547

RESUMO

Labeling of hepatocytes with micron-sized iron oxide particles (MPIOs) enables cell detection using clinical magnetic resonance equipment. For clinical applications, large numbers of cells must be labeled in a simple and rapid manner and have to be applied in suspension. However, all existing protocols are based on adhesion culture labeling with subsequent resuspension, only suitable for small experimental settings. The aim of this study was to investigate the feasibility of preparing MPIO-labeled primary human hepatocytes in a temporary suspension culture. Human hepatocytes were isolated from 16 donors and labeled with MPIOs in suspension, using the Rotary Cell Culture System. Particle incorporation was investigated by light and electron microscopy. Cells were compared with adhesion culture-labeled and subsequently enzymatically resuspended cells. During a period of 5 days, hepatocyte-specific parameters of cell damage (aspartate aminotransferase and alanine aminotransferase) and metabolic activity (urea and albumin) were analyzed (n=7). Suspension cultures showed a higher outcome in cell recovery compared with the conventional labeling method. When incubated with 180 particles/viable cell for 4 h, the mean particle uptake was 28.8 particles/cell at a labeling efficiency of 95.1%. Labeling in suspension had no adverse effects on cell integrity or metabolic activity. We conclude that labeling of human hepatocytes in suspension is feasible and simple and may serve future large-scale processing of cells.


Assuntos
Compostos Férricos/análise , Hepatócitos/ultraestrutura , Coloração e Rotulagem/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas de Cultura de Células , Sobrevivência Celular , Células Cultivadas , Hepatócitos/citologia , Humanos , Microscopia Eletrônica , Microscopia de Contraste de Fase , Pessoa de Meia-Idade , Tamanho da Partícula , Adulto Jovem
17.
Eur J Cardiothorac Surg ; 40(2): 352-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21242090

RESUMO

OBJECTIVE: Insufficient myocardial protection is still a considerable cause for in-hospital mortality in children. The purpose of our study was to investigate underlying the basic mechanisms of cardioplegic cardioprotection during hypothermic and normothermic ischemia in a cardiomyocyte cell culture model. METHODS: We cooled cardiomyocytes to 20°C for 20min; during this time, cardiac arrest was simulated by oxidative damage with 2mM H2O2 and cardioplegic solution, followed by rewarming to 37°C. Later on, we analyzed cardiomyocyte cell morphology (phase-contrast-microscopy), viability (trypan blue staining), inflammation (cyclooxygenase-2 (Cox-2) and phosphorylated-extracellular signal-regulated kinase (pERK) 1/2 expression in Western blot analysis), and expression of Akt survival protein (Western blot technique). RESULTS: Hypothermia increases cell survival of cardiomyocytes after cardioplegic ischemia, as demonstrated in significantly higher cell viability and less cell death in these cells compared with normothermic H2O2-damaged cardiomyocytes. As a possible underlying cellular mechanism, we found that, during cold cardioplegic ischemia, ERK 1/2 enzyme is less phosphorylated than under conditions of normothermic cardioplegic ischemia. This is in line with significantly diminished Cox-2 expression during cold cardioplegic ischemia. Moreover, hypothermic cardioplegia preserved cell survival by upregulation of Akt transcription factor in cardiomyocytes. CONCLUSION: In the present cell culture study, we clearly demonstrated that hypothermia exerts additional protection for cardiomyocytes during cardioplegic ischemia. The understanding of underlying basic mechanisms is evident to improve current techniques of myocardial protection.


Assuntos
Temperatura Baixa , Parada Cardíaca Induzida , Isquemia Miocárdica/prevenção & controle , Miócitos Cardíacos/fisiologia , Soluções Cardioplégicas/farmacologia , Sobrevivência Celular/fisiologia , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Ativação Enzimática/fisiologia , Humanos , Peróxido de Hidrogênio/farmacologia , Microscopia de Contraste de Fase , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Estresse Oxidativo/fisiologia , Fosforilação/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
18.
Cardiol Young ; 20(5): 505-8, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20470449

RESUMO

Patients with cyanotic congenital cardiac disease often develop major aortopulmonary collaterals. Vascular endothelial growth factor is a key promoter of angiogenesis. Its soluble receptor-1 acts as a potent antagonist. We studied 30 infants with cyanotic congenital cardiac disease and 27 infants with acyanotic congenital cardiac disease. Central venous plasma vascular endothelial growth factor and soluble vascular endothelial growth factor receptor-1 levels were measured before, and 24 and 96 hours after surgery. There was no difference between plasma vascular endothelial growth factor levels in infants with cyanotic and those with acyanotic congenital cardiac disease. In cyanotic infants, the soluble vascular endothelial growth factor receptor-1 levels tended to be higher than in the acyanotic infants. In conclusion, there is no significant difference in the plasma levels of vascular endothelial growth factor and its soluble receptor-1 between infants with cyanotic and those with acyanotic congenital cardiac disease.


Assuntos
Cardiopatias Congênitas/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Biomarcadores/sangue , Ponte Cardiopulmonar/métodos , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Cardiopatias Congênitas/cirurgia , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença
19.
Eur J Neurosci ; 31(5): 779-87, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20374279

RESUMO

Despite the widespread interest in the clinical applications of hypothermia, the cellular mechanisms of hypothermia-induced neuroprotection have not yet been clearly understood. Therefore, the aim of this study was to elucidate the cellular effects of clinically relevant hypothermia and rewarming on the morphological and functional characteristics of microglia. Microglial cells were exposed to a dynamic cooling and rewarming protocol. For stimulation, microglial cells were treated with 1 microg/mL lipopolysaccharide (LPS). We found that hypothermia led to morphological changes from ramified to ameboid cell shapes. At 2 h after hypothermia and rewarming, microglial cells were again ramified with extended branches. Moreover, we found enhanced cell activation after rewarming, accompanied by increased phagocytosis and adenosine triphosphate consumption. Interestingly, hypothermia and rewarming led to a time-dependent significant up-regulation of the anti-inflammatory cytokines interleukin-10 and interleukin-1 receptor antagonist in stimulated microglial cells. This is in line with the reduced proliferation and time-dependent down-regulation of the pro-inflammatory cytokines tumor necrosis factor-alpha and monocyte chemotactic protein-1 in comparison to normothermic control cells after LPS stimulation. Furthermore, degradation of the inhibitor of the nuclear transcription factor-kappaB (IkappaB-alpha) was diminished and delayed under conditions of cooling and rewarming in LPS-stimulated microglial cells. Thus, our results show that hypothermia and rewarming activate microglial cells, increase phagocytosis and shift the balance of cytokine release in stimulated microglial cells towards the anti-inflammatory cytokines. This could be a new cellular mechanism of hypothermia-induced neuroprotection mediated by activated microglial cells.


Assuntos
Citocinas/biossíntese , Hipotermia Induzida , Microglia/metabolismo , Microglia/patologia , Transdução de Sinais/fisiologia , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Técnicas In Vitro , Camundongos
20.
Brain Pathol ; 20(4): 771-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20070303

RESUMO

Systemic or brain-selective hypothermia is a well-established method for neuroprotection after brain trauma. There is increasing evidence that hypothermia exerts beneficial effects on the brain and may also support regenerative responses after brain damage. Here, we have investigated whether hypothermia influences neurite outgrowth in vitro via modulation of the post-injury cytokine milieu. Organotypic brain slices were incubated: deep hypothermia (2 h at 17 degrees C), rewarming (2 h up to 37 degrees C), normothermia (20 h at 37 degrees C). Neurite density and cytokine release (IL 1beta, IL-6, IL-10, and TNF-alpha) were investigated after 24 h. For functional analysis mice deficient in NT-3/NT-4 and TNF-alpha as well as the TNF-alpha inhibitor etanercept were used. Hypothermia led to a significant increase of neurite outgrowth, which was independent of neurotrophin signaling. In contrast to other cytokines investigated, TNF-alpha secretion by organotypic brain slices was significantly increased after deep hypothermia. Moreover, hypothermia-induced neurite extension was abolished after administration of the TNF-alpha inhibitor and in TNF-alpha knockout mice. We demonstrate that TNF-alpha is responsible for inducing neurite outgrowth in the context of deep hypothermia and rewarming. These data suggest that hypothermia not only exerts protective effects in the CNS but may also support neurite outgrowth as a potential mechanism of regeneration.


Assuntos
Temperatura Baixa , Córtex Entorrinal/metabolismo , Neuritos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Córtex Entorrinal/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Etanercepte , Imunoglobulina G/farmacologia , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Fatores de Crescimento Neural/metabolismo , Neuritos/efeitos dos fármacos , Neurotrofina 3/metabolismo , Técnicas de Cultura de Órgãos , Receptores do Fator de Necrose Tumoral , Reaquecimento , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/antagonistas & inibidores
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