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1.
Lakartidningen ; 1162019 Oct 08.
Artigo em Sueco | MEDLINE | ID: mdl-31593285

RESUMO

The recently documented high survival of extremely preterm infants in Sweden is related to a high degree of centralization of pre- and postnatal care and to recently issued national consensus guidelines providing recommendations for perinatal care at 22-24 gestational weeks. The prevalence of major neonatal morbidity remains high and exceeded 60 % in a recent study of extremely preterm infants born at < 27 gestational weeks delivered in Sweden in 2014-2016 and surviving to 1 year of age. Damage to immature organ systems inflicted during the neonatal period causes varying degrees of functional impairment with lasting effects in the growing child. There is an urgent need for evidence-based novel interventions aiming to prevent neonatal morbidity with a subsequent improvement of long-term outcome.


Assuntos
Lactente Extremamente Prematuro , Doenças do Prematuro , Nascimento Prematuro , Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/fisiopatologia , Displasia Broncopulmonar/prevenção & controle , Serviços Centralizados no Hospital , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/fisiopatologia , Hemorragia Cerebral/prevenção & controle , Ventrículos Cerebrais/irrigação sanguínea , Ventrículos Cerebrais/diagnóstico por imagem , Enterocolite Necrosante/epidemiologia , Enterocolite Necrosante/fisiopatologia , Enterocolite Necrosante/prevenção & controle , Feminino , Humanos , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Doenças do Prematuro/epidemiologia , Doenças do Prematuro/fisiopatologia , Doenças do Prematuro/prevenção & controle , Assistência Perinatal/organização & administração , Gravidez , Nascimento Prematuro/mortalidade , Retinopatia da Prematuridade/sangue , Retinopatia da Prematuridade/epidemiologia , Retinopatia da Prematuridade/fisiopatologia , Retinopatia da Prematuridade/prevenção & controle , Taxa de Sobrevida , Suécia/epidemiologia
2.
Cochrane Database Syst Rev ; 9: CD013201, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31549743

RESUMO

BACKGROUND: Germinal matrix-intraventricular haemorrhage (GMH-IVH) remains a substantial issue in neonatal intensive care units worldwide. Current therapies to prevent or treat GMH-IVH are limited. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, and/or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal studies. OBJECTIVES: To determine the benefits and harms of stem cell-based interventions for prevention or treatment of germinal matrix-intraventricular haemorrhage (GM-IVH) in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1), in the Cochrane Library; MEDLINE via PubMed (1966 to 7 January 2019); Embase (1980 to 7 January 2019); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 7 January 2019). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We attempted to identify randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing (1) stem cell-based interventions versus control; (2) mesenchymal stromal cells (MSCs) of type or source versus MSCs of other type or source; (3) stem cell-based interventions other than MSCs of type or source versus stem cell-based interventions other than MSCs of other type or source; or (4) MSCs versus stem cell-based interventions other than MSCs. For prevention studies, we included extremely preterm infants (less than 28 weeks' gestation), 24 hours of age or less, without ultrasound diagnosis of GM-IVH; for treatment studies, we included preterm infants (less than 37 weeks' gestation), of any postnatal age, with ultrasound diagnosis of GM-IVH. DATA COLLECTION AND ANALYSIS: For each of the included trials, two review authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, type and source of MSCs, other stem cell-based interventions) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). Primary outcomes considered in this review are all-cause neonatal mortality, major neurodevelopmental disability, GM-IVH, and extension of pre-existing non-severe GM-IVH. We planned to use the GRADE approach to assess the quality of evidence. MAIN RESULTS: Our search strategy yielded 769 references. We did not find any completed studies for inclusion. One randomised controlled trial is currently registered and ongoing. Five phase 1 trials are described in the excluded studies. AUTHORS' CONCLUSIONS: Currently no evidence is available to show the benefits or harms of stem cell-based interventions for treatment or prevention of GM-IVH in preterm infants.


Assuntos
Hemorragia Cerebral/prevenção & controle , Circulação Cerebrovascular/fisiologia , Mortalidade Infantil , Lactente Extremamente Prematuro , Doenças do Prematuro/prevenção & controle , Células-Tronco , Humanos , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Doenças do Prematuro/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Cochrane Database Syst Rev ; 9: CD003248, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31529790

RESUMO

BACKGROUND: Infants born preterm (before 37 weeks' gestation) have poorer outcomes than infants at term, particularly if born before 32 weeks. Early cord clamping has been standard practice over many years, and enables quick transfer of the infant to neonatal care. Delayed clamping allows blood flow between the placenta, umbilical cord and baby to continue, and may aid transition. Keeping baby at the mother's side enables neonatal care with the cord intact and this, along with delayed clamping, may improve outcomes. Umbilical cord milking (UCM) is proposed for increasing placental transfusion when immediate care for the preterm baby is needed. This Cochrane Review is a further update of a review first published in 2004 and updated in 2012. OBJECTIVES: To assess the effects on infants born at less than 37 weeks' gestation, and their mothers of: 1) delayed cord clamping (DCC) compared with early cord clamping (ECC) both with immediate neonatal care after cord clamping; 2) DCC with immediate neonatal care with cord intact compared with ECC with immediate neonatal care after cord clamping; 3) DCC with immediate neonatal care after cord clamping compared with UCM; 4) UCM compared with ECC with immediate neonatal care after cord clamping. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 November 2017), and reference lists of retrieved studies. We updated the search in November 2018 and added nine new trial reports to the awaiting classification section to be assessed at the next update. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing delayed with early clamping of the umbilical cord (with immediate neonatal care after cord clamping or with cord intact) and UCM for births before 37 weeks' gestation. Quasi-RCTs were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Random-effects are used in all meta-analyses. Review authors assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: This update includes forty-eight studies, involving 5721 babies and their mothers, with data available from 40 studies involving 4884 babies and their mothers. Babies were between 24 and 36+6 weeks' gestation at birth and multiple births were included. The data are mostly from high-income countries. Delayed clamping ranged between 30 to 180 seconds, with most studies delaying for 30 to 60 seconds. Early clamping was less than 30 seconds and often immediate. UCM was mostly before cord clamping but some were milked after cord clamping. We undertook subgroup analysis by gestation and type of intervention, and sensitivity analyses by low risk of selection and attrition bias.All studies were high risk for performance bias and many were unclear for other aspects of risk of bias. Certainty of the evidence using GRADE was mostly low, mainly due to imprecision and unclear risk of bias.Delayed cord clamping (DCC) versus early cord clamping (ECC) both with immediate neonatal care after cord clamping (25 studies, 3100 babies and their mothers)DCC probably reduces the number of babies who die before discharge compared with ECC (average risk ratio (aRR) 0.73, 95% confidence interval (CI) 0.54 to 0.98, 20 studies, 2680 babies (moderate certainty)).No studies reported on 'Death or neurodevelopmental impairment' in the early years'.DCC may make little or no difference to the number of babies with severe intraventricular haemorrhage (IVH grades 3 and 4) (aRR 0.94, 95% CI 0.63 to 1.39, 10 studies, 2058 babies, low certainty) but slightly reduces the number of babies with any grade IVH (aRR 0.83, 95% CI 0.70 to 0.99, 15 studies, 2333 babies, high certainty).DCC has little or no effect on chronic lung disease (CLD) (aRR 1.04, 95% CI 0.94 to 1.14, 6 studies, 1644 babies, high certainty).Due to insufficient data, we were unable to form conclusions regarding periventricular leukomalacia (PVL) (aRR 0.58, 95% CI 0.26 to 1.30, 4 studies, 1544 babies, low certainty) or maternal blood loss of 500 mL or greater (aRR 1.14, 95% CI 0.07 to 17.63, 2 studies, 180 women, very low certainty).We identified no important heterogeneity in subgroup or sensitivity analyses.Delayed cord clamping (DCC) with immediate neonatal care with cord intact versus early cord clamping (ECC) (one study, 276 babies and their mothers)There are insufficient data to be confident in our findings, but DCC with immediate neonatal care with cord intact may reduce the number of babies who die before discharge, although the data are also compatible with a slight increase in mortality, compared with ECC (aRR 0.47, 95% CI 0.20 to 1.11, 1 study, 270 babies, low certainty). DCC may also reduce the number of babies who die or have neurodevelopmental impairment in early years (aRR 0.61, 95% CI 0.39 to 0.96, 1 study, 218 babies, low certainty). There may be little or no difference in: severe IVH; all grades IVH; PVL; CLD; maternal blood loss ≥ 500 mL, assessed as low certainty mainly due to serious imprecision.Delayed cord clamping (DCC) with immediate neonatal care after cord clamping versus umbilical cord milking (UCM) (three studies, 322 babies and their mothers) and UCM versus early cord clamping (ECC) (11 studies, 1183 babies and their mothers)There are insufficient data for reliable conclusions about the comparative effects of UCM compared with delayed or early clamping (mostly low or very low certainty). AUTHORS' CONCLUSIONS: Delayed, rather than early, cord clamping may reduce the risk of death before discharge for babies born preterm. There is insufficient evidence to show what duration of delay is best, one or several minutes, and therefore the optimum time to clamp the umbilical cord remains unclear. Whilst the current evidence supports not clamping the cord before 30 seconds at preterm births, future trials could compare different lengths of delay. Immediate neonatal care with the cord intact requires further study, and there are insufficient data on UCM.The nine new reports awaiting further classification may alter the conclusions of the review once assessed.


Assuntos
Recém-Nascido Prematuro , Circulação Placentária/fisiologia , Cordão Umbilical , Transfusão de Sangue/estatística & dados numéricos , Hemorragia Cerebral/prevenção & controle , Parto Obstétrico , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Gravidez , Resultado da Gravidez , Nascimento Prematuro , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
4.
Cochrane Database Syst Rev ; 9: CD003436, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31503327

RESUMO

BACKGROUND: Brain arteriovenous malformations (AVMs) are the single most common cause of intracerebral haemorrhage in young adults. Brain AVMs also cause seizure(s) and focal neurological deficits (in the absence of haemorrhage, migraine or an epileptic seizure); approximately one-fifth are incidental discoveries. Various interventions are used in an attempt to eradicate brain AVMs: neurosurgical excision, stereotactic radiosurgery, endovascular embolization, and staged combinations of these interventions. This is an update of a Cochrane Review first published in 2006, and last updated in 2009. OBJECTIVES: To determine the effectiveness and safety of the different interventions, alone or in combination, for treating brain AVMs in adults compared against either each other, or conservative management, in randomized controlled trials (RCTs). SEARCH METHODS: The Cochrane Stroke Group Information Specialist searched the Cochrane Stroke Group Trials Register (last searched 7 January 2019), the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1) in the Cochrane Library, MEDLINE Ovid (1980 to 14 January 2019), and Embase OVID (1980 to 14 January 2019). We searched international registers of clinical trials, the contents pages of relevant journals, and bibliographies of relevant articles (November 2009). We also contacted manufacturers of interventional treatments for brain AVMs (March 2005). SELECTION CRITERIA: We sought RCTs of any intervention for brain AVMs (used alone or in combination), compared against each other or against conservative management, with relevant clinical outcome measures. DATA COLLECTION AND ANALYSIS: One author screened the results of the updated searches for potentially eligible RCTs for this updated review. Both authors independently read the potentially eligible RCTs in full and confirmed their inclusion according to the inclusion criteria. We resolved disagreement by discussion. We assessed the risk of bias in included studies and applied GRADE. MAIN RESULTS: We included one trial with 226 participants: A Randomized trial of Unruptured Brain Arteriovenous Malformations (ARUBA), comparing intervention versus conservative management for unruptured brain AVMs (that had never bled). The quality of evidence was moderate because we found just one trial that was at low risk of bias other than a high risk of performance bias due to participants and treating physicians not being blinded to allocated treatment. Data on functional outcome and death at a follow-up of 12 months were provided for 218 (96%) of the participants in ARUBA. In this randomized controlled trial (RCT), intervention compared to conservative management increased death or dependency (modified Rankin Scale score ≥ 2, risk ratio (RR) 2.53, 95% confidence interval (CI) 1.28 to 4.98; 1 trial, 226 participants; moderate-quality evidence) and the proportion of participants with symptomatic intracranial haemorrhage (RR 6.75, 95% CI 2.07 to 21.96; 1 trial, 226 participants; moderate-quality evidence), but there was no difference in the frequency of epileptic seizures (RR 1.14, 95% CI 0.63 to 2.06; 1 trial, 226 participants; moderate-quality evidence). Three RCTs are ongoing. AUTHORS' CONCLUSIONS: We found moderate-quality evidence from one RCT including adults with unruptured brain AVMs that conservative management was superior to intervention with respect to functional outcome and symptomatic intracranial haemorrhage over one year after randomization. More RCTs will help to confirm or refute these findings.


Assuntos
Malformações Arteriovenosas Intracranianas/terapia , Adulto , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/prevenção & controle , Tratamento Conservador , Embolização Terapêutica , Epilepsia/etiologia , Epilepsia/prevenção & controle , Humanos , Malformações Arteriovenosas Intracranianas/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Eur J Pharmacol ; 854: 128-138, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30853532

RESUMO

Protocatechuic acid (PCA) has been well studied for its neuroprotection value in several diseases, but the effect in intracerebral haemorrhage (ICH) has not been reported. Here we verified the protection of PCA in ICH, and investigated the relative mechanisms. ICH model mice were established by injection of collagenase IV. The mice were treated with PCA once per day for 3 days, starting immediately after operation. The modified neurological severity score (mNSS) of mice at 1st, 3rd and 7th day after operation were recorded. And some of mice were euthanized at 3rd day to compare brain water content, pro-inflammatory cytokines expression, and cell apoptosis in perihematomal tissue. Additionally, SH-SY5Y cells were treated hemin to mimic secondary injury of ICH. Cells were incubated with PCA for treatment. The cell viability, ROS, apoptosis rate and protein expression of apoptosis-relative protein and MAPKs and NF-κB were detected and analysed. The results revealed PCA alleviated the cerebral oedema at 3rd post ICH, and significantly improved neurological functions. PCA also attenuated the protein and gene expression of TNF-а, IL-1ß and IL-6 vivo. PCA dose-dependently decreased the generation of ROS and apoptosis rate. Furthermore, PCA treatment dose-dependently decreased the expression of bax, cleaved caspase-3, increased bcl-2 expression; PCA downregulated P38/JNK-NF-κB pathway. In conclusion, PCA effectively improves prognosis of ICH mice by inhibiting oxidative stress, inflammation and apoptosis. The mechanism possibly results of downregulating of P38/JNK-NF-κB pathway, and PCA can be a potential therapeutic agent for ICH.


Assuntos
Hemorragia Cerebral/patologia , Hemorragia Cerebral/prevenção & controle , Hidroxibenzoatos/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Edema Encefálico/complicações , Linhagem Celular Tumoral , Hemorragia Cerebral/complicações , Hemorragia Cerebral/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
6.
J Pediatr ; 206: 56-65.e8, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30471715

RESUMO

OBJECTIVE: To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants. STUDY DESIGN: This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 230/7 weeks to 276/7 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 µg/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 296/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 404/7 weeks. Target exposure was ≥70% IGF-1 measurements within 28-109 µg/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures. RESULTS: Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures. CONCLUSIONS: rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01096784.


Assuntos
Hemorragia Cerebral/prevenção & controle , Fator de Crescimento Insulin-Like I/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Retinopatia da Prematuridade/prevenção & controle , Displasia Broncopulmonar/prevenção & controle , Hemorragia Cerebral/terapia , Feminino , Idade Gestacional , Humanos , Lactente Extremamente Prematuro , Recém-Nascido , Recém-Nascido Prematuro , Infusões Intravenosas , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/uso terapêutico , Masculino , Retinopatia da Prematuridade/mortalidade , Retinopatia da Prematuridade/terapia , Índice de Gravidade de Doença , Resultado do Tratamento
8.
J Stroke Cerebrovasc Dis ; 28(2): 267-275, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30385221

RESUMO

BACKGROUND: To identify the vascular risk factors associated with the occurrence of intracerebral hemorrhage (ICH) in Multiple Sclerosis (MS) patients. METHODS: This is an observational, retrospective cohort study using the nationwide electronic medical records (EMR) database. Patients with the diagnosis of MS were extracted from inpatient and outpatient EMR using the international classification of diseases, ninth/tenth revisions, clinical modification codes. We excluded patients younger than 18 years, and those where gender was not specified. Patients were further stratified based on their demographics, risk factors, medications, and comorbidities. Tobacco, diabetes, hypertension, and alcohol were the predicting variables; antiplatelet medication, and anticoagulant agents were the primary exposures for the development of ICH. A validated diagnosis code algorithm defined the diagnosis of ICH. Multivariable logistic regression models were utilized to assess the risk of ICH in MS patients. RESULTS: Of the total 57,099 MS patients (women: 75%, n = 41,517), 107 (.19%) sustained an ICH. Age (OR = 2.74, CI = 1.13-6.62), use of anticoagulants (OR = 2.15, 95% CI = 1.30-3.56, P = .0028), and history of tobacco exposure (OR = 2.44, CI = 1.37-4.36, P = .0025) were associated with increased risk of ICH. Use of antiplatelet and disease-modifying drugs (DMDs) showed a protective trend against ICH. CONCLUSIONS: Tobacco exposure and anticoagulant use were strongly associated with increased risk of ICH in patients with MS. There might be a protective effect that antiplatelet and DMDs have in the pathophysiology of this disease. Further prospective investigations are warranted to establish these associations.


Assuntos
Hemorragia Cerebral/epidemiologia , Esclerose Múltipla/epidemiologia , Adolescente , Adulto , Idoso , Anticoagulantes/efeitos adversos , Antirreumáticos/uso terapêutico , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/prevenção & controle , Comorbidade , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Prognóstico , Fatores de Proteção , Estudos Retrospectivos , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
9.
Br J Neurosurg ; 33(4): 428-431, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28660808

RESUMO

Background: Non traumatic subdural hematomas are rare, especially those associated with intracranial meningiomas. Among the most common meningiomas associated with spontaneous bleeding are angioblastic and malignant meningioma variants. The pathophysiological mechanisms of this association are not yet fully understood. The association of chronic subdural hematoma with microcystic meningioma histological subtype has not yet been described in the literature. Case report: The authors present a case report of a patient with a spontaneous non traumatic chronic subdural hematoma associated with a microcystic subtype grade I meningioma of the parietal convexity. Epidemiological, etiology, natural history, pathophysiology, risk factors of bleeding and treatment options are reviewed. Conclusion: Spontaneous subdural hematomas associated with meningiomas are rare, specially related to the microcystic variant of meningioma. Careful pre-operative consideration of specific anatomy and pathophysiological features are paramount to their full treatment.


Assuntos
Hematoma Subdural Crônico/etiologia , Neoplasias Meníngeas/complicações , Meningioma/complicações , Idoso de 80 Anos ou mais , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/prevenção & controle , Craniotomia/métodos , Feminino , Hematoma Subdural Crônico/cirurgia , Humanos , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Recidiva , Tomografia Computadorizada por Raios X
10.
Cell Mol Neurobiol ; 39(1): 1-10, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30361892

RESUMO

Germinal matrix hemorrhage (GMH) refers to bleeding that derives from the subependymal (or periventricular) germinal region of the premature brain. GMH can induce severe and irreversible damage attributing to the vulnerable structure of germinal matrix and deleterious circumstances. Molecular mechanisms remain obscure so far. In this review, we summarized the newest preclinical discoveries recent years about GMH to distill a deeper understanding of the neuropathology, and then discuss the potential diagnostic or therapeutic targets among these pathways. GMH studies mostly in recent 5 years were sorted out and the authors generalized the newest discoveries and ideas into four parts of this essay. Intrinsic fragile structure of preterm germinal matrix is the fundamental cause leading to GMH. Many molecules have been found effective in the pathophysiological courses. Some of these molecules like minocycline are suggested active to reduce the damage in animal GMH model. However, researchers are still trying to find efficient diagnostic methods and remedies that are available in preterm infants to rehabilitate or cure the sequent injury. Merits have been obtained in the last several years on molecular pathways of GMH, but more work is required to further unravel the whole pathophysiology.


Assuntos
Pesquisa Biomédica , Hemorragia Cerebral/patologia , Animais , Encéfalo/patologia , Hemorragia Cerebral/prevenção & controle , Hemorragia Cerebral/terapia , Humanos , Modelos Biológicos
11.
J Neonatal Perinatal Med ; 11(3): 241-248, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30282376

RESUMO

BACKGROUND: Contradictory evidence exists whether a prophylactic coagulation factor transfusion in the first hours of life (HOL) prevents intraventricular hemorrhage (IVH) in extreme preterm infants (EPI, <28 weeks gestation). We aimed to determine whether selective prophylactic solvent-detergent plasma and cryoprecipitate transfusion within 12 hours of life (SP-SDP/Cryoprecipitate-T) could prevent IVH in EPI. METHOD: This is a retrospective analysis, case-historical control, of prospectively collected data from a pre-existing electronic neonatal database at a Saudi tertiary neonatal intensive care unit. We compared the IVH rate in EPI born in the first 4 years (Jan 2010-Dec 2013) of the SP-SDP/Cryoprecipitate-T period with that of EPI born during the last 4 years (Jan 2006-Dec 2009) of the rescue SDP/Cryoprecipitate-T period. RESULTS: The IVH rate was lower in the SP compared to the rescue- SDP/Cryoprecipitate-T period (30.8% versus 51.2%, odds ratio 0.42, 95% confidence interval 0.21, 0.88, p = 0.02). This difference remained significant after controlling for six other IVH risk factors. CONCLUSIONS: Early SP-SDP/Cryoprecipitate-T may reduce the IVH rate in EPI. A large multicenter clinical trial is required for confirm the short and long-term benefit and risk of this intervention. Until then, early SP-SDP/Cryoprecipitate-T may be considered by an institution with a persistently high IVH rate.


Assuntos
Transfusão de Componentes Sanguíneos/métodos , Hemorragia Cerebral/prevenção & controle , Coagulantes/uso terapêutico , Fator VIII/uso terapêutico , Fibrinogênio/uso terapêutico , Doenças do Prematuro/terapia , Estudos de Casos e Controles , Detergentes/uso terapêutico , Feminino , Idade Gestacional , Humanos , Lactente Extremamente Prematuro , Recém-Nascido , Doenças do Prematuro/fisiopatologia , Unidades de Terapia Intensiva Neonatal , Masculino , Estudos Retrospectivos , Fatores de Risco , Solventes/uso terapêutico , Resultado do Tratamento
12.
Neuropharmacology ; 141: 238-248, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30193808

RESUMO

Hemorrhages occurring within the thalamus lead to a pain syndrome. Clinical treatment of thalamic pain is ineffective, at least in part, due to the elusive mechanisms that underlie the induction and maintenance of thalamic pain. The present study investigated the possible contribution of a protein-protein interaction between postsynaptic density protein 95 (PSD-95) and neuronal nitric oxide synthase (nNOS) to thalamic pain in mice. Thalamic hemorrhage was induced by microinjection of type IV collagenase into unilateral ventral posterior medial/lateral nuclei of the thalamus. Pain hypersensitivities, including mechanical allodynia, heat hyperalgesia, and cold allodynia, appeared at day 1 post-microinjection, reached a peak 5-7 days post-microinjection, and persisted for at least 28 days post-microinjection on the contralateral side. Systemic pre-treatment (but not post-treatment) of ZL006, a small molecule that disrupts PSD-95-nNOS interaction, alleviated these pain hypersensitivities. This effect is dose-dependent. Mechanistically, ZL006 blocked the hemorrhage-induced increase of binding of PSD-95 with nNOS and membrane translocation of nNOS in thalamic neurons. Our findings suggest that the protein-protein interaction between PSD-95 and nNOS in the thalamus plays a significant role in the induction of thalamic pain. This interaction may be a promising therapeutic target in the clinical management of hemorrhage-induced thalamic pain.


Assuntos
Hemorragia Cerebral/prevenção & controle , Proteína 4 Homóloga a Disks-Large/metabolismo , Neuralgia/prevenção & controle , Óxido Nítrico Sintase Tipo I/metabolismo , Tálamo/patologia , Ácidos Aminossalicílicos/farmacologia , Animais , Benzilaminas/farmacologia , Hemorragia Cerebral/induzido quimicamente , Colágeno Tipo IV/administração & dosagem , Relação Dose-Resposta a Droga , Masculino , Camundongos , Microinjeções , Medição da Dor/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Tálamo/irrigação sanguínea
13.
J Neurosurg ; 131(3): 931-935, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30239311

RESUMO

OBJECTIVE: The unexpected intraoperative intraventricular hemorrhage is a rare but feared and life-threatening complication in neuroendoscopic procedures because of loss of endoscopic vision. The authors present their experience with the so-called "dry field technique" (DFT) for the management of intraventricular hemorrhages during purely endoscopic procedures. This technique requires the aspiration of the entire intraventricular CSF to achieve clear visualization of the bleeding source. METHODS: More than 500 neuroendoscopic intraventricular procedures were retrospectively analyzed over the last 24 years for documented severe hemorrhages, which were treated by the application of the DFT. RESULTS: The technique was required in 6 cases, including tumor resection/biopsy, cyst resection, and intraventricular lavage. Additionally, the technique was applied as part of the planned strategy in 3 cases of endoscopic tumor removal. The hemorrhage was stopped in all cases and no associated postoperative deficits occurred. CONCLUSIONS: Although severe hemorrhages are rare, the neurosurgeon needs to be aware of them and has to establish strategies for their management. Most hemorrhages can be stopped by constant irrigation and coagulation. In the other rare cases, the DFT is a safe, reliable technique and can be easily incorporated into endoscopic surgery.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Encefalopatias/cirurgia , Hemorragia Cerebral/prevenção & controle , Neuroendoscopia/efeitos adversos , Encefalopatias/complicações , Encefalopatias/diagnóstico , Hemorragia Cerebral/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sucção , Ventriculostomia
14.
Med Hypotheses ; 119: 11-13, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30122480

RESUMO

In the early postnatal period, intraventricular hemorrhage may develop in infants with extremely low birth weights due to hemodynamic instability. One of the most significant factors in intraventricular hemorrhage development is fluctuations in the cerebral blood flow due to left-to-right shunting as a result of patent ductus arteriosus, and such cases most frequently develop intraventricular hemorrhage within the first 72 h. The frequency of intraventricular hemorrhage may be reduced through the prevention of fluctuations in the cerebral blood flow in this time frame. Based on our hypothesis, we recommend that extremely low birth weight infants should be delivered and monitored in hypobaric rooms for the first three days after birth, as this may reduce left-to-right shunting as a result of patent ductus arteriosus by preventing the rapid drops seen in pulmonary pressure after birth. A more stable hemodynamic status may be achieved by increasing the cerebral blood flow during an acute term in a hypobaric environment. Gradual transition to the normobaric status at the end of the third day may prevent the long-term negative effects of hypobaric conditions.


Assuntos
Pressão do Ar , Hemorragia Cerebral/prevenção & controle , Parto Obstétrico/métodos , Circulação Cerebrovascular , Permeabilidade do Canal Arterial/terapia , Feminino , Hemodinâmica , Humanos , Hipóxia , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Recém-Nascido Prematuro , Pulmão/patologia , Monitorização Fisiológica/métodos , Oxigênio/química , Parto , Gravidez , Fatores de Tempo
15.
IEEE Trans Biomed Eng ; 65(9): 2058-2065, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29989941

RESUMO

OBJECTIVE: Hemorrhagic transformation (HT) is the most severe complication of reperfusion therapy in acute ischemic stroke (AIS) patients. Management of AIS patients could benefit from accurate prediction of upcoming HT. While prediction of HT occurrence has recently provided encouraging results, the prediction of the severity and territory of the HT could bring valuable insights that are beyond current methods. METHODS: This study tackles these issues and aims to predict the spatial occurrence of HT in AIS from perfusion-weighted magnetic resonance imaging (PWI) combined with diffusion weighted imaging. In all, 165 patients were included in this study and analyzed retrospectively from a cohort of AIS patients treated with reperfusion therapy in a single stroke center. RESULTS: Machine learning models are compared within our framework; support vector machines, linear regression, decision trees, neural networks, and kernel spectral regression were applied to the dataset. Kernel spectral regression performed best with an accuracy of $\text{83.7} \pm \text{2.6}\%$. CONCLUSION: The key contribution of our framework formalize HT prediction as a machine learning problem. Specifically, the model learns to extract imaging markers of HT directly from source PWI images rather than from pre-established metrics. SIGNIFICANCE: Predictions visualized in terms of spatial likelihood of HT in various territories of the brain were evaluated against follow-up gradient recalled echo and provide novel insights for neurointerventionalists prior to endovascular therapy.


Assuntos
Hemorragia Cerebral , Interpretação de Imagem Assistida por Computador/métodos , Angiografia por Ressonância Magnética/métodos , Reperfusão/efeitos adversos , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/prevenção & controle , Procedimentos Endovasculares/efeitos adversos , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/terapia
16.
Neurosci Lett ; 681: 110-116, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29870775

RESUMO

Oxidative stress and blood-brain barrier (BBB) dysfunction contribute to brain injury after intracerebral hemorrhage (ICH). Adiponectin (APN) inhibits oxidative stress in the CNS, but the role of APN in ICH is not clear. Thus, we elucidated the possible neuroprotective effect of APN in ICH-induced brain injury in rats and investigated the neuroprotective mechanisms. A lentivirus-carrying APN gene was injected into rats 14 days before ICH induced via intracerebral injection of autologous blood. The effects of lentiviral overexpression of APN on brain injury were evaluated 24 h after ICH. Superoxide dismutase (SOD), glutathione (GSH), and the ratio of oxidized glutathione to reduced glutathione (GSSG/GSH) and malondialdehyde (MDA) were measured. Oxidative stress-related proteins were measured by Western blot and qRT-PCR. APN overexpression improved neurological function, reduced brain edema, preserved the BBB and increased the expression of APN and decreased the expression of NADPH oxidase-2 (NOX 2) compared with null vector controls (p < 0.01). SOD, GSH, and GSSG/GSH increased, and MDA was reduced. Furthermore, tetrabromocinnamic acid (TBCA, a NADPH oxidase activator) blocked the effect of APN on cerebral protection and antioxidant activity. Our results demonstrate the importance of APN in regulating oxidative stress and BBB function and suggest APN may be a novel treatment for brain damage after ICH.


Assuntos
Adiponectina/biossíntese , Lesões Encefálicas/metabolismo , Hemorragia Cerebral/metabolismo , Neuroproteção/fisiologia , Estresse Oxidativo/fisiologia , Adiponectina/genética , Animais , Lesões Encefálicas/prevenção & controle , Hemorragia Cerebral/prevenção & controle , Expressão Gênica , Masculino , Ratos , Ratos Sprague-Dawley
17.
J Neurol Sci ; 390: 212-218, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29801891

RESUMO

BACKGROUND: Even though ticagrelor was beneficial in prior cardiovascular trials, its efficacy in stroke prevention was inconclusive in recent randomized-controlled clinical trials (RCTs). We sought to consolidate the evidence for efficacy and safety of ticagrelor for stroke prevention. METHODS: We conducted a systematic review and meta-analysis of RCTs in major databases reporting following efficacy and safety outcomes among patients with cerebral or cardiovascular risk factors treated with ticagrelor (vs. control): ischemic stroke (IS), combined ischemic and hemorrhagic stroke, myocardial infarction (MI), cardiovascular death (CVD), all-cause mortality, and major bleeding events. We pooled risk ratios (RR) and adjusted hazard ratios (HRadjusted) from each trial using random-effect models, and assessed the heterogeneity using Cochran Q and I2 statistics. RESULTS: We identified 13 RCTs, comprising 64,360 patients. In comparison to control group, ticagrelor reduced the risk of IS (RR = 0.86; 95%CI = 0.78-0.95, p = .003; I2 = 0%), combined ischemic and hemorrhagic strokes (risk ratio: 0.90; 95%CI: 0.81-1.00, p = .05; I2 = 0%), and composite stroke/MI/CVD (RR = 0.90; 95%CI = 0.81-0.99, p = .03; I2 = 47%). Ticagrelor was not associated with increased risk of mortality (RR: 0.95; 95%CI: 0.84-1.07; p = .40) or major bleeding events (RR: 1.18; 95%CI: 0.92-1.50; p = .19). Additional analyses demonstrated that ticagrelor reduced the risk of incident strokes (HRadjusted = 0.87; 95%CI = 0.76-0.98; p = .03) and composite stroke/MI/CVD (HRadjusted = 0.88; 95%CI = 0.78-0.98; p = .02) among patients with prior history of IS or transient ischemic attack. CONCLUSIONS: Ticagrelor seems to be a beneficial option for primary and secondary stroke prevention in patients with cerebral or cardiovascular risk factors. Further RCTs are needed to evaluate the role of ticagrelor in secondary stroke prevention.


Assuntos
Inibidores da Agregação de Plaquetas/uso terapêutico , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controle , Ticagrelor/uso terapêutico , Isquemia Encefálica/prevenção & controle , Hemorragia Cerebral/prevenção & controle , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Lancet Neurol ; 17(6): 509-518, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29778364

RESUMO

BACKGROUND: The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. METHODS: In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. FINDINGS: Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0-3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57-1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20-1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50-0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27-1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. INTERPRETATION: In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. FUNDING: Korea Otsuka Pharmaceutical.


Assuntos
Grupo com Ancestrais do Continente Asiático , Doenças Cardiovasculares/prevenção & controle , Hemorragia Cerebral/prevenção & controle , Cilostazol/uso terapêutico , Fibrinolíticos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Antioxidantes/uso terapêutico , Aspirina/uso terapêutico , Isquemia Encefálica/complicações , Doenças Cardiovasculares/etnologia , Hemorragia Cerebral/etnologia , Hemorragia Cerebral/etiologia , China , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Filipinas , Probucol/uso terapêutico , República da Coreia , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento
19.
Toxicol Appl Pharmacol ; 350: 32-42, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29730311

RESUMO

Impaired vascular integrity leads to serious cerebral vascular diseases such as intracerebral hemorrhage (ICH). In addition, high-dose statin therapy is suggested to cause increased ICH risk due to unclear effects of general inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) on the vascular system. Here we evaluated the protective effects of sodium tanshinone IIA sulfonate (STS), which has high efficacy and safety in clinical studies of ischemic stroke, by using atorvastatin (Ator) induced ICH zebrafish embryos and human umbilical vein endothelial cells (HUVECs). By using double transgenic Tg(fli1a:EGFP)y1 & Tg(gata1a:dsRed)sd2 zebrafish, we demonstrated that STS effectively reduced the occurrence and area of hemorrhage induced by Ator in zebrafish and restored impairment in motor function. We further demonstrated that Ator-induced disruption in VE-cadherin (VEC)-containing cell-cell adherens junctions (AJs) in HUVECs by enhancing Src-induced VEC internalization and RhoA/ROCK-mediated cellular contraction. STS inhibited Ator-induced Src activation and subsequent VEC internalization and actin depolymerization near cell borders, reducing lesions between neighboring cells and increasing barrier functions. STS also inhibited the Ator-induced RhoA/ROCK-mediated cellular contraction by regulating downstream LIMK/cofilin and MYPT1/MLC phosphatase signaling. These results showed that STS significantly promoted the stability of cell junctions and vascular integrity. Moreover, we observed that regulations of both Src and RhoA/ROCK are required for the maintenance of vascular integrity, and Src inhibitor (PP2) or ROCK inhibitors (fasudil and H1152) alone could not reduce the occurrence Ator-induced ICH. Taken together, we investigated the underlying mechanisms of Ator-induced endothelial instability, and provided scientific evidences of STS as potential ICH therapeutics by promoting vascular integrity.


Assuntos
Antígenos CD/metabolismo , Atorvastatina/toxicidade , Caderinas/metabolismo , Hemorragia Cerebral/metabolismo , Endotélio Vascular/metabolismo , Fenantrenos/uso terapêutico , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Animais Geneticamente Modificados , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/prevenção & controle , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fenantrenos/farmacologia , Peixe-Zebra
20.
J Neurophysiol ; 120(3): 1307-1317, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29790836

RESUMO

Intracerebral hemorrhage (ICH) is a devastating disease worldwide with increasing mortality. The present study investigated whether minocycline was neuroprotective and induced M2 microglial polarization via upregulation of the TrkB/BDNF pathway after ICH. ICH was induced via injection of autologous blood into 150 Sprague-Dawley rats. A selective TrkB antagonist [N2-2-2-oxoazepan-3-yl amino] carbonyl phenyl benzo (b) thiophene-2-carboxamide (ANA 12)] and agonist [ N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC)] were used to investigate the mechanism of minocycline-induced neuroprotection. Minocycline improved ICH-induced neurological deficits and reduced M1 microglia marker protein (CD68, CD16) expression as well as M2 microglial polarization (CD206 and arginase 1 protein). Minocycline administration enhanced microglia-neuron cross talk and promoted the proliferation of neuronal progenitor cells, such as DCX- and Tuj-1-positive cells, 24 h after ICH. Minocycline also increased M2 microglia-derived brain-derived neurotrophic factors (BDNF) and the upstream TrkB pathway. ANA 12 reversed the neuroprotective effects of minocycline. HIOC exhibited the same effects as minocycline and accelerated neurogenesis after ICH. This study demonstrated for the first time that minocycline promoted M2 microglia polarization via upregulation of the TrkB/BDNF pathway and promoted neurogenesis after ICH. This study contributes to our understanding of the therapeutic potential of minocycline in ICH. NEW & NOTEWORTHY The present study gives several novel points: 1) Minocycline promotes neurogenesis after intracerebral hemorrhage in rats. 2) Minocycline induces activated M1 microglia into M2 neurotrophic phenotype. 3) M2 microglia secreting BDNF remodel the damaged neurocircuit.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hemorragia Cerebral/prevenção & controle , Microglia/efeitos dos fármacos , Minociclina/administração & dosagem , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Receptor trkB/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Hemorragia Cerebral/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Microglia/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
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