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1.
J Korean Med Sci ; 34(43): e271, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31701701

RESUMO

BACKGROUND: To investigate the incidence of surgical intervention in very low birth weight (VLBW) infants and the impact of surgery on neurodevelopmental outcomes at corrected ages (CAs) of 18-24 months, using data from the Korean Neonatal Network (KNN). METHODS: Data from 7,885 VLBW infants who were born and registered with the KNN between 2013 to 2016 were analyzed in this study. The incidences of various surgical interventions and related morbidities were analyzed. Long-term neurodevelopmental outcomes at CAs of 18-24 months were compared between infants (born during 2013 to 2015, n = 3,777) with and without surgery. RESULTS: A total of 1,509 out of 7,885 (19.1%) infants received surgical interventions during neonatal intensive care unit (NICU) hospitalization. Surgical ligation of patent ductus arteriosus (n = 840) was most frequently performed, followed by laser therapy for retinopathy of prematurity and laparotomy due to intestinal perforation. Infants who underwent surgery had higher mortality rates and greater neurodevelopmental impairment than infants who did not undergo surgery (P value < 0.01, both). On multivariate analysis, single or multiple surgeries increased the risk of neurodevelopmental impairment compared to no surgery with adjusted odds ratios (ORs) of 1.6 with 95% confidence interval (CI) of 1.1-2.6 and 2.3 with 95% CI of 1.1-4.9. CONCLUSION: Approximately one fifth of VLBW infants underwent one or more surgical interventions during NICU hospitalization. The impact of surgical intervention on long-term neurodevelopmental outcomes was sustained over a follow-up of CA 18-24 months. Infants with multiple surgeries had an increased risk of neurodevelopmental impairment compared to infants with single surgeries or no surgeries after adjustment for possible confounders.

2.
Yonsei Med J ; 60(10): 984-991, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31538434

RESUMO

PURPOSE: Despite the increasing use of continuous renal replacement therapy (CRRT) in the neonatal intensive care unit (NICU), few studies have investigated its use in preterm infants. This study evaluated the prognosis of preterm infants after CRRT and identified risk factors of mortality after CRRT. MATERIALS AND METHODS: A retrospective review was performed in 33 preterm infants who underwent CRRT at the NICU of Samsung Medical Center between 2008 and 2017. Data of the demographic characteristics, predisposing morbidity, cardiopulmonary function, and CRRT were collected and compared between surviving and non-surviving preterm infants treated with CRRT. Univariable and multivariable analyses were performed to identify factors affecting mortality. RESULTS: Compared with the survivors, the non-survivors showed younger gestational age (29.3 vs. 33.6 weeks), lower birth weight (1359 vs. 2174 g), and lower Apgar scores at 1 minute (4.4 vs. 6.6) and 5 minutes (6.5 vs. 8.6). At the initiation of CRRT, the non-survivors showed a higher incidence of inotropic use (93% vs. 40%, p=0.017) and fluid overload (16.8% vs. 4.0%, p=0.031). Multivariable analysis revealed that fluid overload >10% at CRRT initiation was the primary determinant of mortality after CRRT in premature infants, with an adjusted odds ratio of 14.6 and a 95% confidence interval of 1.10-211.29. CONCLUSION: Our data suggest that the degree of immaturity, cardiopulmonary instability, and fluid overload affect the prognosis of preterm infants after CRRT. Preventing fluid overload and earlier initiation of CRRT may improve treatment outcomes.


Assuntos
Recém-Nascido Prematuro/fisiologia , Terapia de Substituição Renal , Feminino , Mortalidade Hospitalar , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Análise Multivariada , Terapia de Substituição Renal/mortalidade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
3.
PLoS One ; 14(8): e0221042, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31442245

RESUMO

BACKGROUND: Recent nutrition guidelines for extremely-low-birth-weight infants (ELBWIs) recommend implementation of high initial amino acid (AA) supplementation in parenteral nutrition. OBJECTIVE: We sought to evaluate the influence of AA intake on refeeding syndrome-like electrolyte disturbances including hypophosphatemia in ELBWIs. STUDY DESIGN: Medical records of 142 ELBWIs were reviewed. Demographic, nutritional, outcome, and electrolyte data were compared between ELBWIs with initial low (1.5 g/kg/day) and high (3 g/kg/day) AA intake. Multivariate analysis was conducted to determine the odds ratio of hypophosphatemia with high AA intake and small-for-gestational-age (SGA) ELBWIs. RESULTS: The incidence of hypophosphatemia and severe hypophosphatemia increased from 51% and 8% in period I to 59% and 20% in period II, respectively (p = 0.36 and < 0.01). Specifically, SGA ELBWIs showed higher incidence of hypophosphatemia than appropriate-for-gestational age (AGA) ELBWIs in period II, whereas there was no difference in period I. For severe hypophosphatemia, SGA ELBWIs presented a 27% incidence versus a 2% incidence in AGA ELBWIs, even with low initial AA intake. Despite no difference in phosphate intake between infants with and without hypophosphatemia, serum phosphate level reached a nadir at the sixth postnatal day and gradually recovered over the second week in infants with hypophosphatemia. In multivariate analyses, the odds ratios for severe hypophosphatemia were 3.6 and 6.6 with high AA intake and SGA status, respectively, with the highest being 18.0 with combined high AA intake and SGA status. CONCLUSIONS: In summary, high initial AA intake significantly increased the risk of refeeding syndrome-like electrolyte dysregulations including severe hypophosphatemia in ELBWIs. In SGA ELBWIs, the risk of electrolyte disturbance was significantly higher, even with low initial AA intake. Therefore, new tailored parenteral nutrition protocols starting with lower energy intake and a gradual increase over the first week may be warranted for application in high-risk SGA ELBWIs.

5.
Sci Rep ; 9(1): 9628, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270383

RESUMO

This study investigated the incidence of transient hypothyroxinaemia of prematurity (THOP) associated with survival without composite morbidities and the predictability of THOP severity in extremely low birth weight infants (ELBWIs). We retrospectively reviewed the medical records of 546 ELBWIs who underwent initial thyroid function tests within 14 postnatal days, with 156 ELBWIs from 2000 to 2005 (period I) and 390 from 2006 to 2013 (period II). The infants were stratified into 23-24, 25-26 and 27-28 weeks' gestation subgroups within each period; the initial thyroxine (T4) level, mortality, clinical characteristics and composite morbidities, including bronchopulmonary dysplasia, intraventricular haemorrhage, necrotizing enterocolitis, and retinopathy of prematurity were analysed. The predictive value of the initial T4 level, Apgar score at 5 min, and clinical risk index for babies II (CRIB II) score for estimating mortality and survival with or without composite morbidities was assessed. Comparing period II and period I, the incidence of THOP was significantly decreased along with significantly increased survival without composite morbidities in ELBWIs at 25-28 weeks' gestation. The severity of THOP showed significant associations with mortality and composite morbidities. The initial T4 level was most effective for predicting outcome compared with Apgar and CRIB II scores.

6.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197089

RESUMO

We investigated the role of protease-activated receptor (PAR)-mediated signaling pathways in the biogenesis of human umbilical cord blood-derived mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) and the enrichment of their cargo content after thrombin preconditioning. Immunoblot analyses showed that MSCs expressed two PAR subtypes: PAR-1 and PAR-3. Thrombin preconditioning significantly accelerated MSC-derived EV biogenesis more than five-fold and enriched their cargo contents by more than two-fold via activation of Rab5, early endosomal antigen (EEA)-1, and the extracellular signal regulated kinase (ERK)1/2 and AKT signaling pathways. Blockage of PAR-1 with the PAR-1-specific antagonist, SCH79797, significantly suppressed the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways and subsequently increased EV production and enriched EV cargo contents. Combined blockage of PAR-1 and PAR-3 further and significantly inhibited the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways, accelerated EV production, and enriched EV cargo contents. In summary, thrombin preconditioning boosted the biogenesis of MSC-derived EVs and enriched their cargo contents largely via PAR-1-mediated pathways and partly via PAR-1-independent, PAR-3-mediated activation of Rab5, EEA-1, and the ERK1/2 and AKT signaling pathways.


Assuntos
Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Receptor PAR-1/metabolismo , Transdução de Sinais , Trombina/farmacologia , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/farmacologia , Quinazolinas/farmacologia , Receptor PAR-1/agonistas , Receptor PAR-1/antagonistas & inibidores , Proteínas de Transporte Vesicular/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo
7.
Sci Rep ; 9(1): 6815, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048743

RESUMO

The hexapeptide WKYMVm, which is a strong formyl peptide receptor (FPR) 2 agonist, exhibits pro-angiogenic, anti-inflammatory and anti-apoptotic properties. However, its therapeutic efficacy in bronchopulmonary dysplasia (BPD) has not been tested to date. Here, we investigated whether WKYMVm attenuates hyperoxia-induced lung inflammation and ensuing injuries by upregulating FPR2. The proliferation and tube formation ability of human umbilical vein endothelial cells (HUVECs), along with the level of extracellular signal regulated kinase (ERK) phosphorylation, were evaluated in vitro. Newborn mice were randomly exposed to 80% oxygen or room air for 14 days starting at birth. WKYMVm (2.5 mg/kg) was intraperitoneally administrated daily from postnatal day (P) 5 to P8. At P14, mice were sacrificed for histopathological and morphometric analyses. Along with upregulation of FPR2 and p-ERK, WKYMVm promoted HUVEC cell proliferation and tube formation in vitro. Additionally, WKYMVm promoted proliferation of human pulmonary microvascular endothelial cells (HULEC-5a) and murine pulmonary endothelial and epithelial cells in vitro. WKYMVm significantly attenuated hyperoxia-induced lung inflammation, as evidenced by increased inflammatory cytokines, neutrophils, and alveolar macrophages, and resultant lung injuries, which included impaired alveolarization and angiogenesis, an increased number of apoptotic cells, and reduced levels of growth factors in vivo, such as vascular endothelial growth factor and hepatocyte growth factor. WKYMVm attenuates hyperoxia-induced lung injuries and lung inflammation by upregulating FPR2 and p-ERK.

8.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137455

RESUMO

We investigated whether thrombin preconditioning of human Wharton's jelly-derived mesenchymal stem cells (MSCs) improves paracrine potency and thus the therapeutic efficacy of naïve MSCs against severe hypoxic ischemic encephalopathy (HIE). Thrombin preconditioning significantly enhances the neuroprotective anti-oxidative, anti-apoptotic, and anti-cytotoxic effects of naïve MSCs against oxygen-glucose deprivation (OGD) of cortical neurons in vitro. Severe HIE was induced in vivo using unilateral carotid artery ligation and hypoxia for 2 h and confirmed using brain magnetic resonance imaging (MRI) involving >40% of ipsilateral hemisphere at postnatal day (P) 7 in newborn rats. Delayed intraventricular transplantation of 1 × 105 thrombin preconditioned but not naïve MSCs at 24 h after hypothermia significantly enhanced observed anti-inflammatory, anti-astroglial, and anti-apoptotic effects and the ensuing brain infarction; behavioral tests, such as cylinder rearing and negative geotaxis tests, were conducted at P42. In summary, thrombin preconditioning of human Wharton's jelly-derived MSCs significantly boosted the neuroprotective effects of naïve MSCs against OGD in vitro by enhancing their anti-oxidative, anti-apoptotic, and anti-cytotoxic effects, and significantly attenuated the severe HIE-induced brain infarction and improved behavioral function tests in vivo by maximizing their paracrine anti-inflammatory, anti-astroglial, and anti-apoptotic effects.


Assuntos
Hipóxia-Isquemia Encefálica/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Trombina/farmacologia , Animais , Apoptose , Hipóxia Celular , Células Cultivadas , Hipóxia Fetal/complicações , Humanos , Hipóxia-Isquemia Encefálica/etiologia , Recém-Nascido , Masculino , Ratos , Ratos Sprague-Dawley
9.
J Clin Med ; 8(4)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003433

RESUMO

The aim of this study was to determine the optimal preconditioning regimen for the wound healing therapeutic efficacy of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs). To this end, we compared various preconditioning regimens for both the quantitative and qualitative production of MSC-derived EVs, and their therapeutic efficacy for proangiogenic activity in vitro and cutaneous wound healing in vivo. After preconditioning with thrombin (40 U), H2O2 (50 µM), lipopolysaccharide (1 µg/mL), or hypoxia (10% O2), EV secretion was assessed quantitatively by measuring production per cell and protein quantification, and qualitatively by measuring a proteome profiler and an enzyme-linked immunosorbent assay (ELISA) contained within EVs. The therapeutic efficacy of EVs was assessed in vitro by proliferation, migration and tube formation assays of human umbilical cord blood endothelial cells (HUVECs), and in vivo by quantification of cutaneous wound healing. Thrombin preconditioning optimally boosted EV production and enriched various growth factors including vascular endothelial growth factor and angiogenin contained within EVs compared to other preconditioning regimens. Thrombin preconditioning optimally enhanced proliferation, the migration and tube formation of HUVECs in vitro via pERK1/2 and pAKT signaling pathways, and cutaneous wound healing in vivo compared to other preconditioning regimens. Thrombin preconditioning exhibited optimal therapeutic efficacy compared with other preconditioning regimens in promoting proangiogenic activity in vitro and in enhancing cutaneous wound healing in vivo. These preconditioning regimen-dependent variations in therapeutic efficacy might be mediated by boosting EV production and enriching their cargo content.

10.
Yonsei Med J ; 60(5): 484-486, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31016912

RESUMO

Infantile cortical hyperostosis, or Caffey's disease, usually presents with typical radiological features of soft tissue swelling and cortical thickening of the underlying bone. The disease can be fatal when it presents antenatally, especially before a gestational age of 35 weeks. This fatal, premature form of the disease is known to occur in various ethnic groups around the globe, and approximately 30 cases have been reported in English literature. This paper is unique in that it is the first paper to report a lethal form of prenatal-type infantile cortical hyperostosis diagnosed in South Korea. Born at gestational age of 27 weeks and 4 days, the patient had typical features of polyhydramnios, anasarca, hyperostosis of multiple bones, micrognathia, pulmonary hypoplasia, and hepatomegaly. The patient was hypotonic, and due to pulmonary hypoplasia and persistent pulmonary hypertension, had to be supported with high frequency ventilation throughout the entire hospital course. Due to the disease entity itself, as well as prolonged parenteral nutrition, liver failure progressed, and the patient expired on day 38 when uncontrolled septic shock was superimposed. The chromosome karyotype of the patient was normal, 46, XX, and COL1A1 gene mutation was not detected.


Assuntos
Hiperostose Cortical Congênita/patologia , Adulto , Evolução Fatal , Feminino , Idade Gestacional , Humanos , Hiperostose Cortical Congênita/diagnóstico por imagem , Recém-Nascido , Masculino , Gravidez , República da Coreia
11.
PLoS One ; 14(2): e0212256, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30759169

RESUMO

This study aimed to determine the natural course of patent ductus arteriosus (PDA) with noninterventional conservative management and whether the presence and/or prolonged duration of hemodynamically significant (HS) PDA increased the risk of mortality and morbidities in extremely preterm (EPT) infants. We retrospectively reviewed the medical records of EPT infants born at 23-28 weeks of gestation (n = 195) from January 2011 to June 2014, when PDA was managed with noninterventional conservative treatment. We stratified infants into three subgroups of 23-24, 25-26, and 27-28 weeks and analyzed the prevalence and natural evolution of HS PDA, defined as ventilator dependency and PDA size ≥2 mm. Multivariate regression analyses determined if the presence and/or prolonged duration of HS PDA increased the risk for mortality and/or morbidities. The overall incidence of HS PDA was 57% (111/195) at the end of the first postnatal week. In subgroup analyses, infants with 23-24 weeks of gestation had the highest incidence (93%, 50/54), with 64% (47/74) for 25-26 weeks and 21% (14/67) for 27-28 weeks. Six (5%) of 111 infants with HS PDA were discharged without ductus closure, 4 had spontaneous PDA closure on follow up, and device closure was performed for 2 infants. In the multivariate analyses, the presence or prolonged duration (per week) of HS PDA was not associated with the risk of mortality and/or morbidities. Spontaneous closure of HS PDA was mostly achieved, even in EPT infants, with a noninterventional conservative approach. In conclusion, our data showed the incidence and natural course of HS PDA in EPT infants and suggested that the presence or prolonged duration of HS PDA might not increase the rate of mortality or morbidities.


Assuntos
Permeabilidade do Canal Arterial , Canal Arterial/fisiopatologia , Mortalidade Infantil , Lactente Extremamente Prematuro , Tratamento Conservador , Permeabilidade do Canal Arterial/mortalidade , Permeabilidade do Canal Arterial/fisiopatologia , Permeabilidade do Canal Arterial/terapia , Feminino , Seguimentos , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco
12.
J Matern Fetal Neonatal Med ; 32(12): 1938-1945, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29279020

RESUMO

OBJECTIVE: To determine the updated outcomes of preterm infants with acute hypoxic respiratory failure attributable to presumed pulmonary hypoplasia (PH) following maternal midtrimester prolonged preterm premature rupture of membranes (PPROM). STUDY DESIGN: Among preterm infants with birthweight <1500 g and 23-34 weeks gestational age in a single center, infants exposed to maternal prolonged (≥7 days) PPROM before 25 gestational weeks (PPPROM25, n = 76) were retrospectively reviewed. They were 1:1 matched with infants of matched control group (n = 76) who were unexposed to or exposed to maternal PPROM within 24 hours of delivery by year, gestational age, and weight at birth, sex, and antenatal steroid exposure. The PPPROM25 group was subdivided into infants with and without acute hypoxic respiratory failure attributable to PH (with PH, n = 20, without PH, n = 56, respectively). Clinical characteristics and major outcomes were compared. Risk factors for mortality and morbidity were analyzed using a multivariate logistic regression in the PPPROM25 group. RESULTS: The PH incidence rates were 1.3 and 26.3% and in the matched control and PPPROM25 group, respectively (p < .05). The survival rates were 92.1 and 81.6% in the matched control and PPPROM25 group (p > .05); 87.5 in the PPPROM25 group without PH and 65.0% in group with PH, respectively (p < .05). While there were no significant differences between matched control and PPROM25 group, the PPROM25 with PH group had a significantly higher rate of periventricular leukomalacia (PVL) and composite morbidity, including mortality, bronchopulmonary dysplasia, high-grade intraventricular hemorrhage, and PVL than PPPROM25 without PH group. PH was a significant risk factor for mortality and composite morbidity in the PPPROM25 group. CONCLUSIONS: Despite the improved outcomes in the infants with maternal prolonged PPROM before 25 gestational weeks, presumed PH is still a significant risk factor for their mortality and morbidity.


Assuntos
Ruptura Prematura de Membranas Fetais/mortalidade , Síndrome do Desconforto Respiratório do Recém-Nascido/mortalidade , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Gravidez , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco
13.
Stem Cell Res Ther ; 9(1): 326, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30463591

RESUMO

BACKGROUND: Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have been shown to prevent brain damage and improve neurocognition following intraventricular hemorrhage (IVH). However, the molecular mechanisms underlying the effects of hUCB-MSCs are still elusive. Thus, as the hippocampus is essential for learning, memory, and cognitive functions and is intimately involved in the ventricular system, making it a potential site of IVH-induced injury, we determined the molecular basis of the effects of hUCB-derived MSCs on hippocampal neurogenesis and the recovery of hippocampal neural circuits after IVH in a rodent model. METHODS: We inflicted severe IVH injury on postnatal day 4 (P4) in rats. After confirmation of successful induction of IVH using MRI (P5), intracerebroventricular administration of MSCs (ICV-MSC) was performed at 2 days post-injury (P6). For hippocampal synaptic determination, a rat entorhinal-hippocampus (EH) organotypic slice co-culture (OSC) was performed using day 3 post-IVH brains (P7) with or without ICV-MSCs. A similar strategy of experiments was applied to those rats receiving hUCB-MSC transfected with BDNF-Si-RNA for knockdown of BDNF or scrambled siRNA controls after IVH. The molecular mechanism of the MSCs effects on neurogenesis and the attenuation of neuron death was determined by evaluation of BDNF-TrkB-Akt-CREB signaling axis. RESULTS: We showed that treatment with hUCB-MSCs attenuated neuronal loss and promoted neurogenesis in the hippocampus, an area highly vulnerable to IVH-induced brain injury. hUCB-MSCs activate BDNF-TrkB receptor signaling, eliciting intracellular activation of Akt and/or Erk and subsequent phosphorylation of CREB, which is responsible for promoting rat BDNF transcription. In addition to the beneficial effects of neuroprotection and neurogenesis, hUCB-MSCs also contribute to the restoration of impaired synaptic circuits in the hippocampus and improve neurocognitive functions in IVH-injured neonatal rat through BDNF-TrkB-CREB signaling axis activation. CONCLUSIONS: Our data suggest that hUCB-MSCs possess therapeutic potential for treating neuronal loss and neurocognitive dysfunction in IVH through the activation of intracellular TrkB-CREB signaling that is invoked by hUCB-MSC-secreted BDNF.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Hemorragia Cerebral Intraventricular/terapia , Hipocampo/lesões , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína de Ligação a CREB/genética , Modelos Animais de Doenças , Hipocampo/citologia , Humanos , Células-Tronco Mesenquimais/citologia , Neurogênese , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Cordão Umbilical/citologia
14.
PLoS One ; 13(10): e0206306, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30359428

RESUMO

The aim of this study was done to determine whether dexamethasone treatment prevents posthemorrhagic hydrocephalus (PHH) development and attenuates brain damage after severe IVH in newborn rats. Severe IVH was induced by injecting; 100 µL of blood into each lateral ventricle of postnatal day 4 (P4) Sprague-Dawley rats. Dexamethasone was injected intraperitoneally into rat pups at a dose of 0.5 mg/kg, 0.3 mg/kg, and 0.1 mg/kg on P5, P6, and P7, respectively. Serial brain magnetic resonance imaging and behavioral function tests, such as the negative geotaxis test and the rotarod test, were performed. On P32, brain tissues were obtained for histological and biochemical analyses. Dexamethasone treatment significantly improved the severe IVH-induced increase in the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling-positive cells, glial fibrillary acidic protein-positive astrocytes and ED-1 positive microglia, and the decrease in myelin basic protein. IVH reduced a survival of 71%, that showed a tendency to improve to 86% with dexamethasone treatment, although the result was not statistically significant. However, dexamethasone failed to prevent the progression to PHH and did not significantly improve impaired behavioral tests. Similarly, dexamethasone did not decrease the level of inflammatory cytokines such as interleukin (IL) -1α and ß, IL-6, and tumor necrosis factor-α after severe IVH. Despite its some neuroprotective effects, dexamethasone failed to improve the progress of PHH and impaired behavioral tests after severe IVH.


Assuntos
Encéfalo/patologia , Hemorragia Cerebral Intraventricular/complicações , Dexametasona/uso terapêutico , Hidrocefalia/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Animais , Encéfalo/metabolismo , Citocinas/metabolismo , Imuno-Histoquímica , Imagem por Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley
15.
Pediatr Res ; 84(5): 778-785, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30188499

RESUMO

OBJECTIVE: Neonatal meningitis caused by Escherichia coli results in significant mortality and neurological disabilities, with few effective treatments. Recently, we demonstrated that human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) transplantation attenuated E. coli-induced severe pneumonia, primarily by reducing inflammation and enhancing bacterial clearance. This study aimed to determine whether intraventricular transplantation of hUCB-MSCs attenuated the brain injury in E. coli meningitis in newborn rats. METHODS: Meningitis without concomitant bacteremia was induced by intraventricular injection of 5 × 102 colony forming units of K1 (-) E. coli in rats at postnatal day (P)11, and hUCB-MSCs (1 × 105) were transplanted intraventricularly 6 h after induction of meningitis. Antibiotics was started 24 h after modeling. RESULT: Meningitis modeling induced robust proliferation of E. coli in the cerebrospinal fluid and increased mortality in rat pups, and MSC transplantation significantly reduced this bacterial growth and the mortality rate. Impaired sensorimotor function in the meningitis rats was ameliorated by MSCs injection. MSCs transplantation also attenuated meningitis caused brain injury including cerebral ventricular dilatation, brain cell death, reactive gliosis, and inflammatory response. CONCLUSION: Intraventricular transplantation of hUCB-MSCs significantly improved survival and attenuated the brain injury via anti-inflammatory and antibacterial effects in experimental neonatal E. coli meningitis.


Assuntos
Lesões Encefálicas/prevenção & controle , Meningite devida a Escherichia coli/terapia , Transplante de Células-Tronco Mesenquimais , Animais , Animais Recém-Nascidos , Peso Corporal , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Contagem de Colônia Microbiana , Citocinas/metabolismo , Escherichia coli/isolamento & purificação , Mediadores da Inflamação/metabolismo , Imagem por Ressonância Magnética , Meningite devida a Escherichia coli/complicações , Meningite devida a Escherichia coli/diagnóstico por imagem , Meningite devida a Escherichia coli/metabolismo , Ratos , Ratos Sprague-Dawley , Taxa de Sobrevida
16.
Stem Cells Transl Med ; 7(12): 847-856, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30133179

RESUMO

We previously demonstrated that transplanting mesenchymal stem cells (MSCs) improved recovery from brain injury induced by severe intraventricular hemorrhage (IVH) in newborn rats. To assess the safety and feasibility of MSCs in preterm infants with severe IVH, we performed a phase I dose-escalation clinical trial. The first three patients received a low dose of MSCs (5 × 106 cells/kg), and the next six received a high dose (1 × 107 cells/kg). We assessed adverse outcomes, including mortality and the progress of posthemorrhagic hydrocephalus. Intraventricular transplantation of MSCs was performed in nine premature infants with mean gestational age of 26.1 ± 0.7 weeks and birth weight of 808 ± 85 g at 11.6 ± 0.9 postnatal days. Treatment with MSCs was well tolerated, and no patients showed serious adverse effects or dose-limiting toxicities attributable to MSC transplantation. There was no mortality in IVH patients receiving MSCs. Infants who underwent shunt surgery showed a higher level of interleukin (IL)-6 in cerebrospinal fluid (CSF) obtained before MSC transplantation in comparison with infants who did not receive a shunt. Levels of IL-6 and tumor necrosis factor-α in initially obtained CSF correlated significantly with baseline ventricular index. Intraventricular transplantation of allogeneic human UCB-derived MSCs into preterm infants with severe IVH is safe and feasible, and warrants a larger, and controlled, phase II study. Stem Cells Translational Medicine 2018;7:847-856.


Assuntos
Lesões Encefálicas/terapia , Hemorragia Cerebral/patologia , Transplante de Células-Tronco Mesenquimais , Encéfalo/diagnóstico por imagem , Lesões Encefálicas/etiologia , Hemorragia Cerebral/complicações , Sangue Fetal/citologia , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Interleucina-6/líquido cefalorraquidiano , Imagem por Ressonância Magnética , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano
17.
Sci Rep ; 8(1): 7665, 2018 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29769612

RESUMO

Recently, we have demonstrated that concurrent hypothermia and mesenchymal stem cells (MSCs) transplantation synergistically improved severe neonatal hypoxic ischemic encephalopathy (HIE). The current study was designed to determine whether hypothermia could extend the therapeutic time window of MSC transplantation for severe neonatal HIE. To induce HIE, newborn rat pups were exposed to 8% oxygen for 2 h following unilateral carotid artery ligation on postnatal day (P) 7. After approving severe HIE involving >50% of the ipsilateral hemisphere volume, hypothermia (32 °C) for 2 days was started. MSCs were transplanted 2 days after HIE modeling. Follow-up brain MRI, sensorimotor function tests, assessment of inflammatory cytokines in the cerebrospinal fluid (CSF), and histological evaluation of peri-infarction area were performed. HIE induced progressively increasing brain infarction area over time, increased cell death, reactive gliosis and brain inflammation, and impaired sensorimotor function. All these damages observed in severe HIE showed better, robust improvement with a combination treatment of hypothermia and delayed MSC transplantation than with either stand-alone therapy. Hypothermia itself did not significantly reduce brain injury, but broadened the therapeutic time window of MSC transplantation for severe newborn HIE.


Assuntos
Lesões Encefálicas/terapia , Modelos Animais de Doenças , Hipotermia , Hipóxia-Isquemia Encefálica/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Animais Recém-Nascidos , Comportamento Animal , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Masculino , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley
18.
Exp Mol Med ; 50(4): 26, 2018 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-29650962

RESUMO

We previously reported the role of vascular endothelial growth factor (VEGF) secreted by mesenchymal stem cells (MSCs) in protecting against neonatal hyperoxic lung injuries. Recently, the paracrine protective effect of MSCs was reported to be primarily mediated by extracellular vesicle (EV) secretion. However, the therapeutic efficacy of MSC-derived EVs and the role of the VEGF contained within EVs in neonatal hyperoxic lung injury have not been elucidated. The aim of the study was to determine whether MSC-derived EVs attenuate neonatal hyperoxic lung injury and, if so, whether this protection is mediated via the transfer of VEGF. We compared the therapeutic efficacy of MSCs, MSC-derived EVs with or without VEGF knockdown, and fibroblast-derived EVs in vitro with a rat lung epithelial cell line challenged with H2O2 and in vivo with newborn Sprague-Dawley rats exposed to hyperoxia (90%) for 14 days. MSCs (1 × 105 cells) or EVs (20 µg) were administered intratracheally on postnatal day 5. The MSCs and MSC-derived EVs, but not the EVs derived from VEGF-knockdown MSCs or fibroblasts, attenuated the in vitro H2O2-induced L2 cell death and the in vivo hyperoxic lung injuries, such as impaired alveolarization and angiogenesis, increased cell death, and activated macrophages and proinflammatory cytokines. PKH67-stained EVs were internalized into vascular pericytes (22.7%), macrophages (21.3%), type 2 epithelial cells (19.5%), and fibroblasts (4.4%) but not into vascular endothelial cells. MSC-derived EVs are as effective as parental MSCs for attenuating neonatal hyperoxic lung injuries, and this protection was mediated primarily by the transfer of VEGF.


Assuntos
Vesículas Extracelulares/metabolismo , Hiperóxia/metabolismo , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Animais Recém-Nascidos , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Sangue Fetal/citologia , Técnicas de Silenciamento de Genes , Humanos , Recém-Nascido , Mediadores da Inflamação/metabolismo , Lesão Pulmonar/diagnóstico , Lesão Pulmonar/terapia , Estresse Oxidativo , Ratos , Fator A de Crescimento do Endotélio Vascular/genética
19.
PLoS One ; 13(2): e0192232, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29438382

RESUMO

We explored GA, BW, Apgar score, CRIB II score, and serum albumin levels as univariate predictors of mortality in extremely low birth weight infants. Medical records of 564 extremely low birth weight infants were reviewed retrospectively. The infants were grouped as survivors (group I), expired ≤ 7th postnatal day (group II), and expired > 7th postnatal day (group III). The predictive value for mortality of gestational age, birth weight, Apgar scores at 1 and 5 min, clinical risk index for babies II score, and first and lowest serum albumin levels was assessed by calculating the associated area under the curve (AUC) in receiver operating characteristic (ROC) curves. The overall survival and mortality rates of groups I, II, and III were 81.0% (457/564), 7.6% (43/564), and 11.4% (64/564), respectively. Birth weight, Apgar scores at 1 and 5 min, and first serum albumin levels were significantly higher, while the clinical risk index for babies II score was significantly lower in group I when compared to groups II and III. Gestational age and lowest serum albumin level in group I were significantly higher than group III, but not group II. However, gestational age, birth weight, and clinical risk index for babies II score showed gestational age dependent variations regardless of survival or mortality. Apgar score at 5 min (0.756) and lowest serum albumin level (0.771) demonstrated the highest AUC of the ROC curve in predicting mortality in group II and III, respectively. In conclusion, Apgar score at 5 min and lowest serum albumin level were the most effective predictors for mortality in extremely low birth weight infants during ≤ 7th and > 7th postnatal days, respectively.


Assuntos
Índice de Apgar , Peso ao Nascer , Idade Gestacional , Mortalidade Infantil , Albumina Sérica/análise , Causas de Morte , Feminino , Humanos , Lactente , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Masculino , Curva ROC
20.
Pediatr Res ; 83(1-2): 214-222, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28972960

RESUMO

Mesenchymal stem cell (MSC) transplantation represents the next breakthrough in the treatment of currently intractable and devastating neonatal disorders with complex multifactorial etiologies, including bronchopulmonary dysplasia, hypoxic ischemic encephalopathy, and intraventricular hemorrhage. Absent engraftment and direct differentiation of transplanted MSCs, and the "hit-and-run" therapeutic effects of these MSCs suggest that their pleiotropic protection might be attributable to paracrine activity via the secretion of various biologic factors rather than to regenerative activity. The transplanted MSCs, therefore, exert their therapeutic effects not by acting as "stem cells," but rather by acting as "paracrine factors factory." The MSCs sense the microenvironment of the injury site and secrete various paracrine factors that serve several reparative functions, including antiapoptotic, anti-inflammatory, antioxidative, antifibrotic, and/or antibacterial effects in response to environmental cues to enhance regeneration of the damaged tissue. Therefore, the therapeutic efficacy of MSCs might be dependent on their paracrine potency. In this review, we focus on recent investigations that elucidate the specifically regulated paracrine mechanisms of MSCs by injury type and discuss potential strategies to enhance paracrine potency, and thus therapeutic efficacy, of transplanted MSCs, including determining the appropriate source and preconditioning strategy for MSCs and the route and timing of their administration.


Assuntos
Doenças do Recém-Nascido/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Apoptose , Diferenciação Celular , Engenharia Genética , Humanos , Recém-Nascido , Comunicação Parácrina , Ratos , Células-Tronco/citologia , Pesquisa Médica Translacional
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