RESUMEN
Despite recent advances in neonatal intensive care medicine, neonatal disorders such as (bronchopulmonary dysplasia [BPD], intraventricular hemorrhage [IVH], and hypoxic ischemic encephalopathy [HIE]) remain major causes of death and morbidity in survivors, with few effective treatments being available. Recent preclinical studies have demonstrated the pleiotropic host injury-responsive paracrine protective effects of cell therapy especially with mesenchymal stromal cells (MSCs) against BPD, IVH, and HIE. These findings suggest that MSCs therapy might emerge as a novel therapeutic modality for these currently devastating neonatal disorders with complex multifactorial etiologies. Although early-phase clinical trials suggest their safety and feasibility, their clinical therapeutic benefits have not yet been proven. Therefore, based on currently available preclinical research and clinical trial data, we focus on critical issues that need to be addressed for future successful clinical trials and eventual clinical translation such as selecting the right patient and optimal cell type, route, dose, and timing of MSCs therapy for neonatal disorders such as BPD, HIE, and IVH.
RESUMEN
BACKGROUND: Acute lung injury (ALI) following pneumonia involves uncontrolled inflammation and tissue injury, leading to high mortality. We previously confirmed the significantly increased cargo content and extracellular vesicle (EV) production in thrombin-preconditioned human mesenchymal stromal cells (thMSCs) compared to those in naïve and other preconditioning methods. This study aimed to investigate the therapeutic efficacy of EVs derived from thMSCs in protecting against inflammation and tissue injury in an Escherichia coli (E. coli)-induced ALI mouse model. METHODS: In vitro, RAW 264.7 cells were stimulated with 0.1 µg/mL liposaccharides (LPS) for 1 h, then were treated with either PBS (LPS Ctrl) or 5 × 107 particles of thMSC-EVs (LPS + thMSC-EVs) for 24 h. Cells and media were harvested for flow cytometry and ELISA. In vivo, ICR mice were anesthetized, intubated, administered 2 × 107 CFU/100 µl of E. coli. 50 min after, mice were then either administered 50 µL saline (ECS) or 1 × 109 particles/50 µL of thMSC-EVs (EME). Three days later, the therapeutic efficacy of thMSC-EVs was assessed using extracted lung tissue, bronchoalveolar lavage fluid (BALF), and in vivo computed tomography scans. One-way analysis of variance with post-hoc TUKEY test was used to compare the experimental groups statistically. RESULTS: In vitro, IL-1ß, CCL-2, and MMP-9 levels were significantly lower in the LPS + thMSC-EVs group than in the LPS Ctrl group. The percentages of M1 macrophages in the normal control, LPS Ctrl, and LPS + thMSC-EV groups were 12.5, 98.4, and 65.9%, respectively. In vivo, the EME group exhibited significantly lower histological scores for alveolar congestion, hemorrhage, wall thickening, and leukocyte infiltration than the ECS group. The wet-dry ratio for the lungs was significantly lower in the EME group than in the ECS group. The BALF levels of CCL2, TNF-a, and IL-6 were significantly lower in the EME group than in the ECS group. In vivo CT analysis revealed a significantly lower percentage of damaged lungs in the EME group than in the ECS group. CONCLUSION: Intratracheal thMSC-EVs administration significantly reduced E. coli-induced inflammation and lung tissue damage. Overall, these results suggest therapeutically enhanced thMSC-EVs as a novel promising therapeutic option for ARDS/ALI.
Asunto(s)
Lesión Pulmonar Aguda , Vesículas Extracelulares , Células Madre Mesenquimatosas , Ratones Endogámicos ICR , Trombina , Animales , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/microbiología , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/terapia , Ratones , Células Madre Mesenquimatosas/metabolismo , Células RAW 264.7 , Trombina/metabolismo , Escherichia coli , Masculino , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/patología , Infecciones por Escherichia coli/terapia , Resultado del Tratamiento , Modelos Animales de Enfermedad , HumanosRESUMEN
This study investigated the predictive factors for perinatal bacterial transmission in very-low-birth-weight infants (VLBWIs) born to mothers with a history of intrapartum colonization. We retrospectively reviewed the medical records of 173 VLBWIs, wherein pathogens were confirmed in maternal cultures obtained from the blood, urine, and vagina during the intrapartum period from 2013 to 2020. Newborns were categorized based on microbiological tests, including gastric aspirates, endotracheal aspirates, blood, and skin/nasal swab cultures collected immediately after birth. Infants whose cultures matched their maternal pathogens were categorized into the "transmission group" (n = 45), while those who tested negative were assigned to the "control group" (n = 128). The predominant maternal-colonizing pathogen observed was Escherichia coli (30.6%), which also emerged as the primary colonizing pathogen in neonates (35.6%). Transmission group had higher incidences of maternal leukocytosis, chorioamnionitis, and cervical cerclage. Regarding neonatal characteristics, the transmission group demonstrated lower initial base excesses (- 6.3 ± 3.9 vs. - 9.2 ± 4.9, P < 0.05) and higher C-reactive protein levels (0.1 ± 0.3 vs. 0.4 ± 0.8, P < 0.05). Notably, regarding major neonatal outcomes, transmission group had higher mortality rates and incidences of severe intraventricular hemorrhage. These findings may be useful for making decisions when considering antibiotic treatment for infants with a history of maternal colonization.
Asunto(s)
Recién Nacido de muy Bajo Peso , Transmisión Vertical de Enfermedad Infecciosa , Humanos , Femenino , Recién Nacido , Estudios Retrospectivos , Embarazo , Masculino , Adulto , Complicaciones Infecciosas del Embarazo/microbiología , Madres , Factores de Riesgo , Escherichia coli/aislamiento & purificaciónRESUMEN
BACKGROUND: Post-hemorrhagic hydrocephalus (PHH), a common complication of severe intraventricular hemorrhage (IVH) in very low birth weight (BW) infants, is associated with significant morbidity and poor neurological outcomes. The objective of this study was to assess the current status of PHH and analyze the risk factors associated with the necessity of treatment for PHH in infants born between 22 and 28 weeks of gestation, specifically those with severe IVH (grade 3 or 4). METHODS: The analysis was conducted on 1,097 infants who were born between 22-28 gestational weeks and diagnosed with severe IVH, using data from the Korean Neonatal Network. We observed that the prevalence of PHH requiring treatment was 46.3% in infants with severe IVH. RESULTS: Higher rates of mortality, transfer during admission, cerebral palsy, and ventriculoperitoneal shunt after discharge were higher in infants with PHH than in those without PHH. PHH in severe IVH was associated with a higher rate of pulmonary hemorrhage, seizures, and IVH grade 4 in the entire cohort. In addition, it was associated with a lower rate of small for gestational age and chorioamnionitis. In the subgroup analysis, high BW, outborn status, pulmonary hemorrhage, seizure, sepsis, and IVH grade 4 were associated with a higher incidence of PHH between 22 and 25 gestational weeks (GW). In infants born between 26 and 28 GW, a higher incidence of PHH was associated with seizures and IVH grade 4. CONCLUSION: It is necessary to maintain meticulous monitoring and neurological intervention for infants with PHH not only during admission but also after discharge. In addition, identifying the clinical factors that increase the likelihood of developing PHH from severe IVH is crucial.
Asunto(s)
Edad Gestacional , Hidrocefalia , Humanos , Hidrocefalia/complicaciones , República de Corea/epidemiología , Recién Nacido , Femenino , Masculino , Factores de Riesgo , Estudios de Cohortes , Hemorragia Cerebral/complicaciones , Índice de Severidad de la Enfermedad , Hemorragia Cerebral Intraventricular/complicaciones , Derivación Ventriculoperitoneal , Lactante , Recién Nacido de muy Bajo PesoRESUMEN
This study investigated whether late pulmonary hypertension (LPH) independently increases the risk of long-term mortality or neurodevelopmental delay (NDD) in extremely preterm infants (EPIs) with severe bronchopulmonary dysplasia (BPD). Using prospectively collected data from the Korean Neonatal Network, we included EPIs with severe BPD born at 22-27 weeks' gestation between 2013 and 2021. EPIs having severe BPD with LPH (LPH, n = 124) were matched 1:3 with those without pulmonary hypertension (PH) as controls (CON, n = 372), via propensity score matching. LPH was defined as PH with the initiation of medication after 36 weeks' corrected age (CA). Long-term mortality after 36 weeks' CA or NDD at 18-24 months' CA was analyzed. NDD was assessed using composite scores based on various neurodevelopmental assessment modalities. LPH had significantly higher long-term mortality or NDD (45.2% vs. 23.1%, P < 0.001), mortality (24.2% vs. 4.84%, P < 0.001), and NDD (68.4% vs. 37.8%, P = 0.001), respectively than CON, even after adjusting for different demographic factors. Multivariable regression demonstrated that LPH independently increased the risk of mortality or NDD (adjusted odds ratio, 1.95; 95% confidence intervals, 1.17-3.25). When LPH occurs in EPIs with severe BPD, special monitoring and meticulous care for long-term survival and neurodevelopment are continuously needed.
Asunto(s)
Displasia Broncopulmonar , Hipertensión Pulmonar , Lactante , Humanos , Recién Nacido , Displasia Broncopulmonar/complicaciones , Displasia Broncopulmonar/tratamiento farmacológico , Recien Nacido Extremadamente Prematuro , Hipertensión Pulmonar/tratamiento farmacológico , Edad GestacionalRESUMEN
Mitochondrial DNA (mtDNA) released from dead or injured cells can activate inflammation, and mesenchymal stem cell (MSC) transplantation can reduce inflammation and injury. However, it has not been tested whether the release of mtDNA can be reduced by MSC transplantation. We hypothesized that the level of extracellular mtDNA would be increased after hyperoxia-induced lung injury but reduced after lung injury attenuation by MSC therapy in our newborn rat model. In an in vitro study using a rat lung epithelial L2 cell line, we found that the level of extracellular mtDNA was significantly increased with H2O2-induced cell death but reduced after MSC co-incubation. In an in vivo study, we confirmed that the levels of cell death, extracellular mtDNA, and inflammatory cytokines were significantly increased in hyperoxic newborn rat lungs but reduced after MSC transplantation. The levels of extracellular mtDNA were significantly and positively correlated with the levels of the inflammatory cytokines. The TLR9/MyD88/NF-κB pathway, which is activated by binding to mtDNA, was also significantly upregulated but downregulated after MSC transplantation. We found a significant positive correlation between inflammatory cytokines and extracellular mtDNA in intubated neonates. The levels of inflammatory cytokines and extracellular mtDNA changed over time in a similar pattern in transtracheal aspirate samples from intubated neonates. In conclusion, increased levels of extracellular mtDNA are associated with increased inflammation in hyperoxia-induced lung injury, and attenuation of lung inflammation by MSC therapy is associated with reduced levels of extracellular mtDNA.
RESUMEN
This scoping review aimed to explore the characteristics of neonatal palliative care in the neonatal intensive care unit, including the features, contents, and experiences of infants, parents, and nurses during palliative care. Five databases (PubMed, Cochrane, CINAHL, Research Information Sharing Service, and Korean Studies Information Service System) were searched to identify relevant articles published between 2011 and 2020. From the systematic search and review process, 13 studies that met the eligibility criteria were selected for the analysis. From the literature review, 2 key principles were found to facilitate neonatal palliative care: family-centered care and integrative care in the neonatal intensive care unit. In addition, the themes found in this review included (1) providing comfortable care to dying infants with respect to infants and offering parents choices, (2) therapeutic communication, (3) support with respect, and (4) bereavement care for parents of dying infants in the neonatal intensive care unit. Caregivers require effective communication, manpower support, emotional support, educational programs, and well-defined protocols. The evidence mapped and synthesized in this review indicates the need to facilitate the provision of palliative care in the neonatal intensive care unit in line with the unique needs of infants, parents, and nurses.
Asunto(s)
Cuidados Paliativos al Final de la Vida , Atención de Enfermería , Humanos , Lactante , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Cuidados Paliativos/psicología , Padres/psicologíaRESUMEN
Although it has been suggested that toll-like receptor (TLR) 3 and TLR4 activation alters mesenchymal stromal cells (MSCs)' immunoregulatory function as anti- or pro-inflammatory phenotypes, we have previously confirmed that TLR4-primed hUCB-MSCs alleviate lung inflammation and tissue injury in an E. coli-induced acute lung injury (ALI) mouse model. Therefore, we hypothesized that strong stimulation of TLR3 or TLR4 prompts hUCB-MSCs to exhibit an anti-inflammatory phenotype mediated by extracellular vesicles (EVs). In this study, we compared the anti-inflammatory effect of TLR3-primed and TLR4-primed hUCB-MSCs against an LPS-induced ALI in vitro model by treating MSCs, MSC-derived conditioned medium (CM), and MSC-derived extracellular vesicles (EVs). LPS-induced rat primary alveolar macrophage and RAW 264.7 cells were treated with naïve, TLR3-, and TLR4-primed MSCs and their derived CM and EVs. Flow cytometry and ELISA were used to evaluate M1-M2 polarization of macrophages and pro-inflammatory cytokine levels, respectively. LPS-stimulated macrophages showed significantly increased pro-inflammatory cytokines compared to those of the normal control, and the percentage of M2 macrophage phenotype was predominantly low. In reducing the inflammatory cytokines and enhancing M2 polarization, TLR3- and TLR4-primed MSCs were significantly more effective than the naïve MSCs, and this finding was also observed with the treatment of MSC-derived CMs and EVs. No significant difference between the efficacy of TLR3- and TLR-primed MSCs was observed. Strong stimulation of TLR3- and TLR4-stimulated hUCB-MSCs significantly reduced pro-inflammatory cytokine secretion from LPS-induced macrophages and significantly enhanced the M2 polarization of macrophages. We further confirmed that TLR-primed MSC-derived EVs can exert anti-inflammatory and immunosuppressive effects alone comparable to MSC treatment. We hereby suggest that in the LPS-induced macrophage in vitro model, EVs derived from both TLR3 and TLR4-primed MSCs can be a therapeutic candidate by promoting the M2 phenotype.
Asunto(s)
Lesión Pulmonar Aguda , Vesículas Extracelulares , Células Madre Mesenquimatosas , Ratones , Ratas , Animales , Receptor Toll-Like 3 , Lipopolisacáridos/toxicidad , Receptor Toll-Like 4 , Escherichia coli , Macrófagos , Citocinas , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/terapia , Antiinflamatorios/farmacología , Vesículas Extracelulares/fisiologíaRESUMEN
BACKGROUND: Though antenatal magnesium sulfate (MgSO4) is widely used for fetal neuroprotection, suspicions about the long-term neuroprotection of antenatal MgSO4 have been raised. METHODS: We investigated short- and long-term outcomes of antenatal MgSO4 use for 468 infants weighing < 1,500 g with a gestational age of 24-31 weeks. RESULTS: Short-term morbidities and the risk of developmental delay, hearing loss, and cerebral palsy at a corrected age of 18-24 months and 3 years of age did not decrease in the MgSO4 group (infants who were exposed to MgSO4 for any purpose) or neuroprotection group (infants who were exposed to MgSO4 for fetal neuroprotection) compared with the control group (infants who were not exposed to MgSO4). The z-scores of weight, height, and head circumference did not increase in the MgSO4 group or neuroprotection group compared with the control group. CONCLUSION: Antenatal MgSO4 including MgSO4 for neuroprotection did not have beneficial effects on long-term neurodevelopmental and growth outcomes.
Asunto(s)
Fármacos Neuroprotectores , Nacimiento Prematuro , Lactante , Humanos , Embarazo , Femenino , Recién Nacido , Sulfato de Magnesio/uso terapéutico , Nacimiento Prematuro/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Atención Prenatal , Recién Nacido de muy Bajo PesoRESUMEN
Standardized protocols have been designed and developed specifically for clinical information collection and obtaining trio genomic information from infants affected with congenital anomalies (CA) and their parents, as well as securing human biological resources. The protocols include clinical and genomic information collection on multiple CA that were difficult to diagnose using pre-existing screening methods. We obtained human-derived resources and genomic information from 138 cases, including 45 families of infants with CA and their parent trios. For the clinical information collection protocol, criteria for target patient selection and a consent system for collecting and utilizing research resources are crucial. Whole genome sequencing data were generated for all participants, and standardized protocols were developed for resource collection and manufacturing. We recorded the phenotype information according to the Human Phenotype Ontology term, and epidemiological information was collected through an environmental factor questionnaire. Updating and recording of clinical symptoms and genetic information that have been newly added or changed over time are significant. The protocols enabled long-term tracking by including the growth and development status that reflect the important characteristics of newborns. Using these clinical and genetic information collection protocols for CA, an essential platform for early genetic diagnosis and diagnostic research can be established, and new genetic diagnostic guidelines can be presented in the near future.
RESUMEN
Congenital cytomegalovirus (CMV) infection is a common cause of sensorineural hearing loss and neurodevelopmental impairment in newborns. However, congenital CMV infection cannot be diagnosed using samples collected more than 3 weeks after birth because testing after this time cannot distinguish between congenital infection and postnatal infection. Herein, we developed a robust loop-mediated isothermal amplification (LAMP) assay for the large-scale screening of newborns for congenital CMV infection. In contrast to conventional quantitative polymerase chain reaction (qPCR), which detects CMV within a dynamic range of 1.0 × 106 to 1.0 × 102 copies/µL, our quantitative LAMP assay (qLAMP) detects CMV within a dynamic range of 1.1 × 108 to 1.1 × 103 copies/µL. Moreover, the turnaround time for obtaining results following DNA extraction is 90 min in qPCR but only 15 min in qLamp. The colorimetric LAMP assay can also detect CMV down to 1.1 × 103 copies/µL within 30 min, irrespective of the type of heat source. Our LAMP assay can be utilized in central laboratories as an alternative to conventional qPCR for quantitative CMV detection, or for point-of-care testing in low-resource environments, such as developing countries, via colorimetric naked-eye detection. KEY POINTS: ⢠LAMP assay enables large-scale screening of newborns for congenital CMV infection. ⢠LAMP allows colorimetric or quantitative detection of congenital CMV infection. ⢠LAMP assay can be used as a point-of-care testing tool in low-resource environments.
RESUMEN
(1) Background: This study aimed to evaluate whether the implementation of a modified blood-sampling protocol, which focused on need-based laboratory testing and minimized venous sampling by replacing it with point-of-care testing (POCT) via capillary puncture, successfully reduced iatrogenic blood loss, incidence of anemia, and the frequency of blood transfusion among extremely low-birth-weight infants (ELBWIs) without negatively affecting neonatal outcomes. (2) Methods: A retrospective analysis was conducted on 313 ELBWIs with a gestational age (GA) of between 23 and 28 weeks and born between 2013 and 2019. The infants were divided into two groups corresponding to the periods before (period I) and after (period II) the implementation of the modified blood-sampling protocol in January 2016. Propensity score matching was conducted to minimize selection bias. Clinical data, including the frequency and amount of blood sampling, the frequency and volume of blood transfusion, and clinical characteristics, such as gestational age, birth weight, and neonatal outcome data, were collected and compared between the two groups. (3) Results: No significant differences in GA or birth weight between the two periods were observed. The total sampling volume a month after birth (16.7 ± 4.1 mL vs. 15.6 ± 4.4 mL, p = 0.03) and the total sampling volume during hospitalization days (51.4 ± 29.7 mL vs. 44.3 ± 27.5 mL, p = 0.04) in period II were significantly lower than those in period I. There were no differences in terms of anemia (hemoglobin 10.8 ± 2.2 vs. 11.0 ± 1.9, p = 0.43) and mortality or morbidity, such as intraventricular hemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, and sepsis, between the two periods. Although the transfusion frequency and amount did not present significant differences between the periods, we observed a positive correlation between the transfusion frequency and sampling volume (coefficient: 0.09, 95% CI: 0.08-0.11). (4) Conclusions: The modified blood-sampling protocol effectively reduced the level of iatrogenic blood loss without negatively affecting the neonatal outcomes.
RESUMEN
BACKGROUND: We previously performed a phase II randomised double-blind clinical trial of mesenchymal stromal cell (MSCs) transplantation to prevent bronchopulmonary dysplasia in extremely premature infants. Subsequently, we followed the infants enrolled in this clinical trial to determine the safety and effectiveness of MSCs against bronchopulmonary dysplasia at 5-year follow-up. METHODS: We evaluated infants at 5 years of age receiving placebo or MSCs in a prospective follow-up study. RESULTS: In terms of the primary end point of composite respiratory morbidities, including respiratory problem-related readmission, emergency department visits or oxygen therapy, the MSC group had a rate of 60.7% for composite morbidities, while the control group showed a tendency of higher rate of 83.9% for the same outcomes without statistical significance. In terms of the secondary outcomes, the MSC group infants showed a tendency of being less likely to visit emergency department (control 67.7% vs MSC 35.7%) and to receive oxygen therapy (control 29.0% vs MSC 3.6%). No difference was observed in the incidence of respiratory problem-related hospital readmission or wheezing episodes between the groups. CONCLUSION: Intratracheally instilled MSCs showed the possibility of potential to decrease respiratory symptom-related emergency department visits and oxygen therapy episodes in infants born extremely preterm during the 5 years after a phase II randomised controlled, double-blind trial of MSCs transplantation for bronchopulmonary dysplasia. This small size study suggests preliminary insights that can be further tested using larger sample sizes. TRIAL REGISTRATION NUMBER: NCT01897987.
Asunto(s)
Displasia Broncopulmonar , Recién Nacido , Lactante , Humanos , Displasia Broncopulmonar/terapia , Estudios de Seguimiento , Estudios Prospectivos , Células del Estroma , Oxígeno/uso terapéuticoRESUMEN
Mesenchymal stem cells (MSCs) have been studied as novel therapeutic agents because of their immunomodulatory properties in inflammatory diseases. The suppressor of cytokine signaling (SOCS) proteins are key regulators of the immune response and macrophage modulation. In the present study, we hypothesized that SOCS in MCSs might mediate macrophage modulation and tested this in a bacteria-induced acute lung injury (ALI) mouse model. The macrophage phenotype was observed in RAW264.7 alveolar macrophages exposed to lipopolysaccharide (LPS) in an in vitro model, and in the ALI mouse model induced by tracheal administration of Escherichia coli (1 × 107 CFU in 0.05mL PBS). In LPS-exposed RAW264.7 cells, the levels of markers of M1 macrophages, such as CD86 and pro-inflammatory cytokines (IL-1α, IL-1ß, IL-6 and TNF-α), significantly increased, but they significantly reduced after MSC treatment. Meanwhile, the levels of markers of M2 macrophages, such as CD204 and anti-inflammatory cytokines (IL-4 and IL-10), increased after LPS exposure, and further significantly increased after MSC treatment. This regulatory effect of MSCs on M1/M2 macrophage polarization was significantly abolished by SOCS3 inhibition. In the E. coli-induced ALI model, tissue injury and inflammation in the mouse lung were significantly attenuated by the transplantation of MSCs, but not by SOCS3-inhibited MSCs. The regulatory effect of MSCs on M1/M2 macrophage polarization was observed in the lung injury model but was significantly abolished by SOCS3 inhibition. Taken together, our findings suggest that SOCS3 is an important mediator for macrophage modulation in anti-inflammatory properties of MSCs.
Asunto(s)
Lesión Pulmonar Aguda , Células Madre Mesenquimatosas , Ratones , Animales , Proteína 3 Supresora de la Señalización de Citocinas/genética , Lipopolisacáridos/toxicidad , Escherichia coli , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/terapia , Proteínas Supresoras de la Señalización de Citocinas/genética , Antiinflamatorios , Interleucina-1alfa , PulmónRESUMEN
Neonatal brain injury resulting from various intractable disorders including intraventricular hemorrhage and hypoxic ischemic encephalopathy still remains a major cause of mortality and morbidities with few effective treatments. Recent preclinical research results showing the pleiotropic neuroprotective effects of stem cell therapy, specifically mesenchymal stem cells (MSCs), suggest that MSCs transplantation might be a promising new therapeutic modality for neuroprotection against the currently intractable and devastating neonatal brain injury with complex multifactorial etiology. This review summarizes recent advances in preclinical stem cell research for treating neonatal brain injury with a focus on the important issues including the mechanism of neuroprotection, and determining the ideal cell source, route, timing and dose of MSCs transplantation.
Asunto(s)
Lesiones Encefálicas , Hipoxia-Isquemia Encefálica , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Recién Nacido , Humanos , Trasplante de Células Madre Mesenquimatosas/métodos , Hemorragia Cerebral/terapia , Hipoxia-Isquemia Encefálica/terapia , Lesiones Encefálicas/terapiaRESUMEN
OBJECTIVE: Recent evidence suggests that the survival of peri-viable infants with birth weight (BW) ≤500 g could be improved with better care practices in the neonatal intensive care unit (NICU). This study aimed to investigate the care quality level of NICU-dependent variations in the survival rate of infants with BW ≤500 g. METHODS: To determine the quality of NICU care-dependent variations in the survival rate, 226 eligible infants of BW ≤500 g and ≥22 weeks gestation registered in the Korean Neonatal Network between 2013 and 2017 were grouped according to the survival rates of infants at 23-24 weeks gestation, reflecting the care quality level of each NICU as group I (≥50%, n = 107) and group II (<50%, n = 119). RESULTS: The survival rate of group I infants (40.2%, 43/107) was significantly higher than that of group II infants (14.3%, 17/119). Significantly reduced deaths from birth to the age of 7 days due to cardiorespiratory causes were the primary contributors to improved survival. In multivariable Cox hazard model analyses, besides the gestational age and BW, antenatal steroid use, cesarean section, pH, and base excess at admission were associated with improved infant survival. CONCLUSIONS: The survival rate of pre-viable infants with BW ≤500 g could be improved by providing better NICU quality care practices, including better cardiorespiratory management starting from delivery room resuscitation.
Asunto(s)
Cesárea , Cuidado Intensivo Neonatal , Recién Nacido , Humanos , Lactante , Femenino , Embarazo , Peso al Nacer , Tasa de Supervivencia , Estudios de Cohortes , Edad Gestacional , Unidades de Cuidado Intensivo Neonatal , República de Corea/epidemiologíaRESUMEN
BACKGROUND: While recent pieces of evidence suggest that discontinuation of levothyroxine replacement therapy (LRT) earlier than the current guidelines of 3 years is possible, the optimal duration of LRT for delayed hyperthyrotropinemia in extremely low birth weight infants (ELBWIs) remains unknown. OBJECTIVE: This study aimed to investigate the feasibility of early discontinuation of LRT for delayed hyperthyrotropinemia in ELBWIs. METHODS: The medical records of 92 ELBWIs who had shown delayed hyperthyrotropinemia, defined as a delayed rise in thyroid-stimulating hormone (TSH) levels to >20 µIU/mL after initial normal TSH level, were retrospectively reviewed to determine whether the duration of LRT affects the short-term outcomes at discharge from neonatal intensive care unit (NICU) and the long-term outcomes at the corrected age (CA) of 2 years. The infants were grouped into: no LRT required group (n = 21), short-term LRT given until the time of NICU discharge - 90 ± 64 (13-211) days group (n = 36), and long-term LRT given - 749 ± 333 (339-1,967) days group (n = 35). RESULTS: While mortality in the no LRT required group was significantly higher than that in the long-term LRT group, no significant differences were observed in short-term outcomes at discharge from NICU and long-term growth and neurodevelopmental outcomes at CA of 2 years between the short- and long-term LRT groups. CONCLUSIONS: Termination of LRT at around the time of discharge from NICU in well, clinically stable ELBWIs who have delayed hyperthyrotropinemia appears to be safe and feasible and avoids the risk of overtreatment.
Asunto(s)
Recien Nacido con Peso al Nacer Extremadamente Bajo , Tiroxina , Recién Nacido , Lactante , Humanos , Preescolar , Tiroxina/uso terapéutico , Estudios Retrospectivos , Tirotropina , Unidades de Cuidado Intensivo NeonatalRESUMEN
Formyl peptide receptor (FPR) 2 is known to play a critical role in regulating inflammation, including either the pro-inflammatory or pro-resolving effects. However, its role in neonatal hyperoxia-induced lung injury has not been delineated. In this study, we investigate whether mesenchymal stem cells (MSCs) attenuate hyperoxia-induced neonatal lung injury by regulating FPR2 activity. We observed a significant increase in FPR2 levels in alveolar macrophages (RAW264.7 cells) after H2O2-induced stress, which decreased after MSC treatment. In the H2O2-induction model, increased levels of inflammatory cytokines (IL-1α and TNF-α) were significantly reduced in RAW264.7 cells after treatment with WRW4, an inhibitor of FPR2, or MSCs. Viability of lung epithelial cells and endothelial cells was significantly improved when cultured in the conditioned media of RAW264.7 cells treated with WRW4 or MSCs, compared to when cultured in the conditioned media of control RAW265.7 cells exposed to H2O2. For the in vivo study, wild-type and FPR2 knockout (FPR2-/-) C57/BL6 mouse pups were randomly exposed to 80% oxygen or room air from postnatal day (P) 1 to P14. At P5, 2 × 105 MSCs were transplanted intratracheally. MSCs reduced the elevated FPR2 activity at P7 and improved the decreased FPR2 activity as well as the increased immuno-stained FPR2 activity in alveolar macrophages in hyperoxic lungs at P14. Both FPR2-/- and MSCs similarly attenuated impaired alveolarization and angiogenesis, and increased apoptosis and inflammation of hyperoxic lungs without synergistic effects. Our findings suggest that the protective effects of MSCs in hyperoxic lung injury might be related to indirect modulation of FPR2 activity, at least of alveolar macrophages in neonatal mice.
Asunto(s)
Displasia Broncopulmonar , Hiperoxia , Lesión Pulmonar , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Animales , Ratones , Animales Recién Nacidos , Medios de Cultivo Condicionados , Citocinas , Modelos Animales de Enfermedad , Células Endoteliales , Peróxido de Hidrógeno , Hiperoxia/complicaciones , Inflamación , Pulmón , Lesión Pulmonar/etiología , Lesión Pulmonar/terapia , Oxígeno , Receptores de Formil Péptido/genética , Factor de Necrosis Tumoral alfaRESUMEN
We recently reported that transplantation of mesenchymal stem cells (MSCs) significantly reduced bacterial growth and brain injury in neonatal meningitis induced by Escherichia coli (E. coli) infection in newborn rats. As a next step, to verify whether the MSCs protect against brain injury in a paracrine manner, this study was designed to estimate the efficacy of MSC-derived extracellular vesicles (MSC-EVs) in E. coli meningitis in newborn rats. E. coli meningitis was induced without concomitant bacteremia by the intra-cerebroventricular injection of 5 × 102 colony-forming units of K1 (-) E. coli in rats, at postnatal day 11. MSC-EVs were intra-cerebroventricularly transplanted 6 h after the induction of meningitis, and antibiotics were administered for three consecutive days starting at 24 h after the induction of meningitis. The increase in bacterial growth in the cerebrospinal fluid measured at 24 h after the meningitis induction was not significantly reduced following MSC-EV transplantation. However, an increase in brain cell death, reactive gliosis, and inflammation following meningitis were significantly attenuated after MSC-EV transplantation. Taken together, our results indicate that MSCs show anti-apoptotic, anti-gliosis, and anti-inflammatory, but not antibacterial effects, in an EV-mediated paracrine manner in E. coli-induced neonatal meningitis.
RESUMEN
This study aimed to determine the short- and/or long-term outcomes of levothyroxine replacement therapy in extremely low birth weight (ELBW) infants with transient hypothyroxinemia of prematurity (THOP). The medical records of 335 ELBW infants with THOP were reviewed retrospectively to identify whether levothyroxine treatment affects short- and/or long-term outcomes at a corrected age of 2 years. The infants were arbitrarily grouped based on thyroxine (T4) (free T4 [fT4]) levels into group 1 (n = 142), which included infants with T4 (fT4) levels < 2.5 (0.5) ng/dl, and group 2 (n = 193), which included those with T4 (fT4) levels ranging from ≥ 2.5 (0.5) ng/dl to < 4.5 (0.9) ng/dl. Levothyroxine replacement therapy was not associated with beneficial short- or long-term outcomes in ELBW infants with THOP. Short-term outcomes, such as mortality and composite morbidities, and long-term outcomes, such as failure to achieve catch-up height at a corrected age of 2 years, were significantly higher in group 1 than in group 2, regardless of levothyroxine treatment status. Levothyroxine replacement therapy is not associated with short-or long-term advantages in ELBW infants with THOP. This study suggests that the severity of THOP may be the major determinant of adverse outcomes in ELBW infants with THOP, rather than levothyroxine treatment.