Systemic administration of clinical-grade multilineage-differentiating stress-enduring cells ameliorates hypoxic-ischemic brain injury in neonatal rats.

Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative pluripotent stem cells present in the bone marrow, peripheral blood, and organ connective tissues. We assessed the homing and therapeutic effects of systemically administered nafimestrocel, a clinical-grade human Muse cell-based product, without immunosuppressants in a neonatal hypoxic-ischemic (HI) rat model. HI injury was induced on postnatal day 7 (P7) and was confirmed by T2-weighted magnetic resonance imaging on P10. HI rats received a single dose nafimestrocel (1 × 106 cells/body) or Hank's balanced salt solution (vehicle group) intravenously at either three days (on P10; M3 group) or seven days (on P14; M7 group) after HI insult. Radioisotope experiment demonstrated the homing of chromium-51-labeled nafimestrocel to the both cerebral hemispheres. The cylinder test (M3 and M7 groups) and open-field test (M7 group) showed significant amelioration of paralysis and hyperactivity at five weeks of age compared with those in the vehicle group. Nafimestrocel did not cause adverse events such as death or pathological changes in the lung at ten weeks in the both groups. Nafimestrocel attenuated the production of tumor necrosis factor-α and inducible nitric oxide synthase from activated cultured microglia in vitro. These results demonstrate the potential therapeutic benefits and safety of nafimestrocel.

Intraoperative Transpyloric Tube Insertion for Congenital Diaphragmatic Hernia: Analysis of Japanese Study Group Data.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a severe congenital disease. Some CDH infants suffer from gastro-esophageal reflux disease (GERD), even after surgical correction of gastric position. A transpyloric tube (TPT) is inserted into CDH patients under direct observation intraoperatively in some hospitals in Japan to establish early enteral feeding. This strategy avoids gastric expansion to maintain a better respiratory condition. However, it is unclear whether the strategy has a secure effect for patient prognosis. This study aimed to evaluate the effectiveness of intraoperative TPT insertion on enteral feeding and postoperative weight gain. METHODS: The Japanese CDH Study Group database was used to identify infants with CDH born between 2011 and 2016, who were then divided into two groups: the TPT group and gastric tube (GT) group. In the TPT group, infants underwent intraoperative TPT insertion; postoperative insertion/extraction of TPT was irrelevant to the analysis. Weight growth velocity (WGV) was calculated using the exponential model. Subgroup analysis was performed using Kitano's gastric position classification. RESULTS: We analyzed 204 infants, of which 99 and 105 were in the TPT and GT groups, respectively. Enteral nutrition (EN) in the TPT and GT groups was 52 ± 39 and 44 ± 41 kcal/kg/day (p = 0.17) at age 14 days (EN14), respectively, and 83 ± 40 and 78 ± 45 kcal/kg/day (p = 0.46) at age 21 days (EN21), respectively. WGV30 (WGV from day 0 to day 30) in the TPT and GT groups was 2.3 ± 3.0 and 2.8 ± 3.8 g/kg/day (p = 0.30), respectively, and WGV60 (WGV from day 0 to day 60) was 5.1 ± 2.3 and 6.0 ± 2.5 g/kg/day (p = 0.03), respectively. In infants with Kitano's Grade 2 + 3, EN14 in the TPT and GT groups was 38 ± 35 and 29 ± 35 kcal/kg/day (p = 0.24), respectively, EN21 was 73 ± 40 and 58 ± 45 kcal/kg/day (p = 0.13), respectively, WGV30 was 2.3 ± 3.2 and 2.0 ± 4.3 g/kg/day (p = 0.76), respectively, and WGV60 was 4.6 ± 2.3 and 5.2 ± 2.3 g/kg/day (p = 0.30), respectively. CONCLUSION: Intraoperative TPT insertion did not improve nutritional intake and WGV30. WGV60 in TPT was less than that in GT. In Grade 2 + 3 subgroup analysis, TPT also had no advantage. We could not recommend routine TPT insertion at surgery. LEVEL OF EVIDENCE: III.

Case report: High-dose epoprostenol therapy in pediatric patients with pulmonary hypertension and developmental lung disease.

Pulmonary hypertension (PH) with developmental lung disease is a life-threatening disease and accounts for 10%-12% of pediatric PH patients. Administration of specific pulmonary vasodilators to pediatric PH patients has brought about improvement of their long-term prognosis. Intravenous epoprostenol therapy is a gold standard therapy for severe idiopathic pulmonary arterial hypertension (IPAH), but there are few reports demonstrating the efficacy of epoprostenol for pediatric PH patients with developmental lung disease, especially when treating with high doses of epoprostenol. Two cases of pediatric PH patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) and congenital diaphragmatic hernia (CDH) with bronchopulmonary dysplasia (BPD), respectively, treated with epoprostenol above 100 ng/kg/min are presented. In these two cases, severe PH was improved significantly by an aggressive increase of the epoprostenol infusion rate with administration of oral pulmonary vasodilators and appropriate respiratory management, without any significant adverse effects. High-dose epoprostenol therapy may be one of the therapeutic options in pediatric PH patients with developmental lung disease.

Mortality and morbidity of extremely low birth weight infants in Japan, 2015.

BACKGROUND: In Japan, the mortality rate of extremely low birth weight (ELBW) infants is notably low in comparison with other developed countries, but the prevalence of chronic lung disease (CLD) and retinopathy of prematurity (ROP) is relatively high. This study aimed to estimate the mortality and morbidity of ELBW infants born in 2015 who were admitted to neonatal intensive care units (NICUs) in Japan and to examine the factors that affected the short-term outcomes of these infants. We also compared the mortality of ELBW infants born in 2005, 2010, and 2015. METHODS: We analyzed the mortality, morbidity, and factors related to short-term outcomes of ELBW infants, using data from 2782 infants born in 2015 and registered at NICUs in Japan. RESULTS: The mortality rates during NICU stays were 17.0%, 12.0%, and 9.8% for ELBW infants born in 2005, 2010, and 2015, respectively. Among ELBW infants born in 2015, multiple logistic regression analysis showed that short gestational age and low birthweight Z-score contributed to the increased risk of death. Births by cesarean section and antenatal corticosteroid administration were significantly associated with a reduced risk of death. Among infants who survived, CLD was observed in 53.1% and ROP requiring treatment was observed in 30.4%. CONCLUSIONS: Mortality in ELBW infants decreased significantly from 2005 to 2015. As CLD and ROP may affect quality of life and long-term outcomes of infants who survived, prevention strategies and management for these complications are critical issues in neonatal care in Japan.

Prenatal diagnosis of distal 13q deletion syndrome in a fetus with esophageal atresia: a case report and review of the literature.

BACKGROUND: Chromosome 13q deletion syndrome shows variable clinical features related to the different potential breakpoints in chromosome 13q. The severely malformed phenotype is known to be associated with the deletion of a critical region in 13q32. However, esophageal atresia is a rare symptom and the relevant region is unknown. Thus, determining the association between accurate breakpoints and new clinical features is essential. CASE PRESENTATION: A 28-year-old Japanese primigravid woman was referred for fetal growth restriction, absence of a gastric bubble, cerebellar hypoplasia, overlapping fingers, and polyhydramnios at 31 weeks gestation. At 38 + 0 weeks, she delivered a 1774 g female infant. The infant presented with isolated esophageal atresia (Gross type A), Dandy-Walker malformation, right microphthalmia, left coloboma, overlapping fingers, pleurocentrum in the thoracic vertebrae, reduced anogenital distance, and hearing loss. Her karyotype was diagnosed as 46,XX,del(13)(q32.1-qter) by amniocentesis, but array comparative genomic hybridization after birth revealed the deletion of 13q31.3-qter. At 48 days after birth, the infant underwent surgery for esophageal atresia and was later discharged from the hospital at 7 months of age. CONCLUSION: This case report and the literature reviews supports the previous findings on the pathological roles of haploinsufficiency of the ZIC2/ZIC5 in Dandy-Walker malformation and the EFBN2 haploinsufficiency in eye malformation and hearing loss. Furthermore, the possible involvement of IRS2, COLA1, and COLA2 in eye malformation were identified. This is the first case of 13q deletion syndrome with esophageal atresia (Gross A), but it may be a symptom of VATER/VACTER association (vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects), as in the previous cases. These symptoms might also be associated with EFBN2 haploinsufficiency, although further research is required.

A predictive scoring system for small diaphragmatic defects in infants with congenital diaphragmatic hernia.

PURPOSE: To develop a predictive score for small diaphragmatic defects in infants with congenital diaphragmatic hernia (CDH) for determining thoracoscopic surgery indication. METHODS: The Japanese CDH Study Group cohort was randomly divided into derivation (n = 397) and validation (n = 396) datasets. Using logistic regression, a prediction model and weighted scoring system for small diaphragmatic defects were created from derivation dataset and validated with validation dataset. RESULTS: Six weighted variables were selected: no hydramnios, 1 point; 1 min Apgar score of 5-10, 1 point; apex type of the lung (left lung is detected radiographically in apex area), 1 point; oxygenation index < 8, 1 point; abdominal nasogastric tube (tip of the nasogastric tube is detected radiographically in the abdominal area), 2 points; no right-to-left flow of ductus arteriosus, 1 point. In validation dataset, rates of small diaphragmatic defects for Possible (0-3 points), Probable (4-5 points), and Definite (6-7 points) groups were 36%, 81%, and 94%, respectively (p < 0.001). Additionally, sensitivity, specificity, positive predictive value, and C statistics were 0.78, 0.79, 0.88, 0.76, and 0.45, 0.94, 0.94, 0.70 for Probable and Definite groups, respectively. CONCLUSION: Our scoring system effectively predicted small diaphragmatic defects in infants with CDH.

The efficacy of the postnatal nasogastric tube position as a prognostic marker of left-sided isolated congenital diaphragmatic hernia.

PURPOSE: The prenatal diagnosis of the stomach position in congenital diaphragmatic hernia (CDH) has been a reliable prognostic factor, but few studies have focused on the postnatal position. We therefore evaluated the significance of the nasogastric (NG) tube position just after birth. METHODS: The Japanese CDH Study Group database enrolled 1037 CDH neonates over 15 years. In our multicenter retrospective study, 464 cases of left-sided isolated CDH with prenatal diagnoses were divided into two groups: NG tube below the diaphragm (BD; n = 190) or above the diaphragm (AD; n = 274). The primary outcome was the 90-day survival rate, and the secondary outcomes were mechanical ventilation duration, hospitalization duration, and recurrence rate. RESULTS: The BD group had a significantly higher 90-day survival rate (98.4 vs. 89.4%, p < 0.001), shorter mechanical ventilation (11 vs. 19 days, p < 0.001), shorter hospitalization (38 vs. 59 days, p < 0.001), and lower recurrence rate (p = 0.002) than the AD group. A multivariate analysis showed that BD (adjusted odds ratio, 3.68; 95% confidence interval 1.02-13.30) was a favorable prognostic factor for the 90-day survival. CONCLUSION: The assessment of the NG tube position revealed it to be a reliable prognostic factor of left-sided isolated CDH. Therefore, it should be included as a routine assessment.

Prenatal predictors of mortality in fetuses with congenital diaphragmatic hernia: a systematic review and meta-analysis.

PURPOSE: This study aimed to evaluate prenatal predictors of mortality in fetuses with congenital diaphragmatic hernia (CDH). METHODS: A systematic literature search was performed to identify relevant observational studies that evaluated the ability of lung-to-head ratio (LHR), observed-to-expected LHR (o/e-LHR), observed-to-expected total fetal lung volume (o/e-TFLV), lung-to-thorax transverse area ratio (L/T ratio), intrathoracic herniation of the liver and the stomach, and side of diaphragmatic hernia, using a threshold for the prediction of mortality in fetuses with CDH. Study quality was assessed using the QUADAS-2 tool. Hierarchical summary receiver operating characteristic curves were constructed. RESULTS: A total of 50 articles were included in this meta-analysis. The QUADAS-2 tool identified a high risk of bias in more than one domain scored in all parameters. Among those parameters, the diagnostic odds ratio of mortality with o/e-LHR < 25%, o/e-TFLV < 25%, and L/T ratio < 0.08 were 11.98 [95% confidence interval (CI) 4.65-30.89], 11.14 (95% CI 5.19-23.89), and 10.28 (95% CI 3.38-31.31), respectively. The predictive values for mortality were similar between the presence of liver herniation and retrocardiac fetal stomach position. CONCLUSIONS: This systematic review suggests that o/e-LHR, o/e-TFLV, and L/T ratio are equally good predictors of neonatal mortality in fetuses with isolated CDH.

Pulmonary hypertension with bronchopulmonary dysplasia: Aichi cohort study.

BACKGROUND: The incidence of pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD) has not been investigated in regional cohorts. The aim of this study was to clarify the incidence of PH associated with BPD in all very low birthweight infants (VLBWIs) born during the study period in Aichi Prefecture, Japan. METHODS: We conducted a retrospective observational cohort study of all VLBWIs born in Aichi Prefecture. The inclusion criteria were VLB, birth between 1 January 2015 and 31 December 2015, and admission to any neonatal intensive care unit in Aichi Prefecture. BPD28d and BPD36w were defined as the need for supplemental oxygen or any respiratory support at 28 days of age or 36 weeks of postmenstrual age (PMA). The primary outcome was the incidence of PH after 36 weeks' PMA (PH36w) in VLBWIs with BPD28d and BPD36w. The secondary outcomes were the clinical factors related to PH36w in BPD36w patients. Mann-Whitney U-test and Fisher's exact test were used for univariate analysis. Differences were considered statistically significant at P < 0.05. Risk ratio (RR) and 95% confidence interval (CI) were also evaluated. RESULTS: A total of 441 patients were analyzed. A total of 217 and 131 patients met the definition of BPD28d and BPD36w, respectively. Nine patients were diagnosed with PH36w (4.2% and 6.9% of the BPD28d and BPD36w patients, respectively). The presence of oligohydramnios (RR, 2.71; 95% CI: 1.55-4.73, P = 0.014) and sepsis (RR, 3.62; 95% CI: 1.51-8.63, P = 0.025) was significant in the PH36w patients. CONCLUSIONS: The incidence of PH36w was 4.2% and 6.9% in the BPD28d and BPD36w patients, respectively. Oligohydramnios and sepsis were significantly associated with PH36w in VLBWIs.

Best pre-ductal PaO2 prior to extracorporeal membrane oxygenation as predictor of mortality in patients with congenital diaphragmatic hernia: a retrospective analysis of a Japanese database.

PURPOSE: Predicting lethal pulmonary hypoplasia in infants with congenital diaphragmatic hernia (CDH) before extracorporeal membrane oxygenation (ECMO) initiation is difficult. This study aimed to predict lethal pulmonary hypoplasia in patients with CDH prior to ECMO. METHODS: This was a multicenter cohort study involving neonates prenatally diagnosed with isolated unilateral CDH (born 2006-2020). Patients who required ECMO due to respiratory insufficiency were included in this study. Patients who underwent ECMO due to transient disorders were excluded from analysis. Blood gas analysis data within 24 h of birth were compared between survivors and non-survivors. Predictive abilities were assessed for factors with significant differences. RESULTS: Overall, 34 patients were included (18 survivors and 16 non-survivors). The best pre-ductal PaO2 was significantly lower in non-survivors than in survivors (50.4 [IQR 30.3-64.5] vs. 67.5 [IQR 52.4-103.2] mmHg, respectively; p = 0.047). A cutoff PaO2 of 42.9 mmHg had a sensitivity, specificity, and positive predictive value of 50.0%, 94.4%, and 88.9%, respectively, to predict mortality. CONCLUSION: The best PaO2 within 24 h after birth predicted mortality following ECMO initiation. This should be shared to families and caregivers to optimize the best interests of the infants with CDH.

Impact of maternal hypertensive disorders of pregnancy on brain volumes at term-equivalent age in preterm infants: A voxel-based morphometry study.

OBJECTIVES: Infants born to mothers with hypertensive disorders of pregnancy (HDP) reportedly have negative behavioral and neurodevelopmental outcomes. However, the effects of maternal HDP on infant brain growth have not been fully evaluated. We aimed to evaluate brain volumes and brain injury in preterm infants born to mothers with HDP using magnetic resonance (MR) imaging at term-equivalent age. STUDY DESIGN: In this cohort study, MR imaging was performed for 94 preterm infants born before 34 weeks of gestation at Nagoya University Hospital between 2010 and 2018. Twenty infants were born to mothers with HDP and 74 to mothers without HDP. MAIN OUTCOME MEASURES: Total brain volumes and regional volumetric alterations were assessed by voxel-based morphometry, and brain injury was evaluated using the Kidokoro global brain abnormality score. Developmental quotient was assessed at a corrected age of 1.5 years in 59 infants (HDP, n = 11; non-HDP, n = 48). RESULTS: No significant differences were observed in the gray and white matter volumes of the two groups (HDP: 175 ± 24 mL, 137 ± 13 mL, respectively; non-HDP: 172 ± 24 mL, 142 ± 13 mL, respectively). Additionally, no regional volumetric alterations were observed between the two groups after covariate adjustment (gestational age and infant sex). The total Kidokoro score and developmental quotient were similar in both groups. CONCLUSIONS: No significant differences in the global and regional brain volumes were observed. Further research is needed to confirm our findings at different time points of MR imaging and in different populations.

Thoracoscopic repair of congenital diaphragmatic hernia in neonates: findings of a multicenter study in Japan.

PURPOSE: We compared the efficacy of thoracoscopic repair (TR) with that of open repair (OR) for neonatal congenital diaphragmatic hernia (CDH). METHODS: The subjects of this multicenter retrospective cohort study were 524 infants with left-sided isolated CDH, diagnosed prenatally, and treated at one of 15 participating hospitals in Japan between 2006 and 2018. The outcomes of infants who underwent TR and those who underwent OR were compared, applying propensity score matching. RESULTS: During the study period, 57 infants underwent TR and 467 underwent OR. Ten of the infants who underwent TR required conversion to OR for technical difficulties and these patients were excluded from the analysis. The survival rate at 180 days was similar in both groups (TR 98%; OR 93%). Recurrence developed after TR in 3 patients and after OR in 15 patients (TR 7%, OR 3%, p = 0.40). The propensity score was calculated using the following factors related to relevance of the surgical procedure: prematurity (p = 0.1), liver up (p < 0.01), stomach position (p < 0.01), and RL shunt (p = 0.045). After propensity score matching, the multivariate analysis adjusted for severity classification and age at surgical treatment revealed a significantly shorter hospital stay (odds ratio 0.50) and a lower incidence of chronic lung disease (odds ratio 0.39) in the TR group than in the OR group. CONCLUSIONS: TR can be performed safely for selected CDH neonates with potentially better outcomes than OR.

Mortality and neurological outcomes in extremely and very preterm infants born to mothers with hypertensive disorders of pregnancy.

To evaluate the impact of maternal hypertensive disorders of pregnancy (HDP) on mortality and neurological outcomes in extremely and very preterm infants using a nationwide neonatal database in Japan. This population-based retrospective study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, between 22 and 31 weeks' gestation. A total of 21,659 infants were randomly divided into two groups, HDP (n = 4,584) and non-HDP (n = 4,584), at a ratio of 1:1 after stratification by four factors including maternal age, parity, weeks of gestation, and year of delivery. Short-term (neonatal period) and medium-term (3 years of age) mortality and neurological outcomes were compared between the two groups by logistic regression analyses. In univariate analysis, HDP was associated with an increased risk for in-hospital death (crude odds ratio [OR], 1.31; 95% confidence interval, 1.04-1.63) and a decreased risk for severe intraventricular haemorrhage (0.68; 0.53-0.87) and periventricular leukomalacia (0.60; 0.48-0.77). In multivariate analysis, HDP was significantly associated with a lower risk for in-hospital death (adjusted OR, 0.61; 0.47-0.80), severe intraventricular haemorrhage (0.47; 0.35-0.63), periventricular leukomalacia (0.59; 0.45-0.78), neonatal seizures (0.40; 0.28-0.57) and cerebral palsy (0.70; 0.52-0.95) at 3 years after adjustment for covariates including birth weight. These results were consistent with those of additional analyses, which excluded cases with histological chorioamnionitis and which divided the infants into two subgroups (22-27 gestational weeks and 28-31 gestational weeks). Maternal HDP was associated with an increased risk for in-hospital death without adjusting for covariates, but it was also associated with a lower risk for mortality and adverse neurological outcomes in extremely and very preterm infants if all covariates except HDP were identical.

Optimal timing of surgery in infants with prenatally diagnosed isolated left-sided congenital diaphragmatic hernia: a multicenter, cohort study in Japan.

PURPOSE: To date, there is no compelling evidence of the optimal timing of surgery for congenital diaphragmatic hernia (CDH). This study aimed to establish the optimal timing of surgery in neonates with isolated left-sided CDH. METHODS: This multicenter cohort study enrolled 276 patients with isolated left-sided CDH at 15 institutions. Based on the timing of surgery, the patients were classified into four groups [< 24 h (G1), 24-47 h (G2), 48-71 h (G3), and ≥ 72 h (G4)]. The clinical outcomes were compared among the groups using a logistic regression model, after adjusting for potential confounders, such as disease severity. RESULTS: Multivariate analyses showed that G2 also had a lower mortality rate than the other groups. In mild and severe cases, there were no significant differences in mortality across the four groups. In moderate cases, G2 resulted in significantly increased survival rates, compared with G1. CONCLUSION: The study results suggest that surgery within 24 h of birth is not recommended for patients with moderate severity CDH, that there is no benefit in the delay of surgery for more than 72 h in mild severity CDH patients, and that there is no definite optimal time to perform surgery in severe cases of CDH.

Weight gain velocity and adequate amount of nutrition for infants with congenital diaphragmatic hernia.

PURPOSE: Growth retardation is a severe morbidity in infants with congenital diaphragmatic hernia (CDH). This study aimed to determine when catch-up growth starts in infants with CDH and to determine the adequate amount of nutrition required during catch-up growth. METHODS: This was a multicenter retrospective cohort study involving neonates with isolated CDH (born 2006-2010; n = 98). Weight gain velocity (WGV) was calculated using body weight Z-scores. The minimum required weight gain was defined as WGV ≥ 0. Patients were dichotomized into severe and non-severe cases according to diaphragmatic defects. RESULTS: Average monthly WGV changed from < 0 to ≥ 0 at 2 months of age. Total caloric intake at 2 months of age was lower when the WGV between 1 and 3 months was < 0 in both severe cases [122 (95% confidence interval (CI) 116-128) vs. 97 (95% CI 84-110) kcal/kg/day, p = 0.02] and non-severe cases [115 (95% CI 110-120) vs. 99 (95% CI 87-111) kcal/kg/day, p < 0.001)]. CONCLUSION: Catch-up growth started at approximately 2 months of age. During this period, total caloric intake of > 122 kcal/kg/day was needed to avoid decreases in the body weight Z-score in severe cases.

Prognosis of conventional vs. high-frequency ventilation for congenital diaphragmatic hernia: a retrospective cohort study.

OBJECTIVE: To determine the appropriate initial ventilatory mode for neonatal congenital diaphragmatic hernia (CDH) by comparing patient prognosis following conventional mechanical ventilation (CMV) versus high-frequency oscillatory ventilation (HFO). STUDY DESIGN: This multicenter retrospective cohort study was performed at 15 participating hospitals in Japan between 2011 and 2016. The 328 eligible CDH infants were classified into CMV (n = 78) and HFO groups (n = 250) to compare mortality and incidence of bronchopulmonary dysplasia (BPD). Propensity score matching was applied to reduce confounding by indication. RESULT: While crude mortality was significantly higher in the HFO than the CMV group, adjusted odds ratio (OR) did not show significant difference in mortality between groups (OR of HFO group: 0.98, 95% confidence interval (CI): 0.57-1.67). Adjusted OR of BPD incidence showed no significant difference between groups (OR of HFO group: 1.66, 95%CI: 0.50-5.49). CONCLUSION: Initial ventilatory mode in CDH patients, whether CMV or HFO, does not affect prognosis.

Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy.

Perinatal hypoxic ischemic encephalopathy (HIE) results in serious neurological dysfunction and mortality. Clinical trials of multilineage-differentiating stress enduring cells (Muse cells) have commenced in stroke using intravenous delivery of donor-derived Muse cells. Here, we investigated the therapeutic effects of human Muse cells in an HIE model. Seven-day-old rats underwent ligation of the left carotid artery then were exposed to 8% oxygen for 60 min, and 72 hours later intravenously transplanted with 1 × 104 of human-Muse and -non-Muse cells, collected from bone marrow-mesenchymal stem cells as stage-specific embryonic antigen-3 (SSEA-3)+ and -, respectively, or saline (vehicle) without immunosuppression. Human-specific probe revealed Muse cells distributed mainly to the injured brain at 2 and 4 weeks, and expressed neuronal and glial markers until 6 months. In contrast, non-Muse cells lodged in the lung at 2 weeks, but undetectable by 4 weeks. Magnetic resonance spectroscopy and positron emission tomography demonstrated that Muse cells dampened excitotoxic brain glutamatergic metabolites and suppressed microglial activation. Muse cell-treated group exhibited significant improvements in motor and cognitive functions at 4 weeks and 5 months. Intravenously transplanted Muse cells afforded functional benefits in experimental HIE possibly via regulation of glutamate metabolism and reduction of microglial activation.

Identification of most influential co-occurring gene suites for gastrointestinal cancer using biomedical literature mining and graph-based influence maximization.

BACKGROUND: Gastrointestinal (GI) cancer including colorectal cancer, gastric cancer, pancreatic cancer, etc., are among the most frequent malignancies diagnosed annually and represent a major public health problem worldwide. METHODS: This paper reports an aided curation pipeline to identify potential influential genes for gastrointestinal cancer. The curation pipeline integrates biomedical literature to identify named entities by Bi-LSTM-CNN-CRF methods. The entities and their associations can be used to construct a graph, and from which we can compute the sets of co-occurring genes that are the most influential based on an influence maximization algorithm. RESULTS: The sets of co-occurring genes that are the most influential that we discover include RARA - CRBP1, CASP3 - BCL2, BCL2 - CASP3 - CRBP1, RARA - CASP3 - CRBP1, FOXJ1 - RASSF3 - ESR1, FOXJ1 - RASSF1A - ESR1, FOXJ1 - RASSF1A - TNFAIP8 - ESR1. With TCGA and functional and pathway enrichment analysis, we prove the proposed approach works well in the context of gastrointestinal cancer. CONCLUSIONS: Our pipeline that uses text mining to identify objects and relationships to construct a graph and uses graph-based influence maximization to discover the most influential co-occurring genes presents a viable direction to assist knowledge discovery for clinical applications.

A familial case of alveolar capillary dysplasia with misalignment of the pulmonary veins: the clinicopathological features and unusual glomeruloid endothelial proliferation.

BACKGROUND: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare disorder of pulmonary vascular abnormality with persistent pulmonary hypertension of the newborn. The symptom usually presents within hours after birth, leading to an early demise. Heterozygous de novo point mutations and genomic deletions of the FOXF1 (forkhead box F1) gene or its upstream enhancer have been identified in most patients with ACD/MPV. Most cases of ACD/MPV are sporadic; however, familial cases are also reported in 10% of patients. CASE PRESENTATION: We herein report a case of familial ACD/MPV that showed unusual glomeruloid proliferation of endothelial cells. In this family, three of the four siblings died within two to 3 days after birth because of persistent pulmonary hypertension and respiratory failure. Only the second child remains alive and healthy. An autopsy was performed for the third and fourth children, resulting in a diagnosis of ACD/MPV based on the characteristic features, including misalignment of smaller pulmonary veins and lymphangiectasis. In both of these children, glomeruloid endothelial proliferation of vessels was noted in the interlobular septa. The vessels were immunohistochemically positive for D2-40, CD31, Factor VIII, and ERG, suggestive of differentiation for both lymphatic and blood vessels. CONCLUSIONS: Unusual glomeruloid endothelial proliferation was observed in a familial ACD/MPV case. This histologic feature has not been described previously in ACD/MPV or any other pulmonary disease. Although the histogenesis of this histologic feature is unclear, this finding may suggest that ACD/MPV is a compound vascular and lymphovascular system disorder that exhibits various histologic features.

Antenatal Corticosteroids and Outcomes in Preterm Twins.

OBJECTIVE: To estimate whether improvement in outcomes from antenatal corticosteroid treatment in extremely and very preterm twins is similar to that observed in singletons, and to investigate whether antenatal corticosteroid treatment has different effects according to chorionicity or birth order. METHODS: This population-based study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, from gestational ages of 24 0/7 to 31 6/7 weeks of gestation. After propensity score matching, univariate logistic and interaction analyses were performed to compare short-term (neonatal period) and medium-term (3 years of age) outcomes of the children of mothers who received antenatal corticosteroids with those of children of mothers who did not receive antenatal corticosteroids. We focused on differences between singletons and twins, between monochorionic and dichorionic twins and between the first and second twin. RESULTS: The study comprised 23,502 singletons and 6,546 twins. Antenatal corticosteroid treatment was associated with significant decreased short-term neurologic outcomes in both singletons and twins. However, antenatal corticosteroid treatment was associated with significantly decreased mortality (odds ratio [OR] 0.61; 95% CI 0.53-0.70), respiratory distress syndrome (OR 0.71, 95% CI 0.67-0.76), and cerebral palsy (OR 0.85, 95% CI 0.72-0.99) in singletons but not in twins (OR 0.89, 95% CI 0.68-1.17; OR 0.99, 95% CI 0.87-1.12; and OR 0.82, 95% CI 0.61-1.11, respectively). No association was found between chorionicity and the efficacy of antenatal corticosteroid treatment on outcomes. Further, no association was found between birth order and the efficacy of antenatal corticosteroid treatment on outcomes, except for periventricular leukomalacia and necrotizing enterocolitis (interaction: P=.02 and P=.04, respectively). CONCLUSION: Antenatal corticosteroid treatment in twins was associated with a beneficial effect on short-term neurologic outcomes only, without improvement in other short-term and medium-term outcomes. There was no difference related to chorionicity.