Human post-implantation blastocyst-like characteristics of Muse cells isolated from human umbilical cord.

Muse cells, identified as cells positive for the pluripotent surface marker SSEA-3, are pluripotent-like endogenous stem cells located in the bone marrow (BM), peripheral blood, and organ connective tissues. The detailed characteristics of SSEA-3(+) cells in extraembryonic tissue, however, are unknown. Here, we demonstrated that similar to human-adult tissue-Muse cells collected from the BM, adipose tissue, and dermis as SSEA-3(+), human-umbilical cord (UC)-SSEA-3(+) cells express pluripotency markers, differentiate into triploblastic-lineage cells at a single cell level, migrate to damaged tissue, and exhibit low telomerase activity and non-tumorigenicity. Notably, ~ 20% of human-UC-SSEA-3(+) cells were negative for X-inactive specific transcript (XIST), a naïve pluripotent stem cell characteristic, whereas all human adult tissue-Muse cells are XIST-positive. Single-cell RNA sequencing revealed that the gene expression profile of human-UC-SSEA-3(+) cells was more similar to that of human post-implantation blastocysts than human-adult tissue-Muse cells. The DNA methylation level showed the same trend, and notably, the methylation levels in genes particularly related to differentiation were lower in human-UC-SSEA-3(+) cells than in human-adult tissue-Muse cells. Furthermore, human-UC-SSEA-3(+) cells newly express markers specific to extraembryonic-, germline-, and hematopoietic-lineages after differentiation induction in vitro whereas human-adult tissue-Muse cells respond only partially to the induction. Among various stem/progenitor cells in living bodies, those that exhibit properties similar to post-implantation blastocysts in a naïve state have not yet been found in humans. Easily accessible human-UC-SSEA-3(+) cells may be a valuable tool for studying early-stage human development and human reproductive medicine.

Umbilical cord blood as a substitute for neonatal blood in measuring serum albumin and immunoglobulin G levels.

OBJECTIVES: In this study, we investigated the clinical feasibility of using umbilical cord blood as an alternative to neonatal blood for measuring serum albumin and immunoglobulin G (IgG) levels in newborns, including preterm newborns. METHODS: Serum levels of albumin and IgG were measured in cord and neonatal blood from singleton newborns. We analyzed correlations and systematic errors between cord and neonatal blood measurements, stratifying the results for very preterm newborns (VPNs) born at a gestational age of less than 32 weeks and non-VPNs born at a gestational age of 32 weeks or later. RESULTS: Among all 494 newborns (78 VPNs and 416 non-VPNs), serum albumin and IgG levels were determined for 95.7% and 88.7% of them, respectively. Strong correlations between cord and neonatal blood were observed for the serum albumin and IgG levels (rs = 0.864 and 0.966, respectively). Moreover, the measurement errors between cord and neonatal blood were small for all newborns (0.2 g/dL and 65 mg/dL, respectively). These findings were consistent with both VPNs and non-VPNs. CONCLUSIONS: Umbilical cord blood is a suitable substitute for neonatal blood in measuring serum albumin and IgG levels in newborns, even in premature newborns.

Impact of definitive surgery for esophageal atresia on long-term outcomes in patients with trisomy 18.

This study investigates the long-term outcomes of palliative and definitive surgeries for esophageal atresia (EA) in patients with trisomy 18 syndrome. A retrospective study included 25 cases undergoing EA surgery at our center between 2008 and 2022. The Palliative group (n = 16) comprised 13 cases with esophageal banding and 3 with tracheoesophageal fistula (TEF) division. The Definitive group (n = 9) included 5 cases with primary repair and 4 with staged repair following TEF division. The patient characteristics exhibited no significant differences between the groups. In the Definitive group, 56% (5/9) were successfully weaned off mechanical ventilation, compared with none in the Palliative group (p = 0.002). Survival-to-discharge rates were 31% (5/16) in the Palliative group and 67% (6/9) in the Definitive group. Home ventilator management was required for all 5 cases that required ventilation in the Palliative group, whereas only 17% (1/6) in the Definitive group needed it. The Palliative group also required continuous oral suction for persistent saliva removal, with two cases undergoing laryngotracheal separation. Overall, definitive surgery for EA in patients with trisomy 18 syndrome may provide enhanced respiratory stability, thereby improving the survival-to-discharge rate and overall quality of life for patients and their families.

Human Muse cells isolated from preterm- and term-umbilical cord delivered therapeutic effects in rat bleomycin-induced lung injury model without immunosuppressant.

BACKGROUND: Bleomycin (BLM)-induced lung injury is characterized by mixed histopathologic changes with inflammation and fibrosis, such as observed in human patients with bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Although no curative therapies for these lung diseases exist, stem cell therapy has emerged as a potential therapeutic option. Multilineage-differentiating stress-enduring (Muse) cells are endogenous pluripotent- and macrophage-like stem cells distributed in various adult and fetal tissues as stage-specific embryonic antigen-3-positive cells. They selectively home to damaged tissue by sensing sphingosine-1-phosphate and replace the damaged/apoptotic cells by in vivo differentiation. Clinical trials for some human diseases suggest the safety and therapeutic efficacy of intravenously injected human leukocyte antigen-mismatched allogenic Muse cells from adult bone marrow (BM) without immunosuppressant. Here, we evaluated the therapeutic effects of human Muse cells from preterm and term umbilical cord (UC), and adult BM in a rat BLM-induced lung injury model. METHODS: Rats were endotracheally administered BLM to induce lung injury on day 0. On day 3, human preterm UC-Muse, term UC-Muse, or adult BM-Muse cells were administered intravenously without immunosuppressants, and rats were subjected to histopathologic analysis on day 21. Body weight, serum surfactant protein D (SP-D) levels, and oxygen saturation (SpO2) were monitored. Histopathologic lung injury scoring by the Ashcroft and modified American Thoracic Society document scales, quantitative characterization of engrafted Muse cells, RNA sequencing analysis, and in vitro migration assay of infused Muse cells were performed. RESULTS: Rats administered preterm- and term-UC-Muse cells exhibited a significantly better recovery based on weight loss, serum SP-D levels, SpO2, and histopathologic lung injury scores, and a significantly higher rate of both Muse cell homing to the lung and alveolar marker expression (podoplanin and prosurfactant protein-C) than rats administered BM-Muse cells. Rats receiving preterm-UC-Muse cells showed statistically superior results to those receiving term-UC-Muse cells in many of the measures. These findings are thought to be due to higher expression of genes related to cell migration, lung differentiation, and cell adhesion. CONCLUSION: Preterm UC-Muse cells deliver more efficient therapeutic effects than term UC- and BM-Muse cells for treating BLM-induced lung injury in a rat model.

Early changes in serum interleukin-6 levels in extremely premature newborns for detecting fetal inflammation.

BACKGROUND: Fetal inflammatory response syndrome (FIRS) is defined by elevated levels of inflammatory cytokines circulating in fetal blood, which may result in preterm morbidities. Serum interleukin-6 (IL-6) level has been reported to be a good indicator of FIRS; however, changes in IL-6 levels after birth remain to be elucidated. Herein, we characterized early changes in serum IL-6 levels in extremely premature newborns (EPNs, < 28 wks gestation), and then determined the cut-off values for detecting fetal inflammation at each postnatal epoch. METHODS: In this single-center study, 49 EPNs were retrospectively studied. Serum IL-6 measurements are routinely performed at delivery, 1-3, 6-12, and 24-36 h of life. Receiver operating characteristic (ROC) curve analyses were performed for detecting the presence of funisitis, the histologic counterpart of FIRS. RESULTS: Overall, serum IL-6 levels were significantly elevated at 1-3 (298 [31-4719] pg/mL) and 6-12 (29 [2-12,635] pg/mL) hours of life, then returned to at-delivery levels at 24-36 h of life. When comparing serum IL-6 levels at each postnatal epoch, the levels at delivery, 1-3, and 6-12 h of life were significantly higher in the EPNs with funisitis. Serum IL-6 cut-off values at delivery, 1-3, 6-12, and 24-36 h of life for the presence of funisitis were 20, 572, 290, and 13 pg/mL with area under ROCs of 0.75, 0.71, 0.68, and 0.53, respectively. CONCLUSIONS: Serum IL-6 levels in EPNs significantly increase early after birth, then decrease to at-delivery levels by 24-36 h of life. Therefore, postnatal age-dependent cut-off values of serum IL-6 might be considered for detecting fetal inflammation with confirmed funisitis.

Inhaled nitric oxide therapy for preterm infants after 7 days of age: a scoping review protocol.

INTRODUCTION: Inhaled nitric oxide (iNO) use is recommended for persistent pulmonary hypertension of the newborn in term and late preterm infants. Recently, iNO therapy to prevent bronchopulmonary dysplasia (BPD) or rescue for hypoxic respiratory failure and pulmonary hypertension secondary to BPD has increasingly been used in preterm infants after 7 days of postnatal age (in the postacute phase), despite its off-label use. However, the initiation criteria of iNO therapy for preterm infants in the postacute phase are varied. The aim of this scoping review is to identify the clinical and/or echo findings at the initiation of iNO therapy in preterm infants in the postacute phase. METHODS AND ANALYSIS: We will search PubMed, Embase and the Japanese database 'Ichushi.' The following studies will be included in the review: randomised controlled trials, prospective/retrospective cohort studies, case-control studies and case series on iNO therapy for preterm infants in the postacute phase; studies published between January 2003 and August 2023; studies conducted in developed countries and studies written in English or Japanese. We will independently screen, extract and chart data using the population-concept-context framework following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. We will summarise the characteristics and findings of the included studies. ETHICS AND DISSEMINATION: Obtaining an institutional review board approval is not required because of the nature of this review. A final report of review findings will be published and disseminated through a peer-reviewed journal and presentation at relevant conferences. TRIAL REGISTRATION NUMBER: UMIN000051498.

Second nationwide survey of bilirubin encephalopathy in preterm infants in Japan.

OBJECTIVES: To determine the clinical features of bilirubin encephalopathy in preterm infants (pBE) in Japan. METHODS: We performed a retrospective, nationwide questionnaire-based survey. The initial survey determined the number of children with pBE who were born after 2000. Using a structured questionnaire, the second survey clarified the clinical manifestations and characteristics of children with pBE, including demographic data, neurological symptoms, and MRI and auditory brainstem response (ABR) findings. RESULTS: The initial survey identified 41 pBE infants from 18 institutions. After exclusion of patients included in previous studies, clinical information was collected from 30 patients (21 boys and 9 girls) during the secondary survey. The median gestational age was 26 weeks and the median birthweight was 846 g. Chronic lung disease and symptomatic patent ductus arteriosus were common neonatal complications. Head control was observed in 63% and functional gait in 17% of patients. Purposeful hand use was seen in 57% and verbal communication in 50% of patients. MRI showed T2 hyperintensities in the globus pallidus of 29 of 30 patients. ABR abnormalities were present in 11 of 15 patients. None of the variables were significantly different between the 2017 and 2021 surveys. CONCLUSIONS: The pBE infants had severely impaired gross motor function and relatively preserved manual function and verbal communication. MRI and ABR findings aid in the diagnosis of pBE.

Determination and verification of reference intervals of serum immunoglobulin G at birth.

BACKGROUND: To accurately assess hypogammaglobulinemia at birth, it is essential to determine the reference intervals of serum immunoglobulin (IgG) levels in newborns. In the present study, we determined the gestational age (GA)-/birth weight (BW)-dependent percentile-based reference intervals of serum IgG levels and converted them into simple formulas for practical use. METHODS: Serum IgG levels were measured in cord blood from 2902 newborns delivered at 22 to 41 weeks of GA or 264 to 4642 g of BW after exclusion of those with congenital disorders. Linear regression analysis was used to correlate GA and UC-IgG levels and BW and UC-IgG levels. After calculation of the percentile values of UC-IgG levels for each GA or BW, the distributions were approximated by the least-squares method. Fitness was evaluated by the coefficient of determination (R2). RESULTS: Significant positive correlations were found both between GA and UC-IgG levels (rs = 0.790, P < 0.001) and BW and UC-IgG levels (rs = 0.626, P < 0.001). The distribution of the 5%ile of UC-IgG levels (Y) by GA or BW (X) was approximated as a straight line (Y = 37.5 *X - 775.8; Y = 0.161 *X + 95.34, respectively). The fitness was stronger in the GA-derived formula than the BW-derived formula (R2 = 0.973 vs 0.913). CONCLUSIONS: We established GA-/BW-dependent reference percentile-based intervals for serum IgG levels using cord blood from 2902 newborns without congenital disorders. Using GA-dependent reference intervals may be useful for assessing hypogammaglobulinemia at birth.

Impact of tracheostomies on the long-term survival of patients with trisomy 13 syndrome.

In this retrospective cohort study, we investigated the impact of tracheostomies on the long-term survival of children with trisomy 13 syndrome at a Japanese tertiary pediatric center. We compared survival and survival to discharge rates between patients who underwent tracheostomies during their NICU stays (T group, n = 8) and those who did not (non-T group, n = 11). A total of 19 patients enrolled. Median survival in all patients was 673 (266-1535) days. Significant differences in the 1-, 2-, and 3-year survival rates were found between the T and the non-T groups (100% vs. 46%, p = 0.018; 88% vs. 18%, p = 0.006; 63% vs. 9%, p = 0.041, respectively). The survival to discharge rate was higher in the T versus non-T group (75% vs. 45%, p = 0.352). This study highlights a significantly higher long-term survival of patients with trisomy 13 syndrome who underwent tracheostomies during their NICU stays.

Current status of neonatal jaundice management in Japan.

BACKGROUND: This nationwide survey aimed to determine the status of jaundice management in Japan. METHODS: A questionnaire about bilirubin level measurements and neonatal jaundice treatment was sent to 330 institutions providing neonatal care. The responses were analyzed according to institution level. RESULTS: Of 330 institutions, 172 responded (52.1% response rate). Total bilirubin levels were measured in the central laboratory using spectrophotometry at 134 institutions and a blood gas analyzer at 81 institutions. Unbound bilirubin (UB) levels were measured by 79 institutions, while transcutaneous bilirubin measurements were taken at 63 institutions. There was no association between institution level and UB or transcutaneous bilirubin measurement. For phototherapy criteria, the Murata-Imura criteria were adopted by 67 institutions, Nakamura criteria by 36, and Morioka criteria by 39. Light-emitting diodes (LED) were used by 160 institutions versus fluorescent lights by 31. When a blue LED was used, 119 institutions used the high mode. There is no standard for increasing light intensity. No association was found between institution level and phototherapy criteria. UB was measured in 14 of 63 institutions using the Murata-Imura criteria. CONCLUSIONS: There is a large variation in the management and treatment of neonatal jaundice among institutes in Japan.

Corrigendum: Influences of Orogastric and Nasogastric Tubes on Sucking Pressure during Bottle Feeding in Immature Infants.

This corrects the article in Kobe J Med Sci. 2023 May 31; 69(1): E25-E32.

Influences of Orogastric and Nasogastric Tubes on Sucking Pressure during Bottle Feeding in Immature Infants.

Orogastric (OG) and nasogastric (NG) tubes have been reported to delay breastfeeding initiation and affect respiratory function. However, the effects of feeding tubes on sucking pressure have not been well studied. Fourteen preterm infants were enrolled in this study, and their sucking pressures during bottle feeding with an OG tube, NG tube, and without any tube were measured. Sucking pressure significantly increased after changing the OG tube to an NG tube (p = 0.044). However, sucking pressure showed no significant differences after changing the feeding method from an NG tube to oral intake. Thus, NG tubes are superior to OG tubes in terms of sucking pressure.

Sustained lower bilirubin-binding affinity of albumin in extremely preterm infants.

BACKGROUND: Elevated albumin-free or unbound bilirubin (UB) levels beyond the first week of life have been associated with the development of bilirubin encephalopathy in preterm infants. However, the mechanism(s) that induces this prolonged unbound bilirubinemia has remained unknown. We hypothesized that it may due to a sustained lower bilirubin-binding affinity of albumin in extremely premature infants. METHODS: Twenty-two very preterm infants born at 28-31 weeks' gestational age (GA) (VPT Group) and 21 extremely preterm infants born at 22-27 weeks' GA (EPT Group) were retrospectively studied. On days 14, 21, and 28, bilirubin-binding affinity of albumin was assessed by calculating of the UB/total bilirubin ratio, bilirubin-albumin molar ratio (BAMR), and binding affinity (Ka). RESULTS: On days 14, 21, and 28, significantly higher UB/total bilirubin ratios were found in the EPT than in the VPT Group. Although BAMRs were comparable, significantly lower Ka values on days 14, 21, and 28 were observed in the EPT than those in the VPT Group (56.1 vs. 70.9 L/µmol, p < 0.001; 55.2 vs. 74.7 L/µmol, p < 0.001; 53.0 vs. 86.5 L/µmol, p < 0.001, respectively). CONCLUSIONS: EPT infants have a sustained lower bilirubin-binding affinity of albumin beyond the first week of life. IMPACT: Bilirubin encephalopathy is still reported in extremely preterm (EPT) infants. EPT infants often have prolonged unbound bilirubinemia beyond the first week of life. Sustained lower bilirubin-binding affinity of albumin, regardless of the bilirubin-albumin molar ratio (BAMR), is observed in EPT infants. BAMRs should not be used as a surrogate marker of unbound bilirubinemia, especially in EPT infants at a later postnatal period.