Evaluation of the social skills of low birthweight infants using the Interaction Rating Scale.

[Purpose] This study aimed to examine, using the Interaction Rating Scale, the effect of social skills at 18 months of life on the subsequent development of low birthweight infants. [Participants and Methods] The study participants were made up of a total of 23 infants who were admitted to the neonatal intensive care unit of Hospital A and whose developmental indexes were followed up at the outpatient clinic for up to 3 years of age. The survey was conducted twice in each infant, at a corrected age of 18 months and at 36 full months of age. Social skills and developmental indexes were assessed at the corrected age of 18 months, meanwhile only developmental indexes were assessed at 36 full months, to examine associations. The Interaction Rating Scale was used to assess social skills. This scale measures various aspects of social development by observing caregiver-child interactions in situations wherein children are engaged in tasks more difficult for their age. [Results] The results demonstrated that social skills at 18 months were associated with the developmental indexes at 18 and 36 months, whereas more items were associated with the developmental index at 36 months. [Conclusion] The results indicate the need for early prediction of developmental delay and timely intervention, by assessing social skills in low birthweight infants.

[Decreased Serum Copper Concentrations by Zinc Administration in Preterm Infants with Hypozincemia Are Associated with a Lower Postmenstrual Age: A Single-center Retrospective Observational Study].

Copper is one of the essential trace elements in humans, and its deficiency causes various diseases. Zinc acetate dihydrate is administered to treat hypozincemia in preterm infants; however, zinc inhibits the gastrointestinal absorption of copper, which may cause copper deficiency. To safely treat hypozincemia in preterm infants, we retrospectively analyzed the factors reducing serum copper concentrations when zinc is administered to preterm infants with hypozincemia. Seventy preterm infants were included in the present study. Serum zinc and copper concentrations, doses, and other clinical characteristics were retrieved from electronic medical records. The administration of zinc acetate dihydrate decreased serum copper concentrations in 21 out of 70 patients. In comparisons between the two groups with and without a decrease in serum copper concentrations, significant differences were observed in postmenstrual age (34.9 and 35.9 weeks, respectively) and serum zinc concentrations (62.0 and 58.0 µg/dL, respectively) at the start of the zinc acetate dihydrate treatment. A logistic regression analysis identified postmenstrual age as a significant factor decreasing serum copper concentrations. In the ROC curve, the cut-off value for postmenstrual age for a decrease in serum copper concentrations was 34.143 weeks. The present results suggest that when zinc acetate dihydrate is administered to preterm infants with a low postmenstrual age who are at higher risk of decreased serum copper concentrations, particularly to those with a postmenstrual age <34 weeks, it is important to consider copper deficiency and periodically measure serum copper concentrations.

One-rescuer newborn CPR using a face mask or an i-gel supraglottic airway and two-finger compressions - A manikin study with cross-over desgin.

Introduction: When unanticipated neonatal asphyxia occurs, it may be necessary for a single resuscitator to commence advanced resuscitation before others arrive. We hypothesised that a single rescuer can provide positive pressure ventilations and chest compressions using higher inflation pressures and better adherence to the recommended compression rate with an i-gel supraglottic airway than with a face mask. Method: A manikin-based cross-over study was conducted. Twenty-one midwives performed both positive pressure ventilation using a T-piece and chest compressions with the two-finger technique on a newborn manikin alone. They performed ventilation with a face mask or an i-gel. The peak inspiratory pressure (PIP) was set to 30 cmH2O. The actual PIPs were evaluated based on the values displayed on the manometer. The total amount of time taken to complete 30 cycles of three compressions and one ventilation was also evaluated. Results: The mean of the average PIP for each participant was significantly lower with a face mask than with an i-gel (17.3 ± 4.4 vs 28.2 ± 2.0 cmH2O, p < 0.00001). The amount of time taken to complete 30 cycles was significantly longer with a face mask than with an i-gel (66.2 ± 6.1 vs 60.6 ± 3.4 seconds, p < 0.0001). Conclusion: During one-rescuer newborn resuscitation using a T-piece and the two-finger technique, the PIPs are consistently high and 30 cycles of CPR are better adhered to 60 seconds using an i-gel.

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.

PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.

Administration of zinc to preterm infants with hypozincemia does not reduce serum copper concentrations in most cases: a single-center retrospective observational study.

BACKGROUND: Zinc is an essential trace element involved in various physiological functions. In Japan, zinc acetate dihydrate is administered to neonates and infants with hypozincemia. Since serum copper concentrations are reduced by the administration of zinc, we retrospectively investigated changes in serum zinc and copper concentrations in preterm infants with hypozincemia receiving zinc acetate dihydrate. METHODS: Sixty-three preterm infants were included in the present study. Serum zinc and copper concentrations, doses, and other clinical characteristics were retrieved from electronic medical records. RESULTS: The medians and interquartile ranges of the dosage and duration of zinc acetate dihydrate were 2.1 (1.8-2.5) mg/kg/day and 12.0 (10.0-13.0) days, respectively. Its administration increased serum zinc concentrations in 39 patients (61.9%) and to more than 70 µg/dL in 16 patients (25.4%). The group with a serum zinc concentration of 70 µg/dL or higher after administration had a significantly higher zinc dose of 2.5 mg/kg/day than the group with a serum zinc concentration of less than 70 µg/dL. Serum copper concentrations did not decrease in 44 patients (69.8%). In the group with a decreased serum copper concentration, postmenstrual age and body weight were significantly lower, while serum zinc concentrations were significantly higher at the start of administration. CONCLUSION: The present results showed that when zinc acetate dihydrate was administered to preterm infants with hypozincemia, it was possible to increase serum zinc concentrations without decreasing serum copper concentrations in many cases. However, caution may be required when administering zinc to preterm infants with a lower postmenstrual age or milder hypozincemia because serum copper concentrations may decrease.

Normothermic machine perfusion system satisfying oxygen demand of liver could maintain liver function more than subnormothermic machine perfusion.

Liver transplantation plays an important role in the medical field. To improve the quality of a donor liver, there is a need to establish a preservation system to prevent damage and maintain liver function. In response to this demand, machine perfusion (MP) has been proposed as a new liver preservation method instead of the conventional static cold storage. There is controversy about the optimal MP temperature of the donor liver. Since the oxygen consumption of the liver differs depending on the temperature, construction of a system that satisfies the oxygen demand of the liver is crucial for optimizing the preservation temperature. In this study, an MP system, which satisfies the oxygen demand of liver at each temperature, was constructed using an index of oxygen supply; the overall volumetric oxygen transfer coefficient, the amount of oxygen retention of perfusate and oxygen saturation. Both subnormothermic MP (SNMP, 20-25 °C) and normothermic MP (NMP, 37 °C) could maintain liver viability at a high level (94%). However, lactate metabolism of the liver during NMP was more active than that during SNMP. Furthermore, the ammonia metabolism of liver after NMP was superior to that after SNMP. Hence, NMP, which maintains the metabolic activity of the liver, is more suitable for preservation of the donor liver than SNMP, which suppresses the metabolic activity. In summary, normothermia is the optimal temperature for liver preservation, and we succeeded in constructing an NMP system that could suppress liver damage and maintain function.

Management of a case of transient neonatal diabetes mellitus using continuous glucose monitoring.

Neonatal diabetes mellitus (NDM) is a very rare disorder and its diagnosis can be challenging especially in mild and transient cases. Herein, we describe a 2.4-kg female infant born at 38 wk of gestation who showed hyperglycemia (388 mg/dL) on Day 1. Intermittent blood sampling showed glucose concentrations of 100-150 mg/dL on Day 2-5. However, continuous glucose monitoring (CGM) from Day 7 revealed hyperglycemia (> 200 mg/dL) after every feeding. The patient required low-dose (0.1-0.2 U/kg/d) insulin therapy for a short period (7 d). During the treatment, hypoglycemic (< 50 mg/dL) events were not detected by real- time CGM. Follow-up CGM from Day 32 showed normoglycemia for 3 full days; therefore, we ascertained that the diabetes had been transient. Later genetic analysis revealed an abnormal methylation pattern on chromosome 6q24, which is the most frequent cause of transient NDM. Most cases of 6q24-related NDM relapse after puberty, implying that long term follow up is required. We speculate that the NDM in this case might not have been diagnosed without CGM. This report highlights the usefulness of CGM for the initial diagnosis, monitoring during insulin therapy, and confirmation of improvement in patients with transient NDM.

A bioartificial liver device based on three-dimensional culture of genetically engineered hepatoma cells using hollow fibers.

The bioartificial liver (BAL) device is an extracorporeal liver support system incorporating living hepatocytes. A major problem in BAL device development is to obtain a high number of functional cells. In this study, we focused on a genetically engineered mouse hepatoma cell line, Hepa/8F5, in which elevated liver functions are induced via overexpression of liver-enriched transcription factors activated by doxycycline (Dox) addition. We applied a three-dimensional culture technique using hollow fibers (HFs) to Hepa/8F5 cells. Hepa/8F5 cells responded to Dox addition by reducing their proliferative activity and performing liver-specific functions of ammonia removal and albumin secretion. The functional activities of cells depended on the timing of Dox addition. We also found that Hepa/8F5 cells in the HF culture were highly functional in a low rather than high cell density environment. We further fabricated an HF-type bioreactor with immobilized Hepa/8F5 cells as a BAL device. Although ammonia removal activity of this BAL device was lower than that of the small-scale HF bundle, albumin secretion activity was slightly higher. These results indicated that the BAL device with immobilized Hepa/8F5 cells was highly functional with potential to show curative effects in liver failure treatment.

Colonic Perforation in a Term Newborn with Hereditary Protein C Deficiency.

We describe a term infant who experienced recurrent apnea associated with intracranial hemorrhage and later, developed colonic perforation. Plasma protein C activity was below detectable limits and a heterozygous PROC mutation was identified. Neonatal colonic perforation is rare, and this case report highlights the importance of considering congenital Protein C deficiency.

Expansion and differentiation of human iPS cells in a three-dimensional culture using hollow fibers and separation of the specific population by magnetic-activated cell sorting.

In order to employ pluripotent stem cells in the field of regenerative medicine, it is necessary to establish a large-scale culture system for cell differentiation. We have developed a novel three-dimensional method for culturing human induced pluripotent stem (iPS) cells, using hollow fibers (HFs). The cells immobilized inside HFs can proliferate and form multicellular aggregates, capable of achieving a high cell density and promoting further spontaneous cell differentiation. We first cultured human iPS cells for 7 days under conditions that maintained their undifferentiated state and then switched the culture conditions to allow spontaneous cell differentiation. In the 7-day undifferentiated culture, a high cell density of approximately 10-fold that of the initial seeding density was achieved. The upregulation of gene markers for differentiation such as CXCR4 or SOX17 was observed in the culture of differentiated cells. Expression of the lineage-specific cell-surface marker CXCR4 was about 30% at day 5 in the differentiation culture, which was 2-fold higher than that in the traditional monolayer culture. After HF culture, we obtained the CXCR4-positive cell population and performed monolayer culture for further differentiation of the hepatic lineage. In the CXCR4-positive cell population, the expression levels of a few liver-specific gene markers tended to increase. However, there were no significant differences between the separation and non-separation groups, which indicates the need for refinement of the cell separation process and cell maturation procedure in future studies. In conclusion, the HF culture method has potential for achieving the large-scale culturing and spontaneous differentiation of human iPS cells.

TRPV6 Gene Mutation in a Dizygous Twin With Transient Neonatal Hyperparathyroidism.

Maternal-fetal transport of calcium (Ca2+) is important for bone mineralization in fetal development. Insufficient Ca2+ transport causes transient neonatal hyperparathyroidism (TNHP). Transient receptor potential cation channel, subfamily V, member 6 (TRPV6), has been found to play an important role in the active transport of Ca2+ through the placenta. Recently, TRPV6 gene was found to be the gene responsible for TNHP with severe skeletal undermineralization. To date, only seven cases of TNHP caused by TRPV6 recessive mutations have been reported. We present a case of TNHP caused by TRPV6 gene mutations. A female newborn was hospitalized because of respiratory distress. Marked undermineralization of the skeleton was observed in X-ray imaging. Laboratory examination revealed markedly high PTH and absence of hypercalcemia along with vitamin D deficiency. Her twin brother presented with almost no symptoms. Maternal laboratory findings indicated normocalcemia, but vitamin D deficiency with a high PTH level for the lactation period was observed. We initially diagnosed the patient as having secondary hyperparathyroidism because of maternal vitamin D deficiency. Nevertheless, the reasons underlying the discordant clinical manifestations between the twin siblings remained unclear. Our analysis of TRPV6 gene clarified that the patient had compound heterozygote mutations, which were reported previously (p.Ile223Thr and p.Gly428Arg). Pathologic mutations in TRPV6 gene were not detected in the other sibling. The clinical symptoms in the patient were transient: they resolved during infancy. TNHP caused by TRPV6 gene mutations is a unique disease in terms of its transient pathology in utero and relief after birth.

Introduction of laryngeal mask airway in Japan, and its rescue use for newborns.

BACKGROUND: In neonatal resuscitation, laryngeal mask airway (LMA) is recommended when both face mask ventilation and endotracheal intubation fail. Experience of LMA among obstetricians, nurses and midwives in Japan, however, is limited. The aims of the present study were to (i) offer an LMA training course to professionals dealing with low-risk pregnancies at institutions across Japan; and (ii) assess the subsequent use and value of LMA at the participating institutions. METHODS: Between August 2016 and March 2017, a total of 18 training courses for 60 min were provided for around 350 medical personnel from 51 institutes. LMA use over the subsequent 12 months was assessed via a postal questionnaire. RESULTS: After training, a total of 38 institutes introduced LMA. Of 13 254 live births, seven cases of rescue use LMA in "cannot ventilate, cannot intubate" situations were reported. None of these seven newborns had any malformation of the upper airway. LMA insertion resulted in adequate ventilation in all seven cases. CONCLUSION: LMA can be a life-saving tool in neonatal resuscitation. All medical institutions dealing with low-risk pregnancies in Japan should be equipped with this device.

Evaluation of hollow fiber culture for large-scale production of mouse embryonic stem cell-derived hematopoietic stem cells.

Hematopoietic stem cells (HSCs) have the ability to differentiate into all types of blood cells and can be transplanted to treat blood disorders. However, it is difficult to obtain HSCs in large quantities because of the shortage of donors. Recent efforts have focused on acquiring HSCs by differentiation of pluripotent stem cells. As a conventional differentiation method of pluripotent stem cells, the formation of embryoid bodies (EBs) is often employed. However, the size of EBs is limited by depletion of oxygen and nutrients, which prevents them from being efficient for the production of HSCs. In this study, we developed a large-scale hematopoietic differentiation approach for mouse embryonic stem (ES) cells by applying a hollow fiber (HF)/organoid culture method. Cylindrical organoids, which had the potential for further spontaneous differentiation, were established inside of hollow fibers. Using this method, we improved the proliferation rate of mouse ES cells to produce an increased HSC population and achieved around a 40-fold higher production volume of HSCs in HF culture than in conventional EB culture. Therefore, the HF/organoid culture method may be a new mass culture method to acquire pluripotent stem cell-derived HSCs.

Recurrence of Escherichia coli meningitis in a preterm infant and co-infection of echovirus 18.

Introduction: Bacterial meningitis may relapse after adequate antibiotic treatment. In most cases, however, the pathophysiology cannot be identified. Presentation of case: We describe a preterm infant with recurrent episodes of meningitis due to infection with an identical Escherichia coli strain both at birth and at 10 days after cessation of a 3 week course of appropriate antibiotic treatment. At the time of recurrence, the patient presented with fulminant severe cardiac failure due to acute myocarditis, coupled with a concurrent echovirus 18 infection (confirmed by stool culture and serological analysis). Conclusion: Co-infection by echovirus may underlie recurrence of Escherichia coli meningitis in this case.

Alleviating liver failure conditions using an integrated hybrid cryogel based cellular bioreactor as a bioartificial liver support.

Conventionally, some bioartificial liver devices are used with separate plasmapheresis unit to separate out plasma from whole blood and adsorbent column to detoxify plasma before it passes through a hepatocytes-laden bioreactor. We aim to develop a hybrid bioreactor that integrates the separate modules in one compact design improving the efficacy of the cryogel based bioreactor as a bioartificial liver support. A plasma separation membrane and an activated carbon cloth are placed over a HepG2-loaded cryogel scaffold in a three-chambered bioreactor design. This bioreactor is consequently connected extracorporeally to a rat model of acute liver failure for 3 h and major biochemical parameters studied. Bilirubin and aspartate transaminase showed a percentage decrease of 20-60% in the integrated bioreactor as opposed to 5-15% in the conventional setup. Urea and ammonia levels which showed negligible change in the conventional setup increase (40%) and decrease (18%), respectively in the integrated system. Also, an overall increase of 5% in human albumin in rat plasma indicated bioreactor functionality in terms of synthetic functions. These results were corroborated by offline evaluation of patient plasma. Hence, integrating the plasmapheresis and adsorbent units with the bioreactor module in one compact design improves the efficacy of the bioartificial liver device.

Fabrication of a fiber-type hepatic tissue by bottom-up method using multilayer spheroids.

Liver regenerative medicine, a therapy using cultured hepatocytes or hepatic tissues, has the potential to replace liver transplantation. However, this therapeutic strategy has challenges to overcome, including in construction of the hepatic tissues. As an approach to fabricating functional 3D hepatic tissues, we focused on hepatocyte spheroids, which have high cell density and maintain high liver-specific functions. We employed a bottom-up method using spheroids, arranging hepatocytes and endothelial cells regularly at the time of tissue construction. This enabled a vascular network to be formed within the three-dimensional hepatic tissue. We included NIH/3T3 cells, known to promote vasculature formation by endothelial cells. We fabricated hepatocyte spheroids covered with human umbilical vein endothelial cells (HUVECs) and NIH/3T3 cells (EC-3T3-covered hepatocyte spheroids) and constructed the hepatic tissues by stacking these cell types in hollow fibers. We then performed histological and functional analyses of the resulting hepatic tissues. The hepatic tissues constructed by stacking EC-3T3-covered hepatocyte spheroids showed high liver-specific functions; that is, ammonia removal and albumin secretion. The HUVECs formed endothelial networks. In addition, hypoxia-inducible factor-1α (HIF-1α) expression was suppressed in the hepatic tissue throughout the culture period and the hepatic tissue was sufficiently strong for use in certain analyses and applications. In summary, we fabricated a functional 3D hepatic tissue by the bottom-up method using hepatocyte spheroids covered with HUVECs and NIH/3T3 cells.