Novel MYH7 Variant in the Neonate of a Mother with Gestational Diabetes Mellitus Showing Left Ventricular Hypertrophy and Noncompaction.

BACKGROUND: Left ventricular hypertrophy (LVH) is a well-recognized cardiac dysfunction in infants of mothers with gestational diabetes mellitus (GDM). Left ventricular noncompaction (LVNC) is a cardiomyopathy that is morphologically characterized by numerous prominent trabeculations and deep intertrabecular recesses on cardiovascular imaging. However, there have been no case reports on neonates of mothers with GDM showing LVH and LVNC. CASE PRESENTATION: A patient, with LVH of a mother with GDM, was delivered at 36 weeks of gestation. Prominent trabeculations in the LV, suggesting LVNC, instead of LVH, were apparent 1 week after birth. A heterozygous deletion variant in the MYH7 gene (NM_000257.4: c.1090T>C, p.Phe364Leu) was discovered through genetic testing using a cardiomyopathy-associated gene panel in the patient and his father and the older brother who had LVNC. The patient is now 5 years old and does not have major cardiac events, although LVNC persisted. This is the first case of LVH secondary to a mother with GDM and LVNC with a novel variant in the MYH7 gene. CONCLUSION: Genetic testing should be conducted to obtain an accurate outcome and medical care in a patient with LVH and subsequently prominent hypertrabeculation in the LV.

Effects of long-term antenatal magnesium sulfate administration on the bone mineralization of preterm infants.

AIM: To evaluate the relationship between long-term antenatal magnesium sulfate (MgSO4 ) administration and neonatal bone mineralization. METHODS: Infants born at 28-33 weeks of gestation (n = 163) were divided into three groups: long-term Mg administration group (infants received antenatal MgSO4 for ≥40 days), short-term Mg administration group (infants received antenatal MgSO4 for <40 days), and non-Mg group. Serum calcium, phosphorus, Mg, and alkaline phosphatase were measured weekly up to 1 month of age, and the bone speed of sound (SOS) values were measured using quantitative ultrasound (QUS) at 1 week and 1 month after birth. RESULTS: In the long-term Mg administration group, the serum calcium values were significantly lower, and the serum phosphorus, Mg, and alkaline phosphatase values were significantly higher than those in the non-Mg group at birth. Although these biochemical differences disappeared around the age of 2 weeks, the SOS values of the long-term Mg administration group were significantly lower than those of the non-Mg group both at 1 week and 1 month after birth (p = 0.02 and <0.001, respectively). When less than 10th percentile of SOS values at 1 month after birth in the non-Mg group was defined as poor bone mineralization, the cut-off value for the duration of antenatal MgSO4 administration was 67 days. CONCLUSIONS: Long-term antenatal MgSO4 administration affects bone mineralization during the early neonatal period, but the clinically acceptable duration of the administration based on its effects of bone mineralization assessed with QUS might be longer than a few weeks.

Effects of postnatal hydrocortisone on cytokine profile in extremely preterm infants.

BACKGROUND: Systemic hydrocortisone administration has been widely used in preterm infants who are at risk of bronchopulmonary dysplasia (BPD). However, the effects of hydrocortisone on cytokine profiles have not been examined. We aimed to investigate the effects of postnatal hydrocortisone treatment on serum cytokine levels in extremely preterm infants. METHODS: This is a retrospective study of 29 extremely preterm infants born at <28 weeks of gestational age. We obtained serum from blood samples collected during an early phase (5-20 days) and a late phase (28-60 days) after birth. We measured the levels of proinflammatory cytokines (tumor necrosis factors α and ß, interleukin (IL)-1ß, and IL-6), T-helper (Th) 1 cytokines (interferon-γ, IL-2, and IL-12p70), Th2 cytokines (IL-4, IL-5, and IL-10), Th17 cytokine IL-17A, and chemokine IL-8. The cytokine levels between the early and late phases were compared between infants who received postnatal hydrocortisone and those who did not. RESULTS: Thirteen infants (45%) received systemic hydrocortisone treatment at a median age of 15 days (IQR: 10.0-21.5) after birth due to respiratory deterioration. The percentage of BPD was higher in the steroid group than in the non-steroid group (P = 0.008). The ratio of IL-6 for the late-to-early phase was significantly lower in the steroid group than in the non-steroid group (P = 0.04). The concentration of the other cytokines remained unchanged between the phases. CONCLUSIONS: Although the postnatal hydrocortisone treatment provided for respiratory deterioration did not prevent the BPD development, hydrocortisone treatment might suppress IL-6 overproduction in extremely preterm infants.

Correlation between the Bayley-III at 3 years and the Wechsler Intelligence Scale for Children, Fourth Edition, at 6 years.

BACKGROUND: Although several studies have investigated the association between Bayley-III results in infancy and future intellectual development, conclusions remain unclear. We used the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 3 years of age and the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) at 6 years of age to assess the neurodevelopment of very low birthweight infants. METHODS: We investigated the correlation between Bayley-III's cognitive, language, and motor scores and the WISC-IV's Full-Scale Intelligence Quotient (FSIQ). We also determined the optimal cut-off value of Bayley-III to enter the normal development zone (FSIQ ≥ 85). RESULTS: We found a strong correlation between the Bayley-III and the FSIQ. Optimal cut-off scores of the Bayley-III to enter the normal range on the WISC-IV were 95 for the cognitive scale, 89 for the language scale, and 91 for the motor development scale. CONCLUSIONS: Although Bayley-III scores strongly correlated with the WISC-IV FSIQ, the lower normal limit of 85 on the Bayley-III suggests a potential overestimation of development in children who were VLBW infants.

Neurodevelopmental outcomes at 3 years for infants with congenital heart disease and very-low birthweight.

BACKGROUND: Both congenital heart disease (CHD) and very-low birthweight (VLBW) infants are at a very high risk of neurodevelopmental delay. We investigated neurological development at 3 years in pediatric patients with CHD after surgical intervention, those of VLBW, and healthy controls. METHODS: We enrolled pediatric patients with CHD (n = 67), VLBW (n = 67), and healthy controls (n = 81). Infants with CHD were grouped into those with single ventricle and two ventricles, and infants with VLBW were grouped into those with birthweights of <1000 and 1000-1499 g. Neurodevelopmental outcomes at 3 years were evaluated using the Bayley Scales of Infant and Toddler Development, Third Edition. RESULTS: Compared with healthy controls, a significant deficit in the language, cognition, and motor skills scores were observed in infants with CHD and VLBW. Infants with a single ventricle exhibited significantly low scores in language and gross motor skills. No statistically significant difference was observed between the birthweight groups of <1000 and 1000-1499 g. CONCLUSION: Neurodevelopmental outcomes for infants with both CHD and VLBW showed impairment. Notably, neurodevelopmental delays in infants with a single ventricle were remarkable. Thus, because infants with both CHD and VLBW are at high risk of neurodevelopmental disorders, periodic developmental screenings and support are warranted for these children.

Establishment of the MID-NET® medical information database network as a reliable and valuable database for drug safety assessments in Japan.

PURPOSE: To establish a new medical information database network (designated MID-NET® ) to provide real-world data for drug safety assessments in Japan. METHODS: This network was designed and developed by the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency in collaboration with 23 hospitals from 10 healthcare organizations across Japan. MID-NET® is a distributed and closed network system that connects all collaborative organizations through a central data center. A wide variety of data are available for analyses, including clinical and administrative information. Several coding standards are used to standardize the data stored in MID-NET® to allow the integration of information originating from different hospitals. A rigorous and consistent quality management system was implemented to ensure that MID-NET® data are of high quality and meet Japanese regulatory standards (good post-marketing study practice and related guidelines). RESULTS: MID-NET® was successfully established as a reliable and valuable medical information database and was officially launched in April 2018. High data quality with almost 100% consistency was confirmed between original data in hospitals and the data stored in MID-NET® . A major advantage is that approximately 260 clinical laboratory test results are available for analysis. CONCLUSIONS: MID-NET® is expected to be a major data source for drug safety assessments in Japan. Experiences and best practices established in MID-NET® may provide a model for the future development of similar database networks.

Clinical Factors That Affect the Relationship between Head Circumference and Brain Volume in Very-Low-Birth-Weight Infants.

BACKGROUND AND PURPOSE: Measuring head circumference (HC) in infants is an easy screening procedure with which to detect abnormalities in brain growth. It has been demonstrated that HC can predict total brain volume (TBV) in very-low-birth-weight (VLBW) infants. However, the correlation between HC and TBV was weaker than that observed in healthy term-born toddlers, suggesting that there are factors that influence the relationship between HC and TBV. The aim of this study was to identify the clinical risk factors that caused a deviation from the regression line obtained between HC and TBV. METHODS: The study population was based on 37 VLBW infants, who underwent a clinical magnetic resonance imaging (MRI) examination at a term-equivalent age, during 2013-2015, at Toyama University Hospital. The HC and the TBV were both adjusted for sex, multiple births, and postmenstrual age. The relationship between TBV/HC and clinical characteristics was evaluated. RESULTS: There was a positive correlation between HC and TBV (r = .58, P = .000168). Two clinical factors, the lower birth body weight (BBW) (r = .38, P = .02) and dolichocephaly (r = 0.46, P = .006), were identified as factors that negatively affected the TBV/HC ratio. After excluding infants with low BBW or with dolichocephaly, the correlation between HC and TBV was higher (r = .63). CONCLUSIONS: Although HC has predictive value for TBV in VLBW infants, care should be taken in infants with low BBW (BBW less than 600 g) or dolichocephaly (MRI-based cranial index less than .68), which were related to overestimation of TBV.

Effect of preterm birth on growth and cardiovascular disease risk at school age.

BACKGROUND: Low birthweight is associated with increased risk for cardiovascular disease (CVD) in later life, but whether premature birth is also a risk factor for CVD has not been fully determined. The aim of this study was to investigate the relationship between gestational age and risk factors for CVD at school age. METHODS: Using medical check-up data of school children, the relationship between gestational age and height, weight, body mass index, blood pressure, and lipid profiles at ages 9 and 12 years were investigated in children born preterm and admitted to neonatal intensive care unit at birth (n = 182; 115 boys and 67 girls). These data were also compared between preterm small for gestational age (SGA) children and preterm appropriate for gestational age (AGA) children. RESULTS: Gestational age was positively associated with height, and inversely associated with systolic blood pressure at school age. Preterm SGA children were significantly shorter and lighter at 9 and 12 years of age compared with preterm AGA children, but there were no significant differences in any CVD risk factors between the groups. CONCLUSIONS: In preterm infants, a shorter duration of gestation is associated with higher systolic blood pressure at school age.

Protective effect of geranylgeranylacetone via enhanced induction of HSPB1 and HSPB8 in mitochondria of the failing heart following myocardial infarction in rats.

The mechanisms underlying mitochondrial impairment in the failing heart are not yet clear. In a previous study, we found that the levels of small heat shock proteins (HSP) such as mitochondrial HSPB1 and HSPB8 in the failing heart following myocardial infarction were decreased. In the present study, to verify the hypothesis that mitochondrial dysfunction in the failing heart is associated with alterations in mitochondrial small heat shock proteins, we examined the effects of geranylgeranylacetone, a heat shock protein inducer, on the cardiac mitochondrial function after myocardial infarction. When hemodynamic parameters of rats with myocardial infarction were measured at the 8th (8W) week after coronary artery ligation (CAL), the 8W-CAL showed signs of chronic heart failure concomitant with a reduced mitochondrial oxygen consumption rate. HSPB1 and HSPB8 contents in the mitochondrial fraction prepared from the failing heart were decreased, suggesting that an attenuation of mitochondrial translocation of HSPB1 and HSPB8 had led to an impairment of mitochondrial energy-producing ability. Geranylgeranylacetone treatment from the 2nd to 8th week after myocardial infarction attenuated the reduction in mitochondrial HSPB1 and HSPB8 contents. Furthermore, the mitochondrial energy-producing ability and cardiac pump function were preserved by orally administered geranylgeranylacetone during the development of heart failure. These results suggest that the induction of small heat shock proteins in the infarcted heart by geranylgeranylacetone treatment contributed to the preservation of mitochondrial function, leading to an improvement of cardiac contractile function.

Intrauterine growth restriction modifies gene expression profiling in cord blood.

BACKGROUND: Small-for-gestational-age (SGA) newborns are at an increased risk for perinatal morbidity and mortality and development of metabolic syndromes such as cardiovascular disease and type 2 diabetes mellitus (T2DM) in adulthood. The mechanism underlying this increased risk remains unclear. In this study, genetic modifications of cord blood were investigated to characterize fetal change in SGA newborns. METHODS: Gene expression in cord blood cells was compared between 10 SGA newborns and 10 appropriate-for-gestational-age (AGA) newborns using microarray analysis. Pathway analysis was conducted using the Ingenuity Pathways Knowledge Base. To confirm the microarray analysis results, quantitative real-time polymerase chain reaction (RT-PCR) was performed for upregulated genes in SGA newborns. RESULTS: In total, 775 upregulated and 936 downregulated probes were identified in SGA newborns and compared with those in AGA newborns. Of these probes, 1149 were annotated. Most of these genes have been implicated in the development of cardiovascular disease and T2DM. There was good agreement between the RT-PCR and microarray analyses results. CONCLUSIONS: Expression of certain genes was modified in SGA newborns in the fetal period. These genes have been associated with metabolic syndrome. To clarify the association between modified gene expression in cord blood and individual vulnerability to metabolic syndrome in adulthood, these SGA newborns will be have long-term follow up for examination of genetic and postnatal environmental factors. Gene expression of cord blood can be a useful and non-invasive method of investigation of genetic alterations in the fetal period.

Changes in small heat shock proteins HSPB1, HSPB5 and HSPB8 in mitochondria of the failing heart following myocardial infarction in rats.

The mechanisms underlying mitochondrial impairment in the failing heart are not yet clearly defined. In the present study, we examined the involvement of changes in small heat shock proteins (HSPs) such as HSPB1, HSPB5 and HSPB8 in mitochondrial dysfunction of the failing heart. Hemodynamic parameters of rats with myocardial infarction at the 2nd and 8th weeks (2W- and 8W-) after coronary artery ligation (CAL) were measured. The 8W-CAL rats, but not the 2W-CAL ones, showed the signs of the chronic heart failure concomitant with a reduced mitochondrial oxygen consumption rate. In the mitochondrial fraction prepared from the heart of the 2W-CAL animals, the contents of small HSPs and phosphorylated small HSPs were increased, suggesting that these increases contributed to the preservation of the mitochondrial energy-producing ability. In the failing heart, HSPB1 and HSPB8 contents and phosphorylated small HSP contents in the mitochondrial fraction were decreased, suggesting that a reduction in mitochondrial translocation of these small HSPs led to impaired mitochondrial energy-producing ability. To further define the submitochondrial locations of these small HSPs, we performed mitochondrial subfractionation. The contents of small HSPs in the 2W-CAL rats were increased in the mitochondrial inner-membrane fraction, whereas those of the 8W-CAL rats were reversed to those of the control animals. These findings suggest that small HSPs, at least in part, play an important role in the development of the impaired mitochondrial energy-producing ability that leads to heart failure after a myocardial infarction.

[Preliminary study on automated detection of cerebral vessels from head CTA images].

We propose an approach for automated detection of cerebral vessels from head CT angiographic images. This approach contains two major features. First, instead of using the well-known image-processing techniques such as thresholding and labeling, a novel Laplacian-like filter is developed and employed in the region of interest in an image to be processed. Second, not only is the axial-view image reconstructed from head CT angiographic images used, but, in addition, the sagittal- and coronal-view images are reconstructed and used. By applying these major features in the process of detection of brain vessels, more accurate results can be achieved. To validate the effectiveness of the proposed method, we applied the method to three clinical cases, all of which were head CT angiograms. Our preliminary results showed that the proposed method has the potential to automatically detect cerebral vessels in head CT angiograms with acceptable accuracy.