Miharu Ito

Serial diffusion-weighted imaging of neonatal herpes encephalitis: A case report

We reported a patient with neonatal herpes simplex encephalitis in whom diffusion-weighted imaging was performed repeatedly. Diffusion-weighted imaging at 20h after the onset of seizures revealed scattered small spotty high intensity lesions in both hemispheres and a high intensity area in the left fronto-temporal lobe. There was no abnormal finding on conventional magnetic resonance imaging. Second diffusion-weighted imaging 72h after the onset revealed expanded scattered high intensity lesions in the bilateral hemisphere, a high intensity area in the left fronto-temporal lobe, and a new high intensity area in the right temporal lobe. There was no report on neonatal herpes simplex encephalitis that showed scattered high intensities in diffusion-weighted imaging. Scattered small high intensities on diffusion-weighted imaging may suggest endothelial cell infection with swelling and small vessel necrosis. Early diffusion-weighted imaging will be valuable for early detection and diagnosis of neonatal herpes simplex encephalitis.

Effect of hospital volume on the mortality of congenital diaphragmatic hernia in Japan

During the last decade, new supportive modalities and new therapeutic strategies to treat congenital diaphragmatic hernia (CDH) have been introduced. In Japan, the large number of hospitals prevents centralizing infants with CDH in tertiary centers. The aim of this study was to evaluate the correlations between the number of CDH patients, survival rates, and the current strategies employed to treat CDH at the individual hospitals.

Dexamethasone administration to the neonatal rat results in neurological dysfunction at the juvenile stage even at low doses

Dexamethasone (DEX), a synthetic glucocorticoid, has been widely used to prevent the development of a variety of poor health conditions in premature infants including chronic lung disease, inflammation, circulatory failure, and shock. Although there are some reports of neurologic complications related to DEX exposure, its full effects on the premature brain have not been examined in detail. To investigate the effects of DEX on neural development, we first administered low doses (0.2 mg/kg bodyweight or less) of the glucocorticoid to neonatal rats on a daily basis during the first postnatal week and examined subsequent behavioral alterations at the juvenile stage. DEX-treated rats exhibited not only a significant reduction in both somatic and brain weights but also learning disabilities as revealed in the shuttle avoidance test. The hippocampi of DEX-treated rats displayed a high apoptotic and a low mitotic cell density compared to control rats on day 7 after birth. In a subsequent experiment, neural stem/progenitor cells were cultured in the presence of DEX for 6 days. The glucocorticoid inhibited cell growth without an increase in cell death. These results suggest that administration of DEX to premature infants induces neurological dysfunction via inhibition of the proliferation of neural stem/progenitor cells.

Atypical social development in neonatal intensive care unit survivors at 12 months

Background:  Owing to advances in neonatal intensive care, many infants who are hospitalized in neonatal intensive care units (NICU) can survive and grow, and are referred to as NICU survivors. However, social development in NICU survivors has not been fully explored.

Rat umbilical cord blood cells attenuate hypoxic–ischemic brain injury in neonatal rats

Increasing evidence has suggested that human umbilical cord blood cells (hUCBC) have a favorable effect on hypoxic–ischemic (HI) brain injury. However, the efficacy of using hUCBCs to treat this injury has been variable and the underlying mechanism remains elusive. Here, we investigated its effectiveness using stereological analysis in an allogeneic system to examine whether intraperitoneal injection of cells derived from UCBCs of green fluorescent protein (GFP)-transgenic rats could ameliorate brain injury in neonatal rats. Three weeks after the HI event, the estimated residual brain volume was larger and motor function improved more in the cell-injected rats than in the control (PBS-treated) rats. The GFP-positive cells were hardly detectable in the brain (0.0057% of injected cells) 9 days after injection. Although 60% of GFP-positive cells in the brain were Iba1-positive, none of these were positive for NeuroD or DCX. While the number of proliferating cells increased in the hippocampus, that of activated microglia/macrophages decreased and a proportion of M2 microglia/macrophages increased in the ipsilateral hemisphere of cell-injected rats. These results suggest that intraperitoneal injection of cells derived from UCBCs could ameliorate HI injury, possibly through an endogenous response and not by supplying differentiated neurons derived from the injected stem cells.

Spontaneous spinal epidural hematoma in an infant with undiagnosed hemophilia A

Major symptoms of patients with hemophilia are subcutaneous hemorrhage, intramuscular hemorrhage, and intra-articular hemorrhage. Moreover, central nervous system (CNS) hemorrhage is sometimes seen in hemophilia. This is a serious condition, and appropriate diagnosis and treatment are necessary for a good outcome. Spinal epidural hematoma (SEH) is a rare complication in CNS hemorrhage, compared to the incidence of intracranial hemorrhage. Once established, SEH continuously compresses the spinal cord and nerve roots, and the patient shows neurological abnormalities such as sensory disturbance, paralysis of the extremities or urination disturbance. We encountered an unusual case in a patient with severe hemophilia A, in which SEH was presented as an initial symptom, and it was treated successfully with factor VIII replacement. Magnetic resonance imaging (MRI) findings were reported previously. In this article, we report the detailed clinical course and review the relevant literature.

Dedifferentiated Fat Cells as a Novel Source for Cell Therapy to Target Neonatal Hypoxic-Ischemic Encephalopathy

Neonatal hypoxic-ischemic (HI) encephalopathy (HIE) remains a major cause of mortality and persistent neurological disabilities in affected individuals. At present, hypothermia is considered to be the only applicable treatment option, although growing evidence suggests that cell-based therapy might achieve better outcomes. Dedifferentiated fat (DFAT) cells are derived from mature adipocytes via a dedifferentiation strategy called ceiling culture. Their abundance and ready availability might make them an ideal therapeutic tool for the treatment of HIE. In the present study, we aimed to determine whether the outcome of HIE can be improved by DFAT cell treatment. HI injury was achieved by ligating the left common carotid artery in 7-day-old rat pups, followed by 1-h exposure to 8% O2. Subsequently, the severity of damage was assessed by diffusion-weighted magnetic resonance imaging to assign animals to equivalent groups. 24 h after hypoxia, DFAT cells were injected at 105 cells/pup into the right external jugular vein. To evaluate brain damage in the acute phase, a group of animals was sacrificed 48 h after the insult, and paraffin sections of the brain were stained to assess several acute injury markers. In the chronic phase, the behavioral outcome was measured by performing a series of behavioral tests. From the 24th day of age, the sensorimotor function was examined by evaluating the initial forepaw placement on a cylinder wall and the latency to falling from a rotarod treadmill. The cognitive function was tested with the novel object recognition (NOR) test. In vitro conditioned medium (CM) prepared from cultured DFAT cells was added at various concentrations to neuronal cell cultures, which were then exposed to oxygen-glucose deprivation (OGD). The number of cells that stained positive for the apoptosis marker active caspase-3 decreased by 73 and 52% in the hippocampus and temporal cortex areas of the brain, respectively, in the DFAT-treated pups. Similarly, the numbers of ED-1-positive cells (activated microglia) decreased by 66 and 44%, respectively, in the same areas in the DFAT-treated group. The number of cells positive for the oxidative stress marker 4-hydroxyl-2-nonenal decreased by 68 and 50% in the hippocampus and the parietal cortex areas, respectively, in the DFAT-treated group. The HI insult led to a motor deficit according to the rotarod treadmill and cylinder test, where it significantly affected the vehicle group, whereas no difference was confirmed between the DFAT and sham groups. However, the NOR test indicated no significant differences between any of the groups. DFAT treatment did not reduce the infarct volume, which was confirmed immunohistochemically. According to in vitro experiments, the cell death rates in the DFAT-CM-treated cells were significantly lower than those in the controls when DFAT-CM was added 48 h prior to OGD. The treatment effect of adding DFAT-CM 24 h prior to OGD was also significant. Our results indicate that intravenous injection with DFAT cells is effective for ameliorating HI brain injury, possibly via paracrine effects.

A highly-sulfated chondroitin sulfate, CS-E, adsorbs specifically to neurons with nuclear condensation

A highly sulfated chondroitin sulfate, CS-E, prevents excitatory amino acid-induced neuronal cell death by an as yet unknown mechanism. To reveal this mechanism, we pretreated neurons in culture with various inhibitors, and examined whether N-methyl-D-aspartic acid (NMDA)-induced neuronal cell death was reduced in the presence of CS-E. The inhibitors of protein kinase C (PKC) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) ameliorated NMDA-induced neuronal cell death, but did not affect the neuroprotective activity of CS-E. Among the growth factors with which CS-E can interact, high concentration of BDNF protected against the NMDA-induced neuronal cell death and strengthened neuroprotection by CS-E. CS-E, but neither CS-A nor CS-C, adsorbed to a subclass of neurons with nuclear condensation, namely pyknosis. Contactin-1 (CNTN-1), a putative receptor for neuritogenic activity of CS-E, was present in cortical neurons, but a neutralizing antibody to CNTN-1 did not block neuroprotective activity of CS-E. The results suggest that CS-E may prevent the progression of cell death at the early stages of excitotoxicity through a signaling pathway different from CNTN-1.

Carbohydrate and Energy Metabolism in the Brain of Rats With Thromboxane A2-Induced Fetal Growth Restriction

Fetal growth restriction (FGR) remains a cause of perinatal brain injury, sometimes leading to neurological and intellectual impairment. Although the mechanisms and pathophysiology of CNS injuries have not been elucidated completely, it is possible carbohydrate and energy metabolism may have an important role in the FGR brain. In this study, FGR was induced in rats by administration of synthetic thromboxane A2 (STA2). Pups were delivered by cesarean section. After killing, samples were obtained from the fetuses of both control and FGR rats for evaluation of carbohydrate and energy metabolism in brain tissue. Lactate and pyruvate levels in brain were reduced significantly in the FGR group. Glucose content in brain tissue tended to be increased in the FGR group. In contrast, glycogen content in brain tissue tended to be lower in the FGR group. However, these differences in glucose and glycogen content did not reach statistical significance. Brain high-energy reserves, including ATP, ADP, AMP, and phosphocreatine (P-Cr), were similar in the control and FGR groups. Gluconeogenesis compensated for chronic fetal hypoxia and decreased glycogen storage. Energy metabolism in the FGR brain is likely to be disrupted as a consequence of lower reserves of energy substrates.

Magnetic resonance spectroscopy in preterm infants: association with neurodevelopmental outcomes

Objective To compare magnetic resonance spectroscopy (MRS) metabolite ratios in preterm infants at term-equivalent age with those in term infants and to evaluate the association between MRS metabolites and neurodevelopmental outcomes at 18 months corrected age in preterm infants. Design We studied infants born at a gestational age <37 weeks and weighing <1500 g during 2009–2013 using MRS at term-equivalent age. Infants with major brain abnormalities were excluded. The ratios of N-acetylaspartate (NAA) to creatine (Cre), NAA to choline-containing compounds (Cho) and Cho to Cre in the frontal white matter and thalamus were measured using multivoxel point-resolved proton spectroscopy sequence. Neurodevelopmental outcomes were assessed at 18 months corrected age. Results Thirty-three preterm infants and 16 term infants were enrolled in this study. Preterm infants with normal development at 18 months showed significantly lower NAA/Cho ratios in the frontal white matter than term infants. There were no differences in the Cre/Cho ratios between preterm and term infants. At 18 months corrected age, 9 preterm infants with a mild developmental delay showed significantly lower NAA/Cho ratios in the thalamus than 24 preterm infants with normal development. Conclusions Preterm infants at term-equivalent age showed reduced MRS metabolites (NAA/Cho) compared with term infants. Decreased NAA/Cho ratios in the thalamus were associated with neurodevelopmental delay at 18 months corrected age in preterm infants.