Minoru Shibata

Broad cortical activation in response to tactile stimulation in newborns.

Tactile sensation, which is one of the earliest developing sensory systems, is very important in the perception of an individual’s body and the surrounding physical environment, especially in newborns. However, currently, only little is known about the response of a newborn’s brain to tactile sensation. The objective of the present study was to determine the response of a newborn’s brain to tactile sensation and to compare the brain responses to various sensory stimuli. Ten healthy newborns, 2–9 days after birth, were enrolled. A multichannel near-infrared spectroscopy system was used to measure brain responses. The probe array covered broad cortical areas, including the parietal, temporal, and occipital areas. We measured cortical hemodynamic changes in response to three different types of stimuli: tactile, auditory, and visual. Activated areas were analyzed by t-tests, and the number of activated channels among the three different stimuli was compared by &khgr;2-tests. The results showed that when the brain responded to each type of stimulation, the corresponding primary sensory area was activated, and tactile stimuli induced broader areas of brain activation than the other two types of stimuli (auditory or visual). Thus, broad brain areas, including the temporal and parietal areas, were activated by tactile stimuli in early newborn periods. These results suggest that there are differences in newborns’ reactions to various types of sensory stimuli, which may reflect the importance of tactile sensation in the early newborn period.

Loss of Borealin/DasraB leads to defective cell proliferation, p53 accumulation and early embryonic lethality

Borealin/DasraB is a member of the chromosomal passenger protein complex (CPC) required for proper segregation of chromosomes during mitosis. In Drosophila melanogaster, inactivation of Borealin/DasraB results in polyploidy, delayed mitosis and abnormal tissue development, indicating its critical role for cell proliferation. However, the in vivo role of mammalian Borealin/DasraB remains unclear. Here, we analyzed the expression of Borealin/DasraB and found that borealin is widely expressed in embryonic tissues and later restricted to adult tissues which relies on rapid cell proliferation. To determine the role of borealin during mouse development, we generated borealin-null mice through targeted disruption. While heterozygous mice developed normally, disruption of both borealin alleles resulted in early embryonic lethality by 5.5 dpc (days postcoitus) due to mitotic defects and apoptosis in blastocyst cells that showed microtubule disorganization and no CPC enrichment. At 5.5 dpc, borealin-null embryos exhibited excessive apoptosis and elevated expression of p53. However, loss of p53 did not abrogate or delay embryonic lethality, revealing that Borealin/DasraB inactivation triggered impaired mitosis and apoptosis though p53-independent mechanisms. Our data show that Borealin/DasraB is essential for cell proliferation during early embryonic development, and its early embryonic lethality cannot be rescued by the loss of p53.

Diagnostic Value of Salivary Cortisol in the CRH Stimulation Test in Premature Infants

CONTEXTnAccording to a recent nationwide survey in Japan, a significant proportion of very low birth weight infants (VLBWI) develop late-onset circulatory collapse after the first week of life. Small doses of glucocorticoid are very effective in these patients, and relative adrenal insufficiency is suspected to be the main cause of the condition. Although the CRH test is required to evaluate the hypothalamic-pituitary-adrenal axis, obtaining multiple blood samples is invasive.nnnOBJECTIVESnThe present study was carried out to validate the consistency of the cortisol profiles of matched serum and saliva samples collected as part of the CRH test from VLBWI.nnnSUBJECTS/METHODSnIn 23 VLBWI with a gestational age of less than 29 wk, we performed CRH tests at 2 wk after birth and at term. Their cortisol values were measured at the baseline and 30 min after the administration of a single dose of human CRH (1 μg/kg) using matched serum and saliva samples.nnnRESULTSnIn 26 CRH tests in 19 infants, we were able to measure both serum and salivary cortisol. Significant correlations were detected between the infants serum and salivary cortisol values (r=0.78; P<0.0001), the increases in these values induced in response to the CRH test (r=0.81; P<0.0001), and their peak serum and salivary cortisol values (r=0.68; P=0.0001).nnnCONCLUSIONnThis study indicated that using salivary cortisol measurements for the CRH test could be a reliable method for evaluating the hypothalamic-pituitary-adrenal axis in VLBWI with gestational age of less than 29 wk.

Ttyh1, a Ca2+-binding protein localized to the endoplasmic reticulum, is required for early embryonic development

Using comprehensive genetic studies on neuronal stem/progenitors cells through genome‐wide screening with oligonucleotide arrays, we identified an endoplasmic reticulum (ER) ‐resident protein, Tweety homologue 1 (ttyh1). Ttyh1 encodes a glycosylated protein composed of five predicted transmembrane segments and a C‐terminus that is enriched in negatively charged residues capable of Ca2+ binding. Ttyh1‐containing membranes changed to segmented tubuloreticular structures during mitosis, suggesting that the ER‐containing Ttyh1 could be responsible for Ca2+ sequestration and Ca2+ concentration regulation during mitosis. Ttyh1 inactivation in mice resulted in early embryonic lethality before organization of the nervous system, revealing that ttyh1 is essential in murine embryonic development. Our findings indicate that Ttyh1 plays an indispensable role during mitosis in early embryogenesis, possibly by maintaining Ca2+ homeostasis in the ER. Developmental Dynamics 239:2233–2245, 2010.

Successful cord blood transplantation using a reduced-intensity conditioning regimen for advanced childhood-onset cerebral adrenoleukodystrophy.

Awaya T, Kato T, Niwa A, Hiramatsu H, Umeda K, Watanabe K‐i, Shibata M, Yamanaka Y, Maruya E, Saji H, Nakahata T, Adachi S. Successful cord blood transplantation using a reduced‐intensity conditioning regimen for advanced childhood‐onset cerebral adrenoleukodystrophy.u2028Pediatr Transplantation 2011: 15: E116–E120.

Inactivation of fibroblast growth factor binding protein 3 causes anxiety-related behaviors

The neurobiological mechanisms of emotional modulation and the molecular pathophysiology of anxiety disorders are largely unknown. The fibroblast growth factor (FGF) family has been implicated in the regulation of many physiological and pathological processes, which include the control of emotional behaviors. The present study examined mice with a targeted deletion of the fgf-bp3 gene, which encodes a novel FGF-binding protein, in animal models relevant to anxiety. To define the behavioral consequences of FGF-BP3 deficiency, we evaluated fgf-bp3-deficient mice using anxiety-related behavioral paradigms that provide a conflict between the desire to explore an unknown area or objects and the aversion to a brightly lit open space. The fgf-bp3-deficient mice exhibited alterations in time spent in the central area of the open-field arena, were less active in the lit areas of a light/dark transition test, and had a prolonged latency to feed during a novelty-induced hypophagia test. These changes were associated with alterations in light-induced orbitofrontal cortex (OFC) activation in an extracellular signal-regulated kinase (ERK) pathway-dependent manner. These results demonstrate that FGF-BP3 is a potent mediator of anxiety-related behaviors in mice and suggest that distinct pathways regulate emotional behaviors. Therefore, FGF-BP3 plays a critical role in the regulation of emotional states and in the development of anxiety disorders and should be investigated as a therapeutic target for anxiety disease in humans.

Compound heterozygous deletions in pseudoautosomal region 1 in an infant with mild manifestations of langer mesomelic dysplasia.

Haploinsufficiency of SHOX on the short arm pseudoautosomal region (PAR1) leads to Leri–Weill dyschondrosteosis (LWD), and nullizygosity of SHOX results in Langer mesomelic dysplasia (LMD). Molecular defects of LWD/LMD include various microdeletions in PAR1 that involve exons and/or the putative upstream or downstream enhancer regions of SHOX, as well as several intragenic mutations. Here, we report on a Japanese male infant with mild manifestations of LMD and hitherto unreported microdeletions in PAR1. Clinical analysis revealed mesomelic short stature with various radiological findings indicative of LMD. Molecular analyses identified compound heterozygous deletions, that is, a maternally inherited ∼46u2009kb deletion involving the upstream region and exons 1–5 of SHOX, and a paternally inherited ∼500u2009kb deletion started from a position ∼300u2009kb downstream from SHOX. In silico analysis revealed that the downstream deletion did not affect the known putative enhancer regions of SHOX, although it encompassed several non‐coding elements which were well conserved among various species with SHOX orthologs. These results provide the possibility of the presence of a novel enhancer for SHOX in the genomic region ∼300 to ∼800u2009kb downstream of the start codon.

Effects of Preterm Birth on Intrinsic Fluctuations in Neonatal Cerebral Activity Examined Using Optical Imaging

Medical advancements in neonatology have significantly increased the number of high-risk preterm survivors. However, recent long-term follow-up studies have suggested that preterm infants are at risk for behavioral, educational, and emotional problems. Although clear relationships have been demonstrated between preterm infants and developmental problems during childhood and adolescence, less is known about the early indications of these problems. Recently, numerous studies on resting-state functional connectivity (RSFC) have demonstrated temporal correlations of activity between spatially remote cortical regions not only in healthy adults but also in neuropathological disorders and early childhood development. In order to compare RSFC of the cerebral cortex between preterm infants at term-equivalent ages and full-term neonates without any anatomical abnormality risk during natural sleep, we used an optical topography system, which is a recently developed extension of near-infrared spectroscopy. We clarified the presence of RSFC in both preterm infants and full-term neonates and showed differences between these groups. The principal differences were that on comparison of RSFC between the bilateral temporal regions, and bilateral parietal regions, RSFC was enhanced in preterm infants compared with full-term neonates; whereas on comparison of RSFC between the left temporal and left parietal regions, RSFC was enhanced in full-term neonates compared with preterm infants. We also demonstrated a difference between the groups in developmental changes of RSFC related to postmenstrual age. Most importantly, these findings suggested that preterm infants and full-term neonates follow different developmental trajectories during the perinatal period because of differences in perinatal experiences and physiological and structural development.

Decreased right temporal activation and increased interhemispheric connectivity in response to speech in preterm infants at term-equivalent age

Preterm infants are at increased risk of language-related problems later in life; however, few studies have examined the effects of preterm birth on cerebral responses to speech at very early developmental stages. This study examined cerebral activation and functional connectivity in response to infant-directed speech (IDS) and adult-directed speech (ADS) in full-term neonates and preterm infants at term-equivalent age using 94-channel near-infrared spectroscopy. The results showed that compared with ADS, IDS increased activity in larger brain areas such as the bilateral frontotemporal, temporal, and temporoparietal regions, both in full-term and preterm infants. Preterm infants exhibited decreased activity in response to speech stimuli in the right temporal region compared with full-term infants, although the significance was low. Moreover, preterm infants exhibited increased interhemispheric connectivity compared with full-term controls, especially in the temporal and temporoparietal regions. These differences suggest that preterm infants may follow different developmental trajectories from those born at term owing to differences in intrauterine and extrauterine development.

Salivary biomarkers are not suitable for pain assessment in newborns

BACKGROUND AND AIMSnNewborns admitted to the neonatal intensive care unit are repeatedly subjected to painful or stressful procedures; therefore, objective assessment of their pain is essential. An increasing number of scales for neonatal pain assessment have been developed, many of which are based on physiological and behavioral factors. Recently, salivary biomarkers have been used to assess stress in adults and older infants. This study aimed to determine whether salivary biomarkers can be useful objective indices for assessing newborn pain.nnnSTUDY DESIGNnA total of 47 healthy newborns were enrolled 3-4days after birth. Heel lancing was performed to collect blood for a newborn screening test. Before and after heel lancing, saliva was collected to analyze hormone levels, a video was recorded for behavioral observations, and heart rate was recorded. Two investigators independently assessed newborn pain from the video observations using the Neonatal Infant Pain Scale (NIPS). Salivary chromogranin (sCgA) and salivary amylase (sAA) levels were measured using an enzyme-linked immunosorbent assay kit and a dry chemistry system, respectively.nnnRESULTSnNo definite changes in salivary biomarkers (sCgA or sAA) were detected before and after heel lancing. However, newborn sCgA levels were markedly higher than reported adult levels, with large inter- and intra-subject variability, whereas newborn sAA levels were lower than adult levels. NIPS score and heart rate were dramatically increased after heel lancing.nnnCONCLUSIONSnNIPS score (behavioral assessment) and heart rate are useful stress markers in newborns. However, neither sCgA nor sAA is suitable for assessing newborn pain.