Details of a Researcher - Takahashi, Takao

Papers - Takahashi, Takao

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Pediatric acquired demyelinating syndrome (ADS) in inpatient hospital settings: The hospitalization rate, costs, and outcomes in the US

Minegishi M., Takahashi T., Testa M.

Multiple Sclerosis and Related Disorders (Multiple Sclerosis and Related Disorders) 34 150 - 157 2019.09

ISSN 22110348

© 2019 Elsevier B.V. Background: Although relatively rare among pediatric patients, acquired demyelinating syndromes of the central nervous system (ADS) is a potentially disabling condition that warrants hospitalization and long-term follow-up. As such, a better understanding of the epidemiology and hospital utilization for this condition could provide critical information for health care planning and resource allocation. Objective: To evaluate the trends of hospital utilization and resource use associated with pediatric ADS in the US. Method: We conducted a serial cross-sectional trend analysis with complex sampling and weighting using nationally representative hospital discharge records, from the Kids´ Inpatient Database (KID), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality coded with International Classification of Diseases (Healthcare Cost and Utilization Project (HCUP) 2018), Ninth Revision (ICD-9-CM) for the years 2003, 2006, 2009, and 2012. We also conducted a cross-sectional study for the KID2016 dataset coded with ICD10-CM to estimate the pediatric ADS-related hospital utilization for the year. Excluding transferring discharges: we evaluated the discharge records for those aged 0 to 19 years diagnosed with any of ADS of central nervous systems including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM) and demyelinating disease not specified (DDNS). For the trend analysis, we used variance-weighted regression and Poisson regression for the annual hospitalization rate, total hospital charges and hospital days associated with the ADS hospitalizations for the year 2003 to 2012. Results: We estimated a total of 1,292 ADS-related hospitalizations (95%CI: 1127–1,458) in 2003, 2104 hospitalizations (95%CI: 1823–2385) in 2006, 2851 hospitalizations (95%CI: 2499–3203) in 2009, and 3501 hospitalizations (95%CI: 3058–3945) in 2012 among those aged 19 years or younger with diagnoses of ADS. There was an increase in the proportion of the inpatient hospital cost attributed to ADS from 0.06% in 2003 to 0.20% in 2012. The annual hospitalization rates relative to pediatric ADS were 1.59/100,000 (95%CI: 1.51–1.68) in 2003 and 4.21/100,000 (95%CI: 4.07–4.35) in 2012. In the cross-sectional analysis for the year 2016 coded by ICD10-CM, the number of pediatric ADS related hospitalizations were 4,568, constituting 0.30% of the total pediatric hospitalization cost. The annual hospitalization rate for the year 2016 was estimated to be 5.51/100,000. Conclusion: Hospital utilization by pediatric patients with ADS increased during the period 2003 through 2012. The cross-sectional analysis for the year 2016 indicated that the trend could be ongoing, although the direct comparison was not feasible due to the changes in the coding system of the dataset from ICD9-CM to ICD10-CM. Although relatively rare, pediatric ADS warrant long-term follow-ups and hospitalizations, impacting the developmental trajectory of the affected children and the lives of their family members. Th potentially increasing trend of pediatric ADS hospital utilization should be acknowledged when allocating and planning future resources and supporting programs.

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Noninvasive diagnosis of TRIT1-related mitochondrial disorder by measuring i6A37 and ms2i6A37 modifications in tRNAs from blood and urine samples

Takenouchi T., Wei F., Suzuki H., Uehara T., Takahashi T., Okazaki Y., Kosaki K., Tomizawa K.

American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A) 179 ( 8 ) 1609 - 1614 2019.08

ISSN 15524825

© 2019 Wiley Periodicals, Inc. Subsets of mitochondrial transfer RNA (tRNA) contain the N6-isopentenyladenosine (i6A) or 2-methylthio-N6-isopentenyladenosine (ms2i6A) modification at position A37, which is adjacent to an anticodon. These modifications are essential for efficient protein translation in mitochondria and contribute to energy metabolism. The first step in i6A and ms2i6A modifications is catalyzed by tRNA isopentenyltransferase, which is encoded by the TRIT1 gene. Herein, we report a girl with a developmental delay, frequent episodes of seizures induced by febrile illness, and myoclonic epilepsy who had compound heterozygous missense mutations in TRIT1. A mass spectrometry analysis of RNA nucleoside obtained from the subject's peripheral blood and urine showed a marked decrease in both i6A and ms2i6A modifications. These results suggest that the mitochondrial disorder was caused by defective tRNA isopentenylation arising from a loss-of-function mutation in TRIT1. Furthermore, the present observations suggest that noninvasive biochemical analysis using peripheral blood and urine samples are sufficient for the diagnosis of TRIT1-related disorders, making muscle biopsy for the direct measurement of oxidative phosphorylation unnecessary. Such biochemical analyses before the start of antiepileptic medications would be beneficial to avoid hepatotoxicity in patients with possible mitochondrial disorders.

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Effectiveness of inactivated influenza vaccine in children by vaccine dose, 2013–18

Shinjoh M., Sugaya N., Furuichi M., Araki E., Maeda N., Isshiki K., Ohnishi T., Nakamura S., Yamada G., Narabayashi A., Nishida M., Taguchi N., Nakata Y., Yoshida M., Tsunematsu K., Shibata M., Munenaga T., Hirano Y., Ookawara I., Sekiguchi S., Kobayashi Y., Yamaguchi Y., Yoshida N., Mitamura K., Takahashi T.

Vaccine (Vaccine) 37 ( 30 ) 4047 - 4054 2019.07

ISSN 0264410X

© 2019 Elsevier Ltd Objectives: We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) by vaccine dose in children aged 6 months to 12 years for whom two doses are recommended in Japan to ascertain the appropriate vaccine doses. Methods: VE was assessed according to a test-negative case-control design based on rapid influenza diagnostic test (RIDT) results. Children aged 6 months to 12 years with a fever ≥38 °C who had received an RIDT in outpatient clinics of 24 hospitals were enrolled for all five seasons since 2013/14. VE by vaccine dose (none vs. once or twice, and once vs. twice) was analyzed. Results: In the dose analysis, 20,033 children were enrolled. Both one- and two-dose regimens significantly reduced cases in preventing any influenza, influenza A, and influenza B, but there was no significant difference in adjusted VE between one- and two-dose regimens overall (adjusted OR, 0.560 [95% CI, 0.505–0.621], 0.550 [95% CI, 0.516–0.586]), 0.549 [95% CI, 0.517–0.583], and 1.014 [95% CI, 0.907–1.135], for none vs. once, none vs. twice, none vs. once or twice, and once vs. twice for any influenza, respectively). Both one- and two-dose regimens significantly reduced cases with any influenza and influenza A every season. Also, both regimens significantly reduced cases of any influenza, influenza A, and influenza B among children aged 1–12 years, especially among those aged 1–5 years. In the 2013/14, 2015/16, and 2016/17 seasons, however, only the two-dose regimen was significantly effective in preventing influenza B. Both one- and two-dose regimens significantly reduced cases involving hospitalization due to any influenza and influenza A. Conclusions: Both one- and two-doses regimens of IIV were effective in preventing influenza for children aged 6 months to 12 years. The two-dose regimen was more effective against influenza B in some seasons.

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Further evidence of a causal association between AGO1, a critical regulator of microRNA formation, and intellectual disability/autism spectrum disorder

Sakaguchi A., Yamashita Y., Ishii T., Uehara T., Kosaki K., Takahashi T., Takenouchi T.

European Journal of Medical Genetics (European Journal of Medical Genetics) 62 ( 6 ) 2019.06

ISSN 17697212

© 2018 Elsevier Masson SAS Among the many regulators of microRNA formation, Argonaute 1 (AGO1) plays critical roles in RNA interference, which controls a wide range of biological activities. Recent large-scale genomic studies have identified at least five patients with intellectual disability/autism spectrum disorder who had de novo mutations in AGO1, but detailed clinical information was not available. The recognizable clinical features that are associated with AGO1 mutations remain to be determined. The proposita was a 15-year-old girl with diffuse hypotonia, infrequent seizures, and intellectual disability with an intelligence quotient of 41. She had characteristic facial features consisting of telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures. Serial computed tomography scans showed progressive calcification in the globus pallidus that became evident during childhood. A whole exome analysis in trio revealed a de novo heterozygous mutation in AGO1, i.e., c.595G > A p.(Gly199Ser). The distinctive facial features, i.e., telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures, closely resembled previously reported patients who had a chromosomal microdeletion encompassing AGO1 locus. The combinatory phenotype of such characteristic facial features and radiographic features, i.e. progressive calcification in the globus pallidus, in the presently reported patient suggest that AGO1 mutations lead to a syndromic form of intellectual disability/autism spectrum disorder. Distinctive facial features with early and progressive calcification in the globus pallidus may be suggestive of the presence of AGO1 mutations.

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Large-area fluorescence and electron microscopic correlative imaging with multibeam scanning electron microscopy

Shibata S., Iseda T., Mitsuhashi T., Oka A., Shindo T., Moritoki N., Nagai T., Otsubo S., Inoue T., Sasaki E., Akazawa C., Takahashi T., Schalek R., Lichtman J., Okano H.

Frontiers in Neural Circuits (Frontiers in Neural Circuits) 13 2019.04

ISSN 16625110

© 2019 Shibata, Iseda, Mitsuhashi, Oka, Shindo, Moritoki, Nagai, Otsubo, Inoue, Sasaki, Akazawa, Takahashi, Schalek, Lichtman and Okano. Recent improvements in correlative light and electron microscopy (CLEM) technology have led to dramatic improvements in the ability to observe tissues and cells. Fluorescence labeling has been used to visualize the localization of molecules of interest through immunostaining or genetic modification strategies for the identification of the molecular signatures of biological specimens. Newer technologies such as tissue clearing have expanded the field of observation available for fluorescence labeling; however, the area of correlative observation available for electron microscopy (EM) remains restricted. In this study, we developed a large-area CLEM imaging procedure to show specific molecular localization in large-scale EM sections of mouse and marmoset brain. Target molecules were labeled with antibodies and sequentially visualized in cryostat sections using fluorescence and gold particles. Fluorescence images were obtained by light microscopy immediately after antibody staining. Immunostained sections were postfixed for EM, and silver-enhanced sections were dehydrated in a graded ethanol series and embedded in resin. Ultrathin sections for EM were prepared from fully polymerized resin blocks, collected on silicon wafers, and observed by multibeam scanning electron microscopy (SEM). Multibeam SEM has made rapid, large-area observation at high resolution possible, paving the way for the analysis of detailed structures using the CLEM approach. Here, we describe detailed methods for large-area CLEM in various tissues of both rodents and primates.

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Type 2 inositol 1,4,5-trisphosphate receptor inhibits the progression of pulmonary arterial hypertension via calcium signaling and apoptosis

Shibata A., Uchida K., Kodo K., Miyauchi T., Mikoshiba K., Takahashi T., Yamagishi H.

Heart and Vessels (Heart and Vessels) 34 ( 4 ) 724 - 734 2019.04

ISSN 09108327

© 2018, Springer Japan KK, part of Springer Nature. Pulmonary arterial hypertension (PAH) is a progressive disease associated with vasoconstriction and remodeling. Intracellular Ca 2+ signaling regulates the contraction of pulmonary arteries and the proliferation of pulmonary arterial smooth muscle cells (PASMCs); however, it is not clear which molecules related to Ca 2+ signaling contribute to the progression of PAH. In this study, we found the specific expression of type 2 inositol 1,4,5-trisphosphate receptor (IP 3 R2), which is an intracellular Ca 2+ release channel, on the sarco/endoplasmic reticulum in mouse PASMCs, and demonstrated its inhibitory role in the progression of PAH using a chronic hypoxia-induced PAH mouse model. After chronic hypoxia exposure, IP 3 R2 −/− mice exhibited the significant aggravation of PAH, as determined by echocardiography and right ventricular hypertrophy, with significantly greater medial wall thickness by immunohistochemistry than that of wild-type mice. In IP 3 R2 −/− murine PASMCs with chronic hypoxia, a TUNEL assay revealed the significant suppression of apoptosis, whereas there was no significant change in proliferation. Thapsigargin-induced store-operated Ca 2+ entry (SOCE) was significantly enhanced in IP 3 R2 −/− PASMCs in both normoxia and hypoxia based on in vitro fluorescent Ca 2+ imaging. Furthermore, the enhancement of SOCE in IP 3 R2 −/− PASMCs was remarkably suppressed by the addition of DPB162-AE, an inhibitor of the stromal-interacting molecule (STIM)–Orai complex which is about 100 times more potent than 2-APB. Our results indicate that IP 3 R2 may inhibit the progression of PAH by promoting apoptosis and inhibiting SOCE via the STIM–Orai pathway in PASMCs. These findings suggest a previously undetermined role of IP 3 R in the development of PAH and may contribute to the development of targeted therapies.

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A paradoxical thrombogenic mutation in factor II at the target site of arthropod bleeding toxin

Takenouchi T., Shimada H., Uehara T., Kanai Y., Takahashi T., Kosaki K.

European Journal of Medical Genetics (European Journal of Medical Genetics) 62 ( 2 ) 93 - 95 2019.02

ISSN 17697212

© 2018 Loss-of-function mutations in coagulation cascade proteins lead to bleeding diasthesis. In contrast, gain-of-function mutations in these proteins, which are exceptionally rare, lead to hereditary thrombosis. This is best exemplified by Factor V (i.e., Factor V Leiden) and Factor II (i.e., p.Arg596Leu). Here, we report a family with hereditary thrombosis. The proposita presented with cerebral venous thrombosis accompanied by infarction at the age of 12 years. Despite anticoagulation therapy with oral warfarin, she later developed deep venous thrombosis in her hepatic portal veins at the age of 27 years. A medical exome analysis identified a de novo heterozygous mutation p.Tyr434His in Factor II, which was segregated within the family. A retrospective molecular diagnosis was made using a preserved surgical specimen from the proposita's mother, who had died 10 years earlier. The p.Tyr434 residue, which was substituted in the presently reported family, was located in “exosite I” of thrombin, a critical recognition site for fibrinogen, protein C, and thrombin aptamer. Therefore, the mutant thrombin likely exerted its thrombophilic effect by altering the affinity of thrombin to downstream substrates. Furthermore, the “exosite I” domain of thrombin was inhibited by the arthropod bleeding toxin Triabin (a protein discovered from the saliva of the blood-sucking triatomine bug Triatoma pallidipennis). Our observation that patients with a p.Tyr434His mutation exhibited recurrent thrombosis provides the first proof-of-concept in humans that a pharmacologic agent targeting “exosite I” could be an effective means of specifically modulating the thrombogenic-side of the coagulation system via the inhibition of factor II.

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Nosocomial infection by human bocavirus and human rhinovirus among paediatric patients with respiratory risks

Kobayashi H., Shinjoh M., Sudo K., Kato S., Morozumi M., Koinuma G., Takahashi T., Takano Y., Tamura Y., Hasegawa N.

Journal of Hospital Infection (Journal of Hospital Infection) 2019

ISSN 01956701

© 2019 The Healthcare Infection Society Background: Nosocomial infections by respiratory viruses undetected by rapid tests are not often diagnosed. For paediatric patients with background diseases, nosocomial infection could be fatal. Aim: To determine the relationship between developing symptoms by respiratory viruses undetectable by rapid tests and respiratory risks and to improve the management of infection control. Methods: Two episodes of nosocomial infection by human bocavirus (HBoV) and human rhinovirus (HRV) were retrospectively investigated in a tertiary hospital paediatric ward in Japan. Viruses were identified by polymerase chain reaction to determine infection control management. When viruses of the same species were detected from different patients, the virus homology was investigated. The relationship between respiratory risks and developing symptoms was statistically investigated. Findings: Three and four patients with respiratory risks in the HBoV and HRV outbreaks, respectively, developed respiratory symptoms. The nucleotide sequences of two patients in the HBoV outbreak and all four patients in the HRV outbreak were phylogenetically close. In both outbreaks, the patients with respiratory risks developed significantly more symptoms than those without any risk (P = 0.035 and 0.018, respectively). After the patients with respiratory infection were separated from those with respiratory risks, no additional nosocomial infection occurred. Conclusion: Patients with respiratory risks easily develop respiratory symptoms and acquire severe symptoms of nosocomial infection by those viruses. In a paediatric ward, we should adopt not only standard precautions but also isolation management of the patients with respiratory symptoms, even if they have negative results in rapid tests.

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Symbolic time series analysis of fNIRS signals in brain development assessment

Liang Z., Minagawa Y., Yang H., Tian H., Cheng L., Arimitsu T., Takahashi T., Tong Y.

Journal of Neural Engineering (Journal of Neural Engineering) 15 ( 6 ) 2018.09

ISSN 17412560

© 2018 IOP Publishing Ltd. Objective. Assessing an infant's brain development remains a challenge for neuroscientists and pediatricians despite great technological advances. As a non-invasive neuroimaging tool, functional near-infrared spectroscopy (fNIRS) has great advantages in monitoring an infant's brain activity. To explore the dynamic features of hemodynamic changes in infants, in-pattern exponent (IPE), anti-pattern exponent (APE), as well as permutation cross-mutual information (PCMI) based on symbolic dynamics are proposed to measure the phase differences and coupling strength in oxyhemoglobin (HbO) and deoxyhemoglobin (Hb) signals from fNIRS. Approach. First, simulated sinusoidal oscillation signals and four coupled nonlinear systems were employed for performance assessments. Hilbert transform based measurements of hemoglobin phase oxygenation and deoxygenation (hPod) and phase-locking index of hPod (hPodL) were calculated for comparison. Then, the IPE, APE and PCMI indices from resting state fNIRS data of preterm, term infants and adults were calculated to estimate the phase difference and coupling of HbO and Hb. All indices' performance was assessed by the degree of monotonicity (DoM). The box plots and coefficients of variation (CV) were employed to assess the measurements and robustness in the results. Main results. In the simulation analysis, IPE and APE can distinguish the phase difference of two sinusoidal oscillation signals. Both hPodL and PCMI can track the strength of two coupled nonlinear systems. Compared to hPodL, the PCMI had higher DoM indices in measuring the coupling of two nonlinear systems. In the fNIRS data analysis, similar to hPod, the IPE and APE can distinguish preterm, term infants, and adults in 0.01-0.05 Hz, 0.05-0.1 Hz, and 0.01-0.1 Hz frequency bands, respectively. PCMI more effectively distinguished the term and preterm infants than hPodL in the 0.05-0.1 Hz frequency band. As symbolic time series measures, the IPE and APE were able to detect the brain developmental changes in subjects of different ages. PCMI can assess the resting-state HbO and Hb coupling changes across different developmental ages, which may reflect the metabolic and neurovascular development. Significance. The symbolic-based methodologies are promising measures for fNIRS in estimating the brain development, especially in assessing newborns' brain developmental status.

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Inactivated influenza vaccine effectiveness and an analysis of repeated vaccination for children during the 2016/17 season

Shinjoh M., Sugaya N., Yamaguchi Y., Iibuchi N., Kamimaki I., Goto A., Kobayashi H., Kobayashi Y., Shibata M., Tamaoka S., Nakata Y., Narabayashi A., Nishida M., Hirano Y., Munenaga T., Morita K., Mitamura K., Takahashi T.

Vaccine (Vaccine) 36 ( 37 ) 5510 - 5518 2018.09

ISSN 0264410X

© 2018 Objectives: We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children 6 months to 15 years of age during the 2016/17 season. In addition, we estimated the impact of repeated vaccination in children on VE. Methods: Our study for VEs in preventing influenza and admission due to influenza were conducted according to a test-negative case-control design (TNCC) based on influenza rapid diagnostic test results. We also analyzed the VE by vaccine status in the current and previous seasons for the impact of repeated vaccination. Results: During the 2016/17 season, the quadrivalent IIV was used in Japan. The adjusted VE in preventing influenza illness was 38% (95% CI, 29–46) against influenza A and 39% (95% CI, 18–54) against influenza B. Infants showed no significant VE. The VE in preventing hospitalization was not demonstrated. For the analysis of repeated vaccination, the vaccine was effective only when immunization occurred in the current season. The children who were immunized in two consecutive seasons were more likely to develop influenza compared to those immunized in the current season only (odds ratio, 1.58 [95% CI, 1.05–2.38], adjusted odds ratio, 1.53 [95% CI, 0.99–2.35]). However, the odds ratio of repeated vaccination was not significant when the analysis excluded those who developed influenza in the previous season. Conclusions: VE in children in the 2016/17 season was similar to values previously reported. Repeated vaccination interfered with the VE against any influenza infection in the 2016/17 season. The results of our study suggest that decreased VE by repeat vaccination phenomenon was associated with immunity by influenza infection in the previous season. However, the influenza vaccine should be recommended every season for children.

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Effectiveness of inactivated quadrivalent influenza vaccine in the 2015/2016 season as assessed in both a test-negative case-control study design and a traditional case-control study design

Kimiya T., Shinjoh M., Anzo M., Takahashi H., Sekiguchi S., Sugaya N., Takahashi T.

European Journal of Pediatrics (European Journal of Pediatrics) 177 ( 7 ) 1009 - 1017 2018.07

ISSN 03406199

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Both traditional case-control studies (TCCSs) and test-negative case-control studies (TNCCSs) are commonly used to assess influenza vaccine effectiveness (VE). To compensate for the fact that observational studies are susceptible to bias, we combined both methods to assess VE in one geographical area during the 2015/2016 season, when influenza A (H1N1)pdm was dominant. Our TNCCS covered 331 children aged 6 months to 15 years who visited our hospital with fever, including 182 with influenza, and our TCCS covered 812 pediatric outpatients aged 6 months to 15 years, including 214 with influenza. Influenza infection and vaccination history were reviewed, and VE was calculated as (1 − odds ratio) × 100. In the TNCCS, VE against influenza A was 68% (95% CI 47–81) overall, and 70% (48–83) for those given two doses; against influenza B, VE was 37% (− 12–64) overall and 49% (2–74) for two doses. In the TCCS, VE against influenza A was 44% (15–63) overall and 44% (13–64) for two doses, and VE against influenza B was 24% (− 19–52) overall and 41% (3–64) for two doses. Conclusion: Both studies confirmed significant VE against influenza A, significant two-dose VE against influenza B, and better two-dose VE than one-dose VE.What is Known:• Influenza vaccine effectiveness (VE) varies from year to year.• Observational studies are conventionally used for VE assessment. However, they are inherently susceptible to bias and confounding.What is New:• This is the first report of influenza VE assessment using more than one observational study and performed in a specific area during the same season.• VE estimates obtained in our traditional case-control study were lower than those in our test-negative case-control study, but both studies found significant VE against influenza.

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Effect of mother's voice on neonatal respiratory activity and EEG delta amplitude

Uchida M., Arimitsu T., Yatabe K., Ikeda K., Takahashi T., Minagawa Y.

Developmental Psychobiology (Developmental Psychobiology) 60 ( 2 ) 140 - 149 2018.03

ISSN 00121630

© 2017 The Authors. Developmental Psychobiology Published by Wiley Periodical, Inc. While the influence of the mother's voice on neonatal heart-rate response and its relevant activity on cerebral cortex and the autonomic nervous system (ANS) are well known, few studies have assessed its influence on respiratory activity. We investigated the relationship among the respiration rate, the delta wave amplitudes through electroencephalography, and the basal state of ANS through the respiratory variability index while 22 full-term neonates hear their mother's voice and an unknown voice. It was found that when respiratory variability was large, a transient (<5 s) change in respiration rates was observed in response to an unknown voice, while a greater increase in the delta wave amplitude was observed in the frontal lobe than the parietal one in response to the mother's voice. Conversely, when respiratory variability was small, a sustained increase (>10 s) in respiration rates was observed in response to the mother's voice, while a greater increase in the delta wave amplitude was found in both the frontal and parietal lobes. These results suggest that the basal state of ANS influences the latency of increases in respiration rates. Furthermore, induced by the mother's voice, transient increases in respiration rates are reduced in association with frontal lobe activity, and sustained increases in respiration rates are promoted in association with frontal and parietal lobe activities.

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Three-season effectiveness of inactivated influenza vaccine in preventing influenza illness and hospitalization in children in Japan, 2013–2016

Sugaya N., Shinjoh M., Nakata Y., Tsunematsu K., Yamaguchi Y., Komiyama O., Takahashi H., Mitamura K., Narabayashi A., Takahashi T.

Vaccine (Vaccine) 36 ( 8 ) 1063 - 1071 2018.02

ISSN 0264410X

© 2018 Elsevier Ltd Objectives: We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children 6 months to 15 years of age in 2015/16 season. In addition, based on the data obtained during the three seasons from 2013 to 2016, we estimated the three-season VE in preventing influenza illness and hospitalization. Methods: Our study was conducted according to a test-negative case-control design (TNCC) and as a case-control study based on influenza rapid diagnostic test results. Results: During 2015/16 season, the quadrivalent IIV was first used in Japan. The adjusted VE in preventing influenza illness was 49% (95% confidence interval [CI]: 42–55%) against any type of influenza, 57% (95% CI: 50–63%) against influenza A and 34% (95% CI: 23–44%) against influenza B. The 3-season adjusted VE was 45% (95% CI: 41–49%) against influenza virus infection overall (N = 12,888), 51% (95% CI: 47–55%) against influenza A (N = 10,410), and 32% (95% CI: 24–38%) against influenza B (N = 9232). An analysis by age groups showed low or no significant VE in infants or adolescents. By contrast, VE was highest in the young group (1–5 years old) and declined with age thereafter. The 3-season adjusted VE in preventing hospitalization as determined in a case-control study was 52% (95% CI: 42–60%) for influenza A and 28% (95% CI: 4–46%) for influenza B, and by TNCC design, it was 54% (95% CI: 41–65%) for influenza A and 34% (95% CI: 6–54%) for influenza B. Conclusion: We demonstrated not only VE in preventing illness, but also VE in preventing hospitalization based on much larger numbers of children than previous studies.

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Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1

Takenouchi T., Inaba M., Uehara T., Takahashi T., Kosaki K., Mizuno S.

American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A) 176 ( 2 ) 431 - 437 2018.02

ISSN 15524825

© 2017 Wiley Periodicals, Inc. Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.

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The cerebral hemodynamic response to phonetic changes of speech in preterm and term infants: The impact of postmenstrual age

Arimitsu T., Minagawa Y., Yagihashi T., O. Uchida M., Matsuzaki A., Ikeda K., Takahashi T.

NeuroImage: Clinical (NeuroImage: Clinical) 19 599 - 606 2018.01

© 2018 Higher brain dysfunction, such as language delay, is a major concern among preterm infants. Cerebral substrates of cognitive development in preterm infants remain elusive, partly because of limited methods. The present study focuses on hemodynamic response patterns for brain function by using near-infrared spectroscopy. Specifically, the study investigates gestational differences in the hemodynamic response pattern evoked in response to phonetic changes of speech and cerebral hemispheric specialization of the auditory area in preterm infants (n = 60) and term infants (n = 20). Eighty neonates born between 26 and 41 weeks of gestational age (GA) were tested from 33 to 41 weeks of postmenstrual age (PMA). We analyzed the hemodynamic response pattern to phonemic and prosodic contrasts for multiple channels on temporal regions and the laterality index of the auditory area. Preterm infants younger than 39 weeks of PMA showed significantly atypical hemodynamic patterns, with an inverted response shape. Partial correlation analysis of the typicality score of hemodynamic response revealed a significant positive correlation with PMA. The laterality index of preterm infants from 39 weeks of PMA demonstrated a tendency rightward dominance for prosodic changes similar to term infants. We provide new evidence that alterations in hemodynamic regulation and the functional system for phonemic and prosodic processing in preterm infants catch up by their projected due dates.

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Respiratory arrest at the onset of idiopathic childhood occipital epilepsy of Gastaut.

Funata K, Shike T, Takenouchi T, Yamashita Y, Takahashi T.

Brain Dev (Brain and Development) 40 ( 1 ) 74 - 76 2017

Research paper (scientific journal), Joint Work, ISSN 03877604

© 2017 The Japanese Society of Child Neurology Occipital lobe epilepsy of childhood includes two entities: Panayiotopoulos syndrome in pre-school children, and idiopathic childhood occipital epilepsy of Gastaut (ICOEG) in school-age children. The typical initial manifestation of the former is vomiting, and that of the latter is visual hallucinations. Ictal cardiopulmonary arrest at initial presentation has been reported for Panayiotopoulos syndrome, but not for ICOEG. We document a 7-year-old previously healthy girl who experienced an acute elemental visual hallucination of seeing insects, followed by a new-onset generalized seizure. Upon arrival at the local hospital, she was unconscious and soon thereafter, developed respiratory arrest. She was resuscitated and initiated on mechanical ventilation. An electroencephalogram taken three days after seizure cessation showed frequent occipital spikes, consistent with the diagnosis of ICOEG. The sequence of acute elementary visual hallucination followed by a motor seizure, and then witnessed respiratory arrest illustrated occurrence of life-threatening autonomic involvement at initial onset in ICOEG. We speculate that the epileptic propagation from the occipital lobes eventually compromised the respiratory center in the brainstem. The possibility of occipital lobe epilepsy should be considered in school-age children presenting with acute visual hallucination followed by respiratory arrest. Such a presentation should prompt an urgent electroencephalogram and initiation of antiepileptic treatment if indicated.

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Adverse Effects of Prenatal and Early Postnatal Exposure to Antiepileptic Drugs: Validation From Clinical and Basic Researches.

Fujimura K, Mitsuhashi T, Takahashi T.

Brain Dev 39 635 - 643 2017

Research paper (scientific journal), Joint Work, Accepted

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Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene.

Takenouchi T, Miwa T, Sakamoto Y, Sakaguchi Y, Uehara T, Takahashi T, Kosaki K.

Am J Med Genet 173 1631 - 1634 2017

Research paper (scientific journal), Joint Work

Is that cranial deformity really due to sleeping position?

Kajita H, Sakamoto Y, Takenouchi T, Miwa T, Takahashi T.

Pediatr Int 59 494 - 496 2017

Research paper (scientific journal), Joint Work

Co-occurrence of Sturge-Weber Syndrome and Klippel-Trenaunay-Weber Syndrome Phenotype: Consideration of the Historical Aspect.

Sakaguchi Y, Takenouchi T, Uehara T, Kishi K, Takahashi T, Kosaki K.

Am J Med Genet 2017

Research paper (scientific journal), Joint Work

Successful haploidentical BMT with post-transplant cyclophosphamide for refractory autoimmune pancytopenia after cord blood transplant in pediatric myelodysplastic syndrome.

Shima H, Isshiki K, Yamada Y, Yamazaki F, Takahashi T, Shimada H.

Bone Marrow Transplant 52 653 - 655 2017

Research paper (scientific journal), Joint Work

Changeability of the fully methylated status of the 15q11.2 region in induced pluripotent stem cells derived from a patient with Prader-Willi syndrome.

Okuno H, Nakabayashi K, Abe K, Ando T, Sanosaka T, Kohyama J, Akamatsu W, Ohyama M, Takahashi T, Kosaki K, Okano H.

Congenit Anom (Kyoto) 57 96 - 103 2017

Research paper (scientific journal), Joint Work

Randomized controlled trial of oral immunotherapy for egg allergy in Japanese patients.

Akashi M, Yasudo H, Narita M, Nomura I, Akasawa A, Ebisawa M, Takahashi T, Ohya Y.

Pediatr Int 59 534 - 539 2017

Research paper (scientific journal), Joint Work

A sedation protocol with fasting and shorter sleep leads to MRI success.

Kimiya T, Sekiguchi S, Yagihashi T, Arai M, Takahashi H, Takahashi T.

Pediatr Int 2017

Research paper (scientific journal), Joint Work

Access to Document (DOI)

Childhood Sjögren syndrome presenting as acute brainstem encephalitis.

Matsui Y, Takenouchi T, Narabayashi A, Ohara K, Nakahara T, Takahashi T.

Brain Dev 38 158 - 162 2016

Research paper (scientific journal), Joint Work

Trivalent inactivated influenza vaccine effective against influenza A(H3N2) variant viruses in children during the 2014/15 season, Japan.

Sugaya N, Shinjoh M, Kawakami C, Yamaguchi Y, Yoshida M, Baba H, Ishikawa M, Kono M, Sekiguchi S, Kimiya T, Mitamura K, Fujino M, Komiyama O, Yoshida N, Tsunematsu K, Narabayashi A, Nakata Y, Sato A, Taguchi N, Fujita H, Toki M, Myokai M, Ookawara I, Takahashi T.

Euro Surveill 21 ( 42 ) 2016

Research paper (scientific journal), Joint Work

Conservative follow-up of fractured percutaneously inserted central venous catheter.

Kobayashi H, Mizuno Y, Takahashi T.

Pediatr Int 58 ( 12 ) 1369 - 1370 2016

Research paper (scientific journal), Joint Work

In Utero Exposure to Valproic Acid Induces Neocortical Dysgenesis via Dysregulation of Neural Progenitor Cell Proliferation/Differentiation.

Fujimura K, Mitsuhashi T, Shibata S, Shimozato S, Takahashi T.

J Neurosci 36 10908 - 10919 2016

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Association Between Invisible Basal Ganglia and ZNF335 Mutations: A Case Report.

Sato R, Takanashi J, Tsuyusaki Y, Kato M, Saitsu H, Matsumoto N, Takahashi T.

Pediatrics 138 ( 3 ) 2016

Research paper (scientific journal), Joint Work

Hirschsprung disease as a yet undescribed phenotype in a patient with ARID1B mutation.

Takenouchi T, Yoshihashi H, Sakaguchi Y, Uehara T, Honda M, Takahashi T, Kosaki K, Miyama S.

Am J Med Genet 170 3249 - 3252 2016

Research paper (scientific journal), Joint Work

Keio Pediatric Influenza Research Group. Effectiveness of trivalent inactivated influenza vaccine in children estimated by a test-negative case-control design study based on influenza rapid diagnostic test.

Shinjoh M, Sugaya N, Yamaguchi Y, Tomidokoro Y, Sekiguchi S, Mitamura K, Fujino M, Shiro H, Komiyama O, Taguchi N, Nakata Y, Yoshida N, Narabayashi A, Myokai M, Sato M, Furuichi M, Baba H, Fujita H, Sato A, Ookawara, I , Tsunematsu K, Yoshida M, Kono M, Tanaka F, Kawakami C, Kimiya T, Takahashi T, Iwata S.

PLOS ONE 10 e0136539 2015

Research paper (scientific journal), Joint Work

Assessment of Developing Speech Perception in Preterm Infants Using Near-Infrared Spectroscopy.

Arimitsu T, Minagawa Y, Takahashi T, Ikeda K.

NeoReviews 16 e481 - e489 2015

Research paper (scientific journal), Joint Work

Successful lung transplantation in a case with diffuse pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia

H. Fukushima, T. Mitsuhashi, T. Oto, Y. Sano, K. F. Kusano, K. Goto, M. Okazaki, H. Date, Y. Kojima, H. Yamagishi and T. Takahashi

American Journal of Transplantation 13 ( 12 ) 3278 - 81 2013.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 1600-6143

Diffuse pulmonary arteriovenous malformations (AVMs) are associated with a poor prognosis and the therapeutic strategy remains controversial. We describe a pediatric patient with diffuse pulmonary AVMs associated with hereditary hemorrhagic telangiectasia (HHT), who presented with two cerebral AVMs in the parietal and occipital lobes as well. Of note, successful bilateral lung transplantation not only improved the hypoxemia but also resulted in size reduction of the cerebral AVMs. Although it is essential to consider involvements other than pulmonary AVMs, especially brain AVMs, to decide the indication, lung transplantation can be a viable therapeutic option for patients with diffuse pulmonary AVMs and HHT.

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情報通信技術を活用した大学病院・地域中核病院間連携小児科研修

三橋隆行、高木優樹、三春晶嗣、肥沼悟郎、野村寿博、福島裕之、小崎健次郎、高橋孝雄

日本小児科学会雑誌 115 ( 4 ) 823 - 827 2011.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 0001-6543

地域中核病院と大学病院とをインターネットで結合し、双方の教育環境の共有化を実施した。遠隔カンファレンスは、20ヵ月間に12関連施設と接続して合計11回の公演会を開催し、延べ約1000名が参加した。ストリーミング配信は、20ヵ月間に合計471個の学習内容を作成し、e-learningサイトへの総アクセス数は2083回、延べ1205名がストリーミングを視聴した。情報通信技術(ICT)を用いることにより、地域中核病院や大学病院の教育内容を他の研修施設に提供可能となった。さらに、休職中・留学中の医師・医学生への提供も可能になった。e-learningの長所と限界を認識しつつ、ICTを活用することにより、教育関連施設と大学病院の特徴の補完、かつ臨床研修教育者の負担軽減が可能に成り得ると思われた。

In utero exposure to dioxin causes neocortical dysgenesis through the actions of p27Kip1

T. Mitsuhashi, J. Yonemoto, H. Sone, Y. Kosuge, K. Kosaki and T. Takahashi

Proc Natl Acad Sci U S A 107 ( 37 ) 16331 - 5 2010.09

Joint Work, Accepted, ISSN 1091-6490

Dioxins have been reported to exert various adverse effects, including cell-cycle dysregulation in vitro and impairment of spatial learning and memory after in utero exposure in rodents. Furthermore, children born to mothers who are exposed to dioxin analogs polychlorinated dibenzofurans or polychlorinated biphenyls have developmental impairments in cognitive functions. Here, we show that in utero exposure to dioxins in mice alters differentiation patterns of neural progenitors and leads to decreased numbers of non-GABAergic neurons and thinner deep neocortical layers. This reduction in number of non-GABAergic neurons is assumed to be caused by accumulation of cyclin-dependent kinase inhibitor p27(Kip1) in nuclei of neural progenitors. Lending support to this presumption, mice lacking p27(Kip1) are not susceptible to in utero dioxin exposure. These results show that environmental pollutants may affect neocortical histogenesis through alterations of functions of specific gene(s)/protein(s) (in our case, dioxins), exerting adverse effects by altering functions of p27(Kip1).

Access to Document (DOI)

Embryonic expression profile of chicken CHD7, the ortholog of the causative gene for CHARGE syndrome

M. Aramaki, T. Kimura, T. Udaka, R. Kosaki, T. Mitsuhashi, Y. Okada, T. Takahashi and K. Kosaki

Birth defects research. Part A, Clinical and molecular teratology 79 ( 1 ) 50 - 7 2007.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 1542-0752

BACKGROUND: CHARGE syndrome represents a constellation of malformations: C, coloboma of the iris or retina; H, heart defects; A, atresia of the choanae; R, retardation of growth and/or development; G, genital anomalies; and E, ear abnormalities. Recently, the Chromodomain helicase DNA-binding protein-7 (CHD7) at chromosome 8q12.1 was identified as a causative gene for CHARGE syndrome. Because CHD7 was identified as a causative gene using a positional cloning approach, the role of CHD7 in early embryogenesis needs to be further investigated. METHODS: Fertilized chick eggs were incubated to Hamburger and Hamilton stages 4-20 and were studied using whole mount in situ hybridization. Chicken EST clones corresponding to the chicken CHD7 (cChd7) sequence were identified using the chicken EST sequence database. From the EST clones, a digoxigenin-labeled RNA probe was synthesized and hybridized in situ to the embryonic specimens. RESULTS: The expression of cChd7 was pan-neuronal at stages 8-20. It was expressed throughout the rostral neural ectoderm and along the rostrocaudal axis but was absent from the more lateral, non-neuronal ectoderm. Adjacent to the neural tube, cChd7 transcripts were detected at the optic and otic placodes. At stage 20, cChd7 expression was observed in the branchial arches and olfactory placodes in addition to brain and optic and otic placodes. CONCLUSIONS: cChd7 was expressed in the neural epithelium, the otic placodes, the optic placodes, the branchial arches, and the olfactory placodes, which are the primordial tissues that give rise to organs affected in human CHARGE syndrome patients.

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Genome-wide screening of dioxin-responsive genes in fetal brain: bioinformatic and experimental approaches

H. Fujita, H. Samejima, N. Kitagawa, T. Mitsuhashi, T. Washio, J. Yonemoto, M. Tomita, T. Takahashi and K. Kosaki

Congenital Anomalies 46 ( 3 ) 135 - 43 2006.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0914-3505

Many of the effects of dioxins, which are potent environmental pollutants and teratogens, are mediated through the aryl hydrocarbon receptor, also known as the dioxin receptor. The purpose of the present study was to characterize dioxin-responsive genes in a comprehensive manner using two complementary approaches: bioinformatic analysis and microarray analysis. First, we characterized the overall distribution of the cis-regulatory element for the dioxin-responsive element sequence (DRE) 'gcgtg' within putative promoter regions. We assembled the upstream sequences 10 kb from the transcription start site and evaluated their location and frequency in the human and mouse genomes. Second, we characterized the expression profile of mouse embryonic day 12 fetal brain exposed to 2,3,7,8-tetrarchlorodibenzo-p-dioxin. The distributions of 26,680 DREs among 2,843 human genes and 98,711 DREs among 18,541 mouse genes were examined. In both species, the DREs tended to be located close to the transcription start site. Forty genes exhibited significant induction or repression following dioxin exposure in fetal mice. The set of genes exhibited a strong functional coherence, with statistically significant enrichment in organogenesis and the DNA-dependent regulation of transcription, according to Gene Ontology annotations. In both humans and mice, DREs were preferentially distributed close to transcription start sites. Evolutionary conservation of this unique DRE distribution pattern suggests that DREs may be involved in transcriptional regulation. In mice, prenatal dioxin exposure altered the expression of 10 transcription factors, many of which have been documented to play a role in organogenesis. These genes may represent potential mediators of dioxin's effects in fetal tissues.

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The RNA-binding protein HuD regulates neuronal cell identity and maturation

W. Akamatsu, H. Fujihara, T. Mitsuhashi, M. Yano, S. Shibata, Y. Hayakawa, H. J. Okano, S. Sakakibara, H. Takano, T. Takano, T. Takahashi, T. Noda and H. Okano

Proc Natl Acad Sci U S A 102 ( 12 ) 4625 - 30 2005.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 0027-8424

Neural Hu proteins (HuB/C/D) are RNA-binding proteins that have been shown to induce neuronal differentiation activity when overexpressed in immature neural progenitor cells or undifferentiated neuronal tumors. Newly generated HuD-deficient mice exhibited a transient impaired-cranial-nerve-development phenotype at an early embryonic stage. Adult HuD-deficient mice exhibited an abnormal hind-limb reflex and poor rotarod performance. Analysis of neurosphere formation revealed that the number and self-renewal capacity of the neural stem/progenitor cells were increased in HuD-deficient mice. HuD-deficient primary neurospheres also generated a smaller number of neurons. Cohort analysis of the cellular proliferative activity by using BrdUrd and iododeoxuridine labeling revealed that the number of differentiating quiescent cells in the embryonic cerebral wall was decreased. Long-term administration of BrdUrd revealed that the number of slowly dividing stem cells in the adult subventricular zone was increased in the HuD-deficient mice. Taken together, the results suggest that HuD is required at multiple points during neuronal development, including negative regulation of proliferative activity and neuronal cell-fate acquisition of neural stem/progenitor cells.

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クロバザム極少量投与により副作用を回避し得たCYP2C19*2*3複合ヘテロ接合体の1例

高橋孝雄、三橋隆行、下郷幸子、佐藤玲子、谷川原祐介、田村和代、小崎健次郎

小児科臨床 58 ( 3 ) 407 - 410 2005.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 0021-518X

Colocolic intussusception associated with pneumatosis cystoides intestinalis after cord blood stem cell transplantation.

'TAKAHASHI TAKAOSugita M, Mori T, Shimada H, Shimasaki N, Morikawa Y, Takahashi T'

J Pediatr Gastroenterol Nutr 38 ( 5 ) 549-551 2004.05

Research paper (scientific journal), Joint Work

Altered patterns of neuron production in the p27 knockout mouse

T. Goto, T. Mitsuhashi and T. Takahashi

Dev Neurosci 26 ( 2-4 ) 208 - 17 2004.03

Research paper (scientific journal), Accepted

The number and distribution of neurons in the murine neocortex are altered by loss of function of p27Kip1, a cyclin-dependent kinase inhibitor that regulates cell cycle progression at the G1 phase. We show that a temporary decline in the production of non-GABAergic projection neurons occurs in the dorsomedial neopallium of the p27Kip1 knockout mouse during the mid-term of neuronogenesis. It is followed by an augmentation of neuron production later in neuronogenesis leading to an increased production of projection neurons for the upper layers of the neocortex (layers II-IV). p27Kip1 is likely to play a critical role in cell internal regulatory mechanisms of proliferation/differentiation behavior of neural progenitor cells and may be directly involved in the control of neuron number during the period when non-GABAergic projection neurons for layers II-IV are being produced.

クリニカルカンファレンス　外性器異常を有し生後3週まで社会的性を決定されなかった1例

TAKAHASHI TAKAO

小児科臨床 57 ( 1 ) 113-119 2004

Research paper (scientific journal), Joint Work

Somatic PTPN11 mutation with a heterogeneous clonal origin in children with juvenile myelomonocytic leukemia.

'TAKAHASHI TAKAOShimada H, Mori T, Shimasaki N, Shimizu K, Takahashi T, Kosaki K'

Leukemia 18 ( 6 ) 1142-1144 2004

Research paper (scientific journal), Joint Work

Deficiency of BLNK hampers PLC-gamma2 phosphorylation and Ca2+ influx induced by the pre-B-cell receptor in human pre-B cells.

'TAKAHASHI TAKAOTaguchi T, Kiyokawa N, Takenouch H, Matsui J, Tang WR, Nakajima H, Suzuki K, Shiozawa Y, Saito M, Katagiri YU, Takahashi T, Karasuyama H, Matsuo Y, Okita H, Fujimoto J.'

Immunology 112 ( 4 ) 575-582 2004

Research paper (scientific journal), Joint Work

Holoprosencephaly--topologic variations in a Liveborn series: a general model based upon MRI analysis.

'TAKAHASHI TAKAOTakahashi Tsutomu, Kinsman S, Makris N, Grant E, Haselgrove C, McInerney S, Kennedy DN, Takahashi Takao, Fredrickson K, Mori S, Caviness VS'

J Neurocytol 33 ( 1 ) 23-35 2004

Research paper (scientific journal), Joint Work

Hyperinsulinemic hypoglucemia in a newborn infant with trisomy 13.

'TAKAHASHI TAKAOTamame T, Hori N, Homma H, Yoshida R, Inokuchi M, Kosaki K, Takahashi T, Hasegawa T'

Am J Med Genet 129A ( ? ) 321-322 2004

Research paper (scientific journal), Joint Work

Position-specific expression of Hox genes along the gastrointestinal tract.

'TAKAHASHI TAKAOYahagi N, Kosaki R, Ito T, Mitsuhashi T, Shimada H, Tomita M, Takahashi T, Kosaki K'

Congenit Anom 44 ( 1 ) 18-26 2004

Research paper (scientific journal), Joint Work

小児病棟における，インフルエンザ接触者へのオセルタミビル予防内服効果

TAKAHASHI TAKAO

感染症学雑誌　別刷 78 ( 3 ) 2003.12

Research paper (scientific journal), Joint Work

p27kip1ノックアウトマウスにおける神経前駆細胞の分裂増殖・分化誘導に関する定量解析　大脳皮質発生異常の発症機序に関する研究

高橋孝雄, 後藤知英, 三橋隆行

厚生労働省精神・神経疾患研究委託費総括研究報告書発達期における高次脳機能障害の病態解明に関する研究平成12年度 87 - 91 2003.03

Research paper (other academic), Joint Work

細胞増殖因子p27^kiplを欠損したノックアウトマウス(p27KO)の大脳皮質発生異常の機序解明するため大脳皮質発生過程を定量解析した.生後21日のp27KOでは投射ニューロンが大脳皮質表層(II〜IV層)で特異的に増加すること,胎生14日の神経前駆細胞(NPC)細胞周期長に異常を認めず,NPCが分化を開始する確率(Q値)は低値であることが明らかになった.p27KOにおける大脳皮質形成異常は,投射ニューロンの産生過程において,NPCの分化誘導機構に障害が起こるためである

特集けいれん，意識障害ハンドブック:けいれん時の脳代謝

'Takahashi Takao, Takeoka Masanori'

小児内科 35 ( 2 ) 130 2003.02

Research paper (scientific journal), Joint Work

FK506-associated limbic injury following umbilical cord blood transfusion.

'TAKAHASHI TAKAOYoshida Y, Shimada H, Mori T, Yoshihara M, Takeoka M, Takahashi T'

Bone Marrow Transplantation 32 523-525 2003

Research paper (scientific journal), Joint Work

大脳の発生から考える小児神経疾患

TAKAHASHI TAKAO

東京小児科医会報 22 28-30 2003

Research paper (scientific journal), Single Work

特集　小児の疼痛コントロール、鎮痛補助薬（抗うつ薬、抗不安薬、睡眠薬）

TAKAHASHI TAKAO

小児内科 35 ( 8 ) 1305-1310 2003

Research paper (scientific journal), Joint Work

特集　水・電解質異常症、中枢神経系疾患

TAKAHASHI TAKAO

小児内科 35 ( 11 ) 1822-1825 2003

Research paper (scientific journal), Single Work

クリニカルカンファレンス　小球性低色素性貧血を手がかりとして発見されたサラセミアの一家系

TAKAHASHI TAKAO

小児科臨床 56 ( 9 ) 1875-1879 2003

Research paper (scientific journal), Joint Work

Reference values for urinary steroids in Japanese newborn infants: gas chromatography/mass spectrometry in selected ion monitoring.

'TAKAHASHI TAKAOHomma K, Hasegawa T, Masumoto M, Takeshita E, Watanabe K, Chiba H, Kurosawa T, Takahashi T, Matsuo N'

Endocrine J 50 ( ? ) 783-792 2003

Research paper (scientific journal), Joint Work

Micropenis and the 5a-reductase-2 (SRD5A2) gene: mutation and V89L polymorphism analysis in 81 Japanese patients.

'TAKAHASHI TAKAOSasaki G, Ogata T, Ishii T, Kosaki K, Hasegawa T, Sato S, Homma K, Takahashi T, Matsuo N'

J Clin Endocrinol Metab 32 ( 5 ) 523-525 2003

Research paper (scientific journal), Joint Work

Semilobar holoprosencephaly with midline 'seam': a topologic and morphogenetic model based upon MRI analysis.

'TAKAHASHI TAKAOTakahashi Tsutomu, Kinsman S, Makris N, Grant E, Haselgrove C, McInerney S, Kennedy DN, Takahashi Takao, Fredrickson K, Mori S, Caviness VS'

Cereb Cortex 13 ( 12 ) 1299-1312 2003

Research paper (scientific journal), Joint Work

FK506-associated limbic injury following umbilical cord blood transplantation.

'TAKAHASHI TAKAOYoshida Y, Shimada H, Mori T, Yoshihara H, Takeoka M, Takahashi T'

Bone Marrow Transplant 32 ( 5 ) 523-525 2003

Research paper (scientific journal), Joint Work

Micropenis and the 5a-reductase-2 (SRD5A2) gene: mutation and V89L polymorphism analysis in 81 Japanese patients

'Sasaki Goro, Ogata Tsutomu, Ishii Tomohiro, Kosaki Kenjiro, Sato Seiji, Homma Keiko, Takahashi Takao, Hasegawa Tomonobu, Matsuo Nobutake'

Journal of clinical endocrinology and metabolism 88 ( 7 ) 3431-3436 2003

Research paper (scientific journal), Joint Work

大脳皮質発生の数学モデル

'Mitsuhashi Takayuki, Takahashi Takao'

Brain Medical 14 ( 4 ) 28-32 2002.12

Research paper (scientific journal), Joint Work

Developmental regulation of the effects of fibroblast growth factor-2 and 1-octanol on neuronogenesis: Implications for a hypothesis relating to mitogen-antimitogen opposition

'Goto Tomohide, Takahashi Takao, Miyama Sahoko, Nowakowski Richard S, Bhide Pradeep G, Caviness Verne S Jr'

Journal of Neuroscience Research 69 ( 6 ) 714-722 2002.09

Research paper (scientific journal), Joint Work

神経系前駆細胞の分裂動態と大脳皮質発生

'Mitsuhashi Takayuki, Takahashi Takao'

医学のあゆみ ( 201 ) 754-758 2002.05

Research paper (scientific journal), Joint Work

Psychosomatic disorders in children:an emerging challenge to health care in Japan

'Takahashi Takao, Watanabe Hisako, Matsuo Nobutake'

Pediatrics international 44 ( 2 ) 153-156 2002.04

Research paper (scientific journal), Joint Work

Infectious and inflammatory disorders of the circulatory system and stroke in childhood

'Takeoka Masanori, Takahashi Takao'

Current opinions in neurology 15 ( 2 ) 159-164 2002.04

Research paper (scientific journal), Joint Work

Characterization of the aryl hydrocarbon receptor repressor gene and association of its Pro185Ala polymorphism with micropenis

'Fujita H, Kosaki R, Yoshihashi H, Ogata T, Tomita M, Hasegawa T, Takahashi T, Matsuo N, Kosaki K'

Teratology 65 ( 1 ) 10月18日 2002.01

Research paper (scientific journal), Joint Work

Analysis of cell generation in the telencephalic neuroepithelium

'Takahashi Takao, Caviness Verne S Jr, Bhide Pradeep G'

Methods in molecular biology 198 101-113 2002

Research paper (scientific journal), Joint Work

日本の小児科医学教育（卒前・卒後医学教育）のありかた

Sekiguchi Shinichirou，Takahashi Takao，Matsuo Nobutake

小児科診療 65 13-17 2002

Research paper (scientific journal), Joint Work

Evaluation of autonomic nervous system function with spectral analysis of heart rate variability in a case of tetanus

'Goto T, Fukushima H, Sasaki G, Matsuo N, Takahashi T'

Brain and Development 23 ( 8 ) 791-795 2001.12

Research paper (scientific journal), Joint Work

Continuity with ganglionic eminence modulates interkinetic nuclear migration in the neocortical pseudostratified ventricular epithelium

'Miyama S, Takahashi T, Goto T, Bhide PG, Caviness VS Jr'

Experimental Neurology 169 ( 2 ) 486-495 2001.06

Research paper (scientific journal), Joint Work

Overexpression of p27Kip1 lengthens the G1 phase in a mouse model that targets inducible gene expression to central nervous system progenitor cells

'Mitsuhashi T, Aoki Y, Eksioglu YZ, Takahashi T, Bhide PG, Reeves SA, Caviness VS Jr'

Proc Natl Acad Sci U S A 98 ( 11 ) 6435-6440 2001.05

Research paper (scientific journal), Joint Work

CSF glutamate/GABA concentrations in pyridoxine-dependent seizures: etiology of pyridoxine-dependent seizures and the mechanisms of pyridoxine action in seizure control

'Goto T, Matsuo N, Takahashi T'

Brain Dev 23 ( 1 ) 24-29 2001.03

Research paper (scientific journal), Joint Work

有熱時けいれん，検査に頼らないで診断するコツ　—新医療経済政策への対応—

Takahashi Takao

小児科3月増刊号 42 ( 4 ) 498-501 2001.03

Research paper (scientific journal), Single Work

【卒後臨床研修必修化の問題点を探る】　卒後臨床研修必修化と小児科研修カリキュラム

Matsuo Nobutake，Takahashi Takao

日本医師会雑誌 126 945-948 2001

Research paper (scientific journal), Joint Work

【検査に頼らないで診断するコツ】　症状・症候から診断へ　有熱時けいれん

Takahashi Takao

小児科 42 498-501 2001

Research paper (scientific journal), Single Work

CSF glutamate/GABA concentrations in pyridoxine-dependent seizures: etiology of pyridoxine-dependent seizures and the mechanisms of pyridoxine action in seizure control

'Goto T, Matsuo N, Takahashi T'

Brain Dev 23 ( 1 ) 24-29 2001

Research paper (scientific journal), Joint Work

Independent controls for neocortical neuron production and histogenetic cell death.

'Verney C, Takahashi Takao, Bhide Pradeep G, Nowakowski Richard S, Caviness Verne S Jr.'

Dev Neurosci 125 125-138 2000.02

Research paper (scientific journal), Joint Work

Sequence of neuron origin and neocortical laminar fate: relation to cell cycle of origin in the developing murine cerebral wall.

'Takahashi Takao, Goto Tomohide, Miyama Sahoko, Nowakowski Richard S, Caviness Verne S Jr.'

Journal of Neuroscience 19 ( 23 ) 10357-10371 1999.12

Research paper (scientific journal), Joint Work

Cyclin E-p27 opposition and regulation of the G1 phase of the cell cycle in the murine neocortical PVE: a quantitative analysis of mRNA in situ hybridization.

'Delalle Ivana, Takahashi Takao, Nowakowski Richard S, Tsai L H, Caviness Verne S Jr.'

Cerebral Cortex 9 ( 8 ) 824-832 1999.12

Research paper (scientific journal), Joint Work

Proliferative behavior of the murine cerebral wall in tissue culture: cell cycle kinetics and checkpoints.

'Takahashi Takao, Bhide Pradeep G, Goto Tomohide, Miyama Sahoko, Caviness Verne S Jr.'

Experimental Neurolgy 156 ( 2 ) 407-417 1999.04

Research paper (scientific journal), Joint Work

The G1 restriction point as critical regulator of neocortical neuronogenesis.

'Caviness Verne S Jr, Takahashi Takao, Nowakowski Richard S'

Neurochemical Research 24 ( 4 ) 497-506 1999.04

Research paper (scientific journal), Joint Work

うっ血乳頭で発見された上矢状静脈洞血栓症の2症例

'Kaburaki Akiko, Mashima Yukihiko, Ando Yasutaka, Oguchi Yoshihisa, Takahashi Takao'

神経眼科 15 ( 3 ) 318-324 1998.09

Research paper (scientific journal), Joint Work

La cytogenese neocorticale: le gradient proliferatif de l'epithelium pseudostratifie ventriculaire(PVE) et histogenese du cortex cerebral

'Caviness Verne S Jr, Takahashi Takao'

Percentiel 3 5月10日 1998

Research paper (scientific journal), Joint Work

A gradient in the duration of the G1 phase in the murine neocortical proliferative epithelium

'Miyama S, Takahashi T, Nowakowski RS, Caviness VS Jr.'

Cereb Cortex 7 678-689 1997.10

Research paper (scientific journal), Joint Work

Mathematics of neocortical neruonogenesis

'Takahashi Takao, Nowakowski RS, Caviness VS Jr'

Exp Neurosci 19 17-22 1997.02

Research paper (scientific journal), Joint Work

The leaving or Q fraction of the murine cerebral PVE and a generalmodel of neocortical neuronogenesis

'Takahashi Takao, Nowakowski RS, Caviness VS Jr'

J Neurosci 16 6183-6196 1996.10

Research paper (scientific journal), Joint Work

Interkinetic and migratory behavior of a cohort of neocortical neurons arising in the early embryonic murine cerebral wall

'Takahashi Takao, Nowakowski RS, Caviness VS Jr'

J Neurosci 16 5762-5776 1996.09

Research paper (scientific journal), Joint Work

Number of specific antibody-secreting cells in the peripheral blood among children with Mycoplasma pneumonia

'Iseki Mikiro, Takahashi Takao, Kimura Kyoko, Yamashita Ryoko, Sasaki Tsuguo'

Infect Immun 64 ( 7 ) 2799-2803 1996.07

Research paper (scientific journal), Joint Work

Regulation of normal proliferation in the developing cerebrum:Potentital actions of trophic factors

'Caviness VS Jr, Takahashi Takao, Miyama Sahoko, Nowakowski RS, Ivana Delalle Nowakowski RS, Caviness VS Jr'

Exp Neuro 137 357-366 1996.04

Research paper (scientific journal), Joint Work

'Numbers, time and neocortical neuronogenesis ・ A general developmental and evolutionary model'

'Caviness VS Jr, Takahashi T, Nowakowski RS'

Trends Neurosci 18 ( 9 ) 379-383 1995.12

Research paper (scientific journal), Joint Work

Early ontogeny of the secondary proliferative population of the embryonic murine cerebral wall

'Takahashi T, Nowakowski RS, Caviness Jr VS'

J Neurosci 15 ( 9 ) 6058-6068 1995.09

Research paper (scientific journal), Joint Work

The cell cycle of the pseudostratified ventricular epithelium of the murine cerebral wall

'Takahashi T, Nowakowski RS, Caviness Jr VS'

J Neurosci 15 ( 9 ) 6046-6057 1995.09

Research paper (scientific journal), Joint Work

Proliferative events in the cerebral ventricular zone

'Caviness VS Jr, Takahashi T'

Brain & Development 17 ( 3 ) 159-163 1995.06

Research paper (scientific journal), Joint Work

Mode of cell proliferation in the developing mouse neocortex

T. Takahashi, R. S. Nowakowski and V. S. Caviness, Jr.

Proc Natl Acad Sci, USA 91 ( 1 ) 375 - 9 1994.01

ISSN 0027-8424

There are two proliferative populations in the developing cerebral wall: the pseudostratified ventricular epithelium (PVE) and the secondary proliferative population (SPP). The present experiments provide on embryonic day 14 (E14) in the mouse direct measures of the values for the proportions of daughter cells that continue to proliferate (proliferative, P fraction, or P) and for those that leave the cell cycle (quiescent, Q fraction, or Q; Q = 1 - P) for both of these populations. The range of values of P for the PVE, 0.62-0.66, would provide for the relatively low rate of neuronal output and for an expansion of the proliferative population appropriate for E14. The even higher values of P for the SPP, 0.73-1.0, would expand this population rapidly in preparation for the high glial cell output to occur later in cerebral histogenesis.

Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system

L. H. Tsai, T. Takahashi, V. S. Caviness, Jr. and E. Harlow

Development 119 ( 4 ) 1029 - 40 1993.12

ISSN 0950-1991

Cyclin-dependent kinase 5 (cdk5) was originally isolated on the basis of its close primary sequence homology to the human cdc2 serine/threonine kinase, the prototype of the cyclin-dependent kinases. While kinase activities of both cdc2 and cdk2 are detected in proliferating cells and are essential for cells to progress through the key transition points of the cell cycle, cdk5 kinase activity has been observed only in lysates of adult brain. In this study, we compared the activity and expression of cdk5 with that of cdc2 and cdk2 in the embryonic mouse forebrain. The expression and activity of cdk5 increased progressively as increasing numbers of cells exited the proliferative cycle. In contrast, the expression and activity of cdc2 and cdk2 were maximum at gestational day 11 (E11) when the majority of cells were proliferating and fell to barely detectable levels at E17 at the end of the cytogenetic period. Immunohistochemical studies showed that cdk5 is expressed in postmitotic neurons but not in glial cells or mitotically active cells. Expression of cdk5 was concentrated in fasciculated axons of postmitotic neurons. In contrast to other cell division cycle kinases to which it is closely related, cdk5 appears not to be expressed in dividing cells in the developing brain. These observations suggest that cdk5 may have a role in neuronal differentiation but not in the cell division cycle in the embryonic nervous system.

PCNA-binding to DNA at the G1/S transition in proliferating cells of the developing cerebral wall

T. Takahashi and V. S. Caviness, Jr.

J Neurocytol 22 ( 12 ) 1096 - 102 1993.12

ISSN 0300-4864

Proliferating cell nuclear antigen is a nuclear protein essential to DNA synthesis in eukaryotic cells. It is known to form part of a multi-protein complex which binds to DNA from the outset of S-phase of the cell cycle. We define in this analysis the interval of proliferating cell nuclear antigen binding to DNA (strictly speaking, the interval through which proliferating cell nuclear antigen is stained immunohistochemically after ethanol fixation) with respect to the stages of the cell cycle in the intact mammalian brain. The epithelium of the developing cerebral wall is favourable for such an analysis because nuclei at the same stage of the cell division cycle are spatially aligned with each other at the same depth of the epithelium. Therefore spatial location of a nucleus within the epithelium is a reliable indicator of the stage of the cell cycle for that nucleus. Proliferating cell nuclear antigen-DNA binding in this epithelium is initiated in the final 5% (26 min) of G1-phase and continues through the initial 35% (1.3 h) of S-phase. This phasic pattern of proliferating cell nuclear antigen-DNA binding, as revealed for the first time in the intact cerebral wall, approximates closely the phasic pattern as it has been characterized until now only in vitro in vertebrate cell lines. This analysis illustrates the potential of the cerebral proliferative epithelium for study of the molecular events of the cell cycle under in vivo conditions of histogenetic regulation.

Cell cycle parameters and patterns of nuclear movement in the neocortical proliferative zone of the fetal mouse

T. Takahashi, R. S. Nowakowski and V. S. Caviness, Jr.

J Neurosci 13 ( 2 ) 820 - 33 1993.02

ISSN 0270-6474

Cytogenesis is the critical determinant of the total number of neurons that contribute to the formation of the cerebral cortex and the rate at which the cells are produced. Two distinct cell populations constitute the proliferative population, a pseudostratified ventricular epithelium (PVE) lying within the ventricular zone (VZ) at the margin of the ventricle, and a secondary proliferative population that is intermixed with the PVE within the VZ but also is distributed through the overlying subventricular and intermediate zones of the cerebral wall. The present analysis, based upon cumulative S-phase labeling of the proliferative cells with 5-bromo-2'-deoxyuridine, is principally concerned with the PVE of the gestational-day-14 (E14) murine cerebral wall. It has immediate but also more far reaching general objectives. The most immediate objective, essential to the design and interpretation of later experiments, is to provide estimates of critical parameters of cytogenesis for the PVE. The growth fraction is virtually 100%. The lengths of the overall cell cycle, S-, G2+M-m, and G1-phases are 15.1 hr, 3.8 hr, 2 hr, and 9.3 hr, respectively. The PVE is homogeneous with respect to cell cycle length. For methodological considerations, these estimates are more accurate than estimates of the same parameters obtained in earlier analyses based upon S-phase labeling with tritiated thymidine. It is particularly with respect to a shorter length of S-phase determined here that the present values are different from those obtained with thymidine. At a more innovative level, the temporal and spatial resolution of nuclear movement made possible by the methods developed here will allow, in a way not previously attempted, a fine-grained tracking of nuclear movement as cells execute the successive stages of the cell cycle or exit the cycle subsequent to mitosis. Such observations are pertinent to our understanding of the regulatory mechanisms of neocortical histogenesis and the cell biological mechanisms that govern the proliferative cycle of the ventricular epithelium itself. It is known that the velocity of nuclear movement in the PVE is maximum in G2 (fourfold increase from S-phase) and minimum in M and early G1.(ABSTRACT TRUNCATED AT 400 WORDS)

BUdR as an S-phase marker for quantitative studies of cytokinetic behaviour in the murine cerebral ventricular zone

T. Takahashi, R. S. Nowakowski and V. S. Caviness, Jr.

J Neurocytol 21 ( 3 ) 185 - 97 1992.03

ISSN 0300-4864

BUdR incorporation into replicating DNA, detected immunohistochemically, is used as an S-phase marker in the proliferative cell populations of the cerebral wall of the mouse embryo on the 14th gestational day (E14). The analysis initiates a series of studies concerned with the cytokinetic behaviour and cell output of proliferative populations involved in neocortical histogenesis. On E14 there are two periventricular proliferative zones in the cerebral wall. These are the ventricular and subventricular zones. The ventricular zone is a pseudostratified epithelium. DNA replication occurs with the cell nucleus in the outer zone of the epithelium and mitoses at the ventricular surface. Prior applications of BUdR for studies of cytogenesis in the CNS have been extended in two principal ways: (1) basic fuchsin was used as counterstain for BUdR-negative nuclei and (2) labelling indices were determined separately in strata or bins, 10 microns in height, through the full depth of the ventricular zone and overlying cerebral wall. It was established that a single injection of 50 micrograms g-1 into the pregnant dam was associated with labelling of 100% of nuclei in S-phase over an interval extending from 15 min to at least 2.0 h after injection. The zone where nuclei are undergoing S-phase (S-phase zone) extends through the outer four bins of the ventricular zone. The method has high quantitative reproducibility with an SE for labelling indices in bins within the S-phase zone less than 10% of the average values. Evidence is provided that BUdR incorporation is initiated with the nucleus in the outer aspect of the S-phase zone. The efficiency of incorporation of the marker is reduced as nuclei near the end of DNA replication and move to the inner aspect of the S-phase zone.

The alignment of migrating neural cells in relation to the murine neopallial radial glial fiber system

J. P. Misson, C. P. Austin, T. Takahashi, C. L. Cepko and V. S. Caviness, Jr.

Cereb Cortex 1 ( 3 ) 221 - 9 1991.05

ISSN 1047-3211

The direction of neural cell migration in relation to the pattern of alignment of adjacent radial glial fibers has been studied in the developing neopallium of embryonic days 16-18 mouse embryos. The radial glial fibers were stained with RC2, a monoclonal antibody selective for cells of astroglial lineage in the developing murine brain. Migrating neural cells were stained histochemically with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) following retroviral transduction of the gene encoding beta-galactosidase into proliferating progenitors on E13. The leading processes and, generally, the somata of migrating neurons were found to be aligned in parallel with the radial glial fibers, despite substantial variations in the patterns of alignment of the fiber fascicles. The set of observations is consistent with the hypothesis that neural cell migration is supported by radial glial fibers.

Ontogeny of radial and other astroglial cells in murine cerebral cortex

J. P. Mission, T. Takahashi and V. S. Caviness, Jr.

Glia 4 ( 2 ) 138 - 48 1991

Joint Work, ISSN 0894-1491

Three cell forms of astroglial lineage populate the prenatal and early postnatal murine cerebral wall. In the present review we consider the ontogeny of these cell forms with respect to histogenetic events of the perinatal period. Classic bipolar radial glial cells predominate prior to E17. The bipolar coexist with monopolar radial forms in the perinatal period. Both bipolar and monopolar radial forms coexist with multipolar astrocytes in the course of the first postnatal week and are ultimately succeeded by the multipolar cells. The shift from bipolar to monopolar radial forms is initially coincident with translocation of somata of bipolar cells from the ventricular zone to the upper intermediate zone and cortical strata. Arborization appears to occur both at the growing tips and along the shaft of the processes of both bipolar and monopolar radial cell types. As arborization continues, the processes of the monopolar radial cells come to resemble those of the multipolar astrocytes. Eventually the radial cells are fully transformed into the multipolar astrocytic forms. During this period of transition, radial processes in the cortex appear to be degenerating, suggesting that regressive processes contribute to the cytologic transformation. This sequence of transformations begins late in the period of neuronal migration and continues through the early stages of growth and differentiation in the murine cerebral cortex. The signals that induce these changes may arise from differentiating neurons within the cortex. These transformations occur at a time when radial glial fibers are no longer required as guides for neuronal migration, and the glial population assumes new roles related to the development and operation of cortical neuronal circuits.

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Cerebral lesions of tuberous sclerosis in relation to normal histogenesis

V. S. Caviness, Jr. and T. Takahashi

Annals of the New York Academy of Sciences 615 187 - 95 1991

ISSN 0077-8923

Glial process elongation and branching in the developing murine neocortex: a qualitative and quantitative immunohistochemical analysis

T. Takahashi, J. P. Misson and V. S. Caviness, Jr.

J Comp Neurol 302 ( 1 ) 15 - 28 1990.12

ISSN 0021-9967

Cells of astroglial lineage in the murine cerebrum undergo a succession of transformations during prenatal and early postnatal development. The bipolar radial cell, the earliest astroglial form to appear, provides a radially aligned, parallel array of fibers that serves as a guide to neuronal migration. The multipolar astrocyte is the representative of this lineage that persists in the adult cerebrum. The processes of the multipolar astrocytes form a complex reticulum, which is considered critical to the development, function, and maintenance of neural circuits. A monopolar radial cell appears to be transitional between the two. The shift from the radial glial fiber system to a diffuse glial network is achieved largely in the E17-P2 interval in the mouse. This phenomenon has been studied qualitatively and quantitatively by staining cerebral tissue with monoclonal antibody RC2, a specific and sensitive ligand for cells of astroglial lineage in the mouse. Elongation and branching of glial processes contribute to the glial transformation. Elongation of radial fibers occurs under the guidance of other radial glial fibers (fasciculated elongation) or independently of other fibers (nonfasciculated elongation). Fasciculated elongation results in an increase in the density of radial glial fibers that span the cortical layers. Nonfasciculated elongation appears to be associated with process branching. This is the initial event in transformation of the bipolar radial cells to monopolar radial or multipolar cells. Only nonfasciculated elongation is characteristic of processes of the monopolar radial cells and multipolar astrocytes. Branching of the processes of all three cell forms appears to occur both by bifurcation at the elongating tip and by sprouting from the fiber shaft. Elongating fibers are tipped by growth cones that are relatively simple in shape as compared to those observed at the tips of elongating axons. Growth cones at the tips of nonfasciculated fibers are more complex in form than those at the tips of radial fibers elongating in contact with other radial fibers.

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