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Biomedical subjects

Kenichi Isobe

Publications and source records attributed to Kenichi Isobe.

At least 19 recordsLinked to original sources
PubMed2006

Involvement of neurotrophic factors in aging of noradrenergic innervations in hippocampus and frontal cortex.

In the present study, we investigated the age-dependent changes in the axon terminals of the locus coeruleus (LC) neurons in the frontal cortex and hippocampus, in which a high degree of axonal branching in the middle-aged brain was suggested to occur in our previous electrophysiological study. We used 6-, 13- and 25-month-old male F344/N rats, and performed Western blot analysis of the norepinephrine transporter (NET), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). NET expression level increased in the 13-month-old hippocampus, but was not altered by aging in the frontal cortex. BDNF expression level increased in the hippocampus, but did not change with age in the frontal cortex. On the other hand, GDNF expression level was increased with age in the frontal cortex, but was not in the hippocampus. These results suggest that the LC noradrenergic innervations may be locally regulated by different neurotrophic factors that exert their trophic actions at different target sites.

Aging↗
PubMed2006

A PKC-mediated backup mechanism of the MXXCW motif-linked switch for initiating tyrosine kinase activities.

The cysteine in the M/IXXCW motif is conserved in all but one (threonine in place of cysteine) of the human protein tyrosine kinases (PTKs). We showed that all RET-PTC-1 mutants in which the C in this motif (C376) was replaced with glycine, lysine, threonine or serine lost their activity in vitro. However, the C376T/S mutants showed normal tyrosine phosphorylation in vivo (in cells). Further analyses reveled that protein kinase C (PKC) initiated the activities of the C376T/S mutants in cells. We conclude that the M/IXXCW motif-mediated mechanisms which initiate PTK activities are partially replaced by a PKC-mediated mechanism.

Amino Acid Motifs↗
PubMed2006

Age-dependent interactive changes in serotonergic and noradrenergic cortical axon terminals in F344 rats.

In the frontal cortex of aging rats, we found an increase in sprouting of the noradrenergic (NA) axons originated from the locus coeruleus (LC). The serotonergic (5-HT) axons originating from the dorsal raphe (DR) share the same cortical area and their age-dependent changes and interactions with NA axons were still unclear. To compare quantitatively the extent of axonal sprouting of DR and LC neurons in the frontal cortex, we extracellularly recorded from both DR and LC neurons in the same animals and antidromically stimulated 32 cortical sites (a pair of stimulating electrodes was moved at 100-mum intervals from 500 to 2000 microm in depth). In addition, to examine the effects of degeneration of 5-HT axons on NA axons, and vice versa, we used specific neurotoxins for 5-HT (PCA) or NA (DSP-4) axons. We also used noradrenaline uptake inhibitor (maprotiline) to verify the effects of NA on degeneration of 5-HT axons. Results suggested that 5-HT axons sprouted between 15 and 17 months of age and noradrenaline accelerated the age-dependent change of 5-HT axons.

Adrenergic Uptake Inhibitors↗
PubMed2005

Developmental changes in serum half-life of (EZ)-cyclobilirubin.

BACKGROUND: Phototherapy has been a standard treatment for neonatal hyperbilirubinemia for more than 40 years, but it has remained sub-optimal. AIMS: To clarify the developmental changes in parameters of (4E, 15Z)-cyclobilirubin ((EZ)-C) elimination in order to obtain basic data for establishing optimal phototherapy. STUDY DESIGN: Blood samples were taken at regular intervals after stopping phototherapy, and bilirubin fractions were analyzed by high-performance liquid chromatography. SUBJECTS AND METHODS: The subjects were 46 infants with hyperbilirubinemia who underwent phototherapy. The gestational age and birth weight of the subjects ranged from 25.0 to 41.0 weeks and from 656 to 3810 g, respectively, and the age at cessation of phototherapy was a median of 5 days. A kinetic model of (EZ)-C elimination was established, and the serum half-life of (EZ)-C was calculated on the basis of the determined model. Relationships of the half-life of (EZ)-C with birth weight and gestational age were investigated. RESULTS: Serum (EZ)-C elimination followed a first-order kinetic model in 43 infants and a zero-order kinetic model in three extremely low birth weight infants. The half-life of (EZ)-C calculated on the basis of a first-order elimination model in serum ranged from 68 to 274 min and showed weak negative correlations with birth weight and gestational age. CONCLUSIONS: Serum (EZ)-C excretion followed a first-order kinetic model in most of the neonates. The half-life of (EZ)-C becomes more prolonged in the very low birth weight infant and early gestational age.

Bilirubin↗
PubMed2005

Cortisol levels in umbilical vein and umbilical artery with or without antenatal corticosteroids.

BACKGROUND: The developmental changes of the umbilical cortisol levels in neonates at gestational age of 23-41 weeks were studied and the effect of antenatal steroid administration on the umbilical cortisol levels were examined. METHODS: Cortisol levels in the umbilical vein (UV) and the umbilical artery (UA) were studied in 35 neonates at the gestational age (GA) of 23-41 weeks with or without antenatal administration of corticosteroids. Serum cortisol concentrations were measured by the high performance liquid chromatography method. RESULTS: The correlation between cortisol levels in UV and birthweight (BW) was weak and negative in premature infants. UV cortisol levels in the neonates with antenatal corticosteroid were lower than those in the neonates without antenatal corticosteroid, but the relation was not significant. The developmental changes of UV cortisol levels were the same as those in Murphy's study (spontaneous-onset labor). The cortisol levels in UV and UA had a significantly positive correlation and both had almost equal concentrations. There were no correlations between cortisol levels in UV and placental weight, Apgar Score at 1 and 5 min. CONCLUSIONS: In the neonates whose birthweight was less than 2000 g without antenatal corticosteroid, there was a negative correlation between cortisol levels in UV and BW but there was no correlation between cortisol levels in UV and GA. That the neonates with antenatal corticosteroid would have a suppressed adrenocortical function after birth could not be proved.

Adrenal Cortex Hormones↗
PubMed2005

Estimation of circulating blood volume in infants using the pulse dye densitometry method.

BACKGROUND: Estimation of hemodynamics is important for critically ill infants. Pulse dye densitometry (PDD) using indocyanine green (ICG), which enables measurements of circulating blood volume at the bedside, has recently been developed for adults. METHODS: We conducted a basic investigation to determine whether this method can be applied to infants and measured circulating blood volume in 25 infants whose gestational ages ranged from 24 to 40 weeks (median, 32 weeks). At first, to validate the accuracy of measurements, arterial ICG concentrations determined by blood sample measurements were compared using a spectrophotometer ([ICG blood]) and by noninvasive measurement using PDD ([ICG pdd]) in seven infants. Next, blood volumes in 25 infants were estimated by the PDD method. RESULTS: There was a positive relationships between [ICG blood] and [ICG pdd] (r = 0.913, P < 0.0001). Using Bland Altman analysis, the bias between the two methods was 0.24 +/- 0.30 mg.l(-1) (95% confidence interval: 0.39-0.09 mg.l(-1)) and the limits of agreement (2 sd) were -0.36 and 0.84 mg.l(-1), respectively. Mean (sd) blood volume was 94.9 ml.kg(-1) (24.3). The values obtained by this study are almost the same as previously reported values obtained by using other methods. CONCLUSIONS: PDD using ICG can be used to monitor of hemodynamics in infants.

Blood Pressure↗
PubMed2005

Recurrence potential of diffuse-type giant cell tumor in the foot: radiologic and pathologic features.

BACKGROUND: Aggressive musculoskeletal tumors in the foot, such as diffuse-type giant cell tumors or extra-abdominal desmoid tumors, are difficult to treat because the foot does not have enough soft tissue to allow wide tumor resection. We reviewed the clinical behavior of diffuse-type giant cell tumor in the foot and evaluated the recurrence potential of these tumors from radiologic and pathologic perspectives. METHODS: Six patients with a mean age of 37.6 years were included in this study. Radiologic studies, including sonography, computed tomography (CT), magnetic resonance imaging (MRI), and bone and gallium citrate scintigraphy, were obtained followed by surgical treatment and histologic evaluation of the tumor. RESULTS: Recurrence occurred in three patients. Although CT and MRI findings were similar in the recurrent and nonrecurrent tumors, marked differences were found between the two by scintigraphy; positive radiotracer uptake to the affected foot with gallium citrate scintigraphy was noted only in recurrent tumors, although positive accumulation was seen in all patients with bone scintigraphy. Histologically, the necrotic area and mitotic activity were more apparent in recurrent than in the nonrecurrent tumors, and tumor cell dyscohesion was noted in the former, (the intercellular space was increased). CONCLUSIONS: Repeated recurrence with tumor invasion into tarsal bone resulted in breakage of the tarsal arch that supports the body's weight. Amputation would be necessary for patients in whom the disease had progressed to obtain local cure and relief of pain. In the present study, we found two features of the recurrence potential of diffuse-type giant cell tumors: sparse cell to cell contact on pathologic examination and positive accumulation in the tumor on gallium citrate scintigraphy. We concluded that giant cell tumors with these two features have a strong potential for local recurrence, and thus require intensive followup.

Adolescent↗
PubMed2005

Developmental changes of optical properties in neonates determined by near-infrared time-resolved spectroscopy.

Near-infrared spectroscopy has been used for measurement of changes in cerebral Hb concentrations in infants to study cerebral oxygenation and hemodynamics. In this study, measurements by time-resolved spectroscopy (TRS) were performed in 22 neonates to estimate the values of light absorption coefficient and reduced scattering coefficient (mu'(s)), cerebral Hb oxygen saturation (SCO2), cerebral blood volume (CBV), and differential pathlength factor (DPF), and the relationships between postconceptional age and mu'(s), SCO2, CBV, and DPF were investigated. A portable three-wavelength TRS system with a probe attached to the head of the neonate was used. The mean mu'(s) values at 761, 795, and 835 nm in neonates were estimated to be (mean +/- SD) 6.46 +/- 1.21, 5.90 +/- 1.15 and 6.40 +/- 1.16/cm, respectively. There was a significant positive relationship between postconceptional age and mu'(s) at those three wavelengths. The mean SCO2 value was calculated to be 70.0 +/- 4.6%, and postconceptional age and SCO2 showed a negative linear relationship. The mean value of CBV was 2.31 +/- 0.56 mL/100 g. There was a significant positive relationship between postconceptional age and CBV. The mean DPF values at 761, 795, and 835 nm were estimated to be 4.58 +/- 0.41, 4.64 +/- 0.46, and 4.31 +/- 0.42, respectively. There was no relationship between postconceptional age and DPF at those three wavelengths. The results demonstrated that our near-infrared TRS method can be used to monitor mu'(s), SCO2, CBV, and DPF in the neonatal brain at the bedside in an intensive care unit.

Blood Volume↗
PubMed2005

SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress.

Forkhead transcription factor, DAF-16, regulates genes that contribute both to longevity and resistance to various stresses in C. elegans. We and others have reported that members of the FOXO, mammalian homologs of DAF-16, also regulate genes related to stress resistance, such as GADD45. The NAD-dependent protein deacetylase, SIR2, is required for life span extension in yeast induced by caloric restriction, which also increases longevity in a wide variety of other organisms, including mammals. Sir2.1, a homolog of yeast SIR2, also extends life span by acting in a DAF-16 signaling pathway in C. elegans. We demonstrate that mammalian SIRT1 (Sir2alpha) physiologically interacts with FOXO. Acetylation of FOXO4, by the transcriptional coactivator p300, counteracted transcriptional activation of FOXO4 by p300. In contrast, mammalian SIRT1 was found to bind to FOXO4, catalyze its deacetylation in an NAD-dependent manner, and thereby increase its transactivation activity. The activity of FOXO4 is suppressed or enhanced by SIRT1 inhibitor, nicotinamide, or its activator, resveratrol, respectively. In response to oxidative stress, FOXO accumulates within the nucleus and induces GADD45 expression. FOXO-mediated GADD45 induction is markedly impaired in the cell, which depleted SIRT1 expression by RNA-interference. These results indicate that mammalian SIRT1 plays a pivotal role for FOXO function via NAD-dependent deacetylation in response to oxidative stress, and thereby may contribute to cellular stress resistance and longevity.

Acetylation↗
PubMed2004

Noninvasive optical imaging in the visual cortex in young infants.

During the developmental stage, the brain undergoes anatomic, functional, and metabolic changes necessary to support the complex adaptive behavior of a mature individual. Estimation of developmental changes occurring in different regions of the brain would provide a means of relating various behavioral phenomena to maturation-specific brain structures, thereby providing useful information on structure-function relationships in both normal and disease states. We used multichannel near-infrared spectroscopy (MNIRS), a new noninvasive imaging technique for revealing the course of neural activity in selected brain regions, to monitor the activities of the visual cortex as mirrored by hemodynamic responses in infants subjected to photostimulation during natural sleep. In the infants, oxyhemoglobin and total hemoglobin decreased and deoxyhemoglobin increased in the visual cortex with photostimulation. This pattern of responses was different from the response pattern in adults reported previously. The different patterns of responses to photostimulation in the visual cortices of infants and adults might reflect developmental and behavioral differences. It may reflect a different functional organization of the visual cortex in infants or ongoing retinal development. Our results demonstrated that regional hemodynamic change could be detected in a small area around the visual cortex. MNIRS offers considerable potential for research and noninvasive clinical applications.

Adult↗
PubMed2004

BDNF is necessary for maintenance of noradrenergic innervations in the aged rat brain.

In the axon terminals of the locus coeruleus (LC) neurons, a high level of axonal branching was occurred in the middle-aged brain, and the increased branching was maintained in the aged brain. In the present study, we hypothesized that neurotrophic support is necessary for the morphological age-related changes seen in the noradrenergic innervations from the LC to frontal cortex. Through immunohistochemical and quantitative image analyses, we examined the age-dependent effects of brain-derived neurotrophic factor (BDNF) on the noradrenergic axon terminals in the frontal cortex of F344 rats. We continuously infused BDNF into the frontal cortex of young (6-months-old), middle-aged (13-months-old), or aged (25-months-old) rats. Exogenous BDNF infusion caused a marked increase in the density of noradrenergic axons in the aged brain, but no trophic action of BDNF was observed in the young and middle-aged brain. Neutralization of endogenous BDNF with a specific function-blocking antibody to BDNF led to a reduction in noradrenergic axons in the frontal cortex of 19-month-old rats. The present results suggest that BDNF is not involved in the augmentation of noradrenergic innervations in the aging brain, but it is necessary for the maintenance of noradrenergic innervations in the aged brain.

Aging↗
PubMed2004

Low-voltage electrochemotherapy with low-dose methotrexate enhances survival in mice with osteosarcoma.

Methotrexate plays a key role in adjuvant chemotherapy for treatment of osteosarcoma, but is used at a high dose because it can pass through a cell membrane only with difficulty. Therefore, if the drug delivery of methotrexate to the tumor could be enhanced, antitumor effect and survival would improve. We examined whether enhancement of the antitumor effect of electrochemotherapy was feasible by using low-dose methotrexate in mice with osteosarcoma. The tumor-bearing mice were divided into four groups: no treatment, methotrexate treatment alone, electroporation alone, and methotrexate treatment followed by electroporation. In single-treatment series, the size of the tumors in mice treated with electrochemotherapy decreased substantially 6 days after treatment, whereas continuous growth was observed in the other groups. In the series of treatments repeated three times at 6-day intervals, the original tumors in the electrochemotherapy group decreased consistently and the tumors disappeared in four of seven animals within 16 days. In the other groups, the tumors continued to grow and all host animals died within 58 days. These results show the usefulness of electroporation to enhance the effects of low-dose methotrexate and the potential benefits of electrochemotherapy for the treatment of human osteosarcoma.

Animals↗
PubMed2004

Change of bilirubin photoisomers in the urine and serum before and after phototherapy compared with light source.

BACKGROUND: The clinical effect of phototherapy for neonatal hyperbilirubinemia is based on the production and elimination of cyclobilirubin. Generally, the clinical effect of light sources is estimated by the reduction in the total serum bilirubin level. One procedure with less invasiveness than blood collecting is urine collection. Whether the effectiveness of light sources used for phototherapy could be assessed using measurements of bilirubin photoisomers in urine was studied. METHODS: This study was a retrospective analysis of 38 term infants with hyperbilirubinemia who underwent phototherapy. Bilirubin fractions in serum and urine before and 24 h after the phototherapy were measured by high-performance liquid chromatography. The light sources used for the phototherapy were blue-white light (n = 11), Biliblanket plus high output (n = 13) or green light (n = 14). The relationships between serum and urine bilirubin photoisomers after phototherapy and whether the levels of urine bilirubin photoisomer are affected by the light sources with different wavelength characteristic were analyzed. RESULTS: There was no correlation between serum (ZE)-bilirubin and urine configurational isomers, but a weak positive correlation between serum (EZ)-cyclobilirubin and urine structural isomers after phototherapy. Although serum (ZE)-bilirubin levels depended on the wavelength characteristic of each light source during phototherapy, the urine configurational isomer levels did not depend on it. The increase in serum (EZ)-cyclobilirubin levels and the urine structural isomer levels were mostly in agreement. CONCLUSIONS: The urine bilirubin structural isomers may be used to estimate the serum (EZ)-cyclobilirubin levels and to evaluate the clinical effects of light sources.

Bilirubin↗
PubMed2004

Imaging of ancient schwannoma.

OBJECTIVE: We surveyed the clinical symptoms and radiologic features of ancient schwannoma, a rare variant of schwannoma characterized by degenerative changes. MATERIALS AND METHODS: We present the clinical, radiologic, and pathologic features in seven patients with ancient schwannoma (mean age, 62 years; range, 45-80 years) treated at our department between 1998 and 2003. RESULTS: The most characteristic clinical features were a sign like Tinel's sign and a long interval between the onset of symptoms and surgery (mean interval, 8.3 years). Ancient schwannomas can grow large; the biggest tumor seen in our study was 14 cm long. The highly accurate radiologic assessment made possible with contrast-enhanced MRI and CT scanning showed enhancement at a peridegenerative area and sometimes at a capsule. These findings differ from those of the typical schwannoma and neurofibroma patterns reported to date. Furthermore, bone scintigraphy showed uptake in the tumor, but no accumulation was seen on gallium-67 citrate scintigraphy. CONCLUSION: The characteristic clinical and radiologic findings of ancient schwannoma should make it possible to differentiate it from malignant tumors.

Aged↗
PubMed2003

Transcriptional regulation of ILT family receptors.

Ig-like transcripts (ILT/leukocyte Ig-like receptor/monocyte/macrophage Ig-like receptor or CD85) are encoded on human chromosome 19q13.4, designated the human leukocyte receptor complex, and are predominantly expressed on myeloid lineage cells. We investigated the transcriptional regulation of ILT1, ILT2, and ILT4 genes to elucidate control mechanisms operating on the specific expression of ILT receptors. Inhibitory ILT2 and ILT4 both have a similar genomic structure, in which the approximately 160-bp 5'-flanking regions function as core promoters with critically important PU.1 binding sites. However, an Sp1 family-binding GC-box is more influential in trans-activation of ILT2 than ILT4. Additionally, ILT4 transcription is tightly regulated by chromatin modifications accompanied by histone acetylation, which strictly controls expression within myeloid lineage cells. Activating ILT1 carries a core promoter corresponding to the intronic region of ILT2 and ILT4, where PU.1 and Runx1 binding sites are essential, but a downstream heat shock element also augments promoter activity. Thus, each ILT is regulated by a distinct transcriptional mechanism, although PU.1 acts as a common trans-acting factor. We also found that human CMV infection strongly trans-activates inhibitory ILT2 and ILT4 genes through the expression of immediate-early proteins.

Antigens, CD↗
PubMed2003

Relationship between cerebral interstitial levels of amino acids and phosphorylation potential during secondary energy failure in hypoxic-ischemic newborn piglets.

The aim of this study was to determine the validity of the hypothesis that excitatory amino acids are related to phosphorylation potential during primary and secondary cerebral energy failure observed in asphyxiated infants. We report here the results of experiments using newborn piglets subjected to severe transient cerebral hypoxia-ischemia followed by resuscitation. We examined cerebral energy metabolism by phosphorus nuclear magnetic resonance spectroscopy and changes in levels of amino acid neurotransmitters in the cortex by microdialysis before, during, and up to 24 h after the hypoxic-ischemic insult. The concentrations of aspartate, glutamate, taurine, and gamma-aminobutyric acid were significantly elevated during the hypoxic-ischemic insult compared with prebaseline values. Shortly after resuscitation, glutamate, taurine, and gamma-aminobutyric acid concentrations decreased but then began to increase again. These secondary elevations were greater than the primary elevations. A negative linear correlation was found between primary interstitial levels of glutamate and taurine and minimum values of phosphocreatine/inorganic phosphate during the secondary energy failure. The cerebral energy state depended on the time course of changes in excitatory amino acids, suggesting that amino acids play distinct roles during the early and delayed phases of injury.

Amino Acids↗
PubMed2003

Specific uptake of Abeta1-40 in rat brain occurs in astrocyte, but not in microglia.

In the brain of a patient with Alzheimer's disease, beta amyloid peptide (Abeta) is thought to be taken up by glial cells such as astrocyte and microglia to be degraded. However, it is unclear whether the Abeta is absorbed by astrocyte or microglia. The purpose of our study is to determine which type of glial cell, astrocyte or microglia, can take up Abeta. Beta amyloid 1-40 (Abeta1-40) was directly infused into the frontal cortex or hippocampus for 14 days. Dual-labeling immunohistochemistry for Abeta1-40 with an astrocytic (GFAP) or microglial (CD11b) marker was performed to examine co-localization of Abeta1-40 and glial markers. In the Abeta1-40 infused site, immunoreactivity of Abeta1-40 was observed only in astrocytes, not in microglia. In addition, Abeta40-1, a reverse peptide of Abeta1-40, was not taken up by astrocytes. These results suggested that the astrocyte-specific uptake of Abeta occurred in the rat brain.

Amyloid beta-Peptides↗