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R Fukunaga

Publications and source records attributed to R Fukunaga.

At least 37 records · Page 2Linked to original sources
PubMed1993

Silent brain infarction and coronary artery disease in Japanese patients.

OBJECTIVE: Silent brain infarction is fairly common in the elderly, but predictive factors have not been definitively established. This study focuses attention on ischemic heart disease and cerebrovascular risk factors about the frequency of silent brain infarction. DESIGN: The existence of silent brain infarction, the extent of coronary artery stenosis, and cerebrovascular risk factors of consecutive 92 case series with suspected ischemic heart disease were surveyed. SETTING: A hospital for patients with ischemic heart disease. PATIENTS: Ninety-two consecutive Japanese patients with suspected ischemic heart disease were recruited. MAIN OUTCOME MEASURES: All subjects were evaluated for coronary atherosclerosis (number of coronary arteries with significant stenosis and Gensini score), the number of silent brain infarctions detected by computed tomography, the extent of carotid atherosclerosis as determined by B-mode ultrasonography, and cerebrovascular risk factors. RESULTS: Patients with silent cerebral infarctions were older (66.2 +/- 10.4 years) than those without such events (60.1 +/- 8.8 years) (P < .01). The extent of coronary atherosclerosis in patients with silent cerebral infarctions was significantly greater than in those without such events after adjustment for the effect of age (P < .001). The extent of carotid atherosclerosis and the percentages of individuals with hypertension, diabetes mellitus, a smoking habit, hypercholesterolemia, hypertriglyceridemia, and a low serum high-density lipoprotein cholesterol level did not differ between the groups with and without silent brain infarction. The frequency of silent brain infarction increased with the severity of coronary stenosis. CONCLUSION: Coronary atherosclerosis and age were important risk factors for silent brain infarction.

Adult↗
PubMed1993

Neuronal damage in the rat hippocampus induced by in vivo hypoxia.

Rats were subjected to hypoxia for 30 min in a chamber containing 5% O2 and 95% N2. The distribution of damaged neurons in the hippocampus was then examined at various predetermined times, ranging from 3 hours to 21 days after hypoxia. Hematoxylin-eosin stained sections showed shrunken and eosinophilic neurons in the CA3 and CA4 regions. Similar, but less severe, changes were also observed in the granule cell layer of the dentate gyrus. In contrast, neurons in the CA1 region were relatively resistant to hypoxia. These results showed the susceptibility of the hippocampus to hypoxia, although the affected neurons are not the same as those vulnerable to ischemia.

Animals↗
PubMed1992

Rational design of potent antagonists to the human growth hormone receptor.

A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially--a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

Antibodies, Monoclonal↗
PubMed1992

Chromosomal gene organization of the human granulocyte colony-stimulating factor receptor.

The human chromosomal gene for the granulocyte CSF (G-CSF) receptor was molecularly cloned from a human gene library. The gene is about 16.5 kb long, and present in a single copy per haploid human genome. The human G-CSF receptor gene consists of 17 exons, and the sequences of exons are completely identical to those of cDNAs isolated from human U-937 myeloid leukemia or placenta cDNA libraries. The G-CSF receptor can be subdivided into several regions: an Ig-like domain, a cytokine receptor homologous domain, three fibronectin type III domains, a transmembrane domain, and a cytoplasmic region. Exons 3-17 code for the G-CSF receptor protein, and each subdomain of the receptor is encoded by a set of exons. Primer extension analysis of the G-CSF receptor mRNA identified major and minor transcription start sites. There is no canonical "TATA" box upstream of the CAP site. About 110 nucleotides upstream of the transcription initiation site of the gene, there is an element of 18 nucleotides that is homologous to the sequences found in the promoter of human myeloperoxidase and neutrophil elastase genes.

Amino Acid Sequence↗
PubMed1992

Sequential change of heterogeneous cerebral blood blow patterns after diffuse brain ischemia.

In order to provide an insight into the basic nature of ischemic brain injury, we sequentially studied cerebral blood flow with [99mTc]hexamethylpropyleneamine oxime single photon emission computed tomography (CBF imaging) in a patient with diffuse brain ischemia due to prolonged cardiac arrest. On the 10th postarrest day, concentrated blood flow over superior-medial portion of the occipital lobe was demonstrated. On the 18th postarrest day, the same region became high density on a CT scan, while the concentrated flow on the CBF imaging had diminished. Thus, an abnormal cerebral blood flow (CBF) pattern preceded the density change on CT scan. On the 23rd postarrest day, remarkably concentrated flow over the brainstem was demonstrated. This might have illustrated the reduced metabolic demand of the damaged tissue over the cerebral and cerebellar hemispheres with relative preservation of brainstem perfusion. In patients with diffuse brain ischemia, a CBF imaging may be a useful tool for clarifying pathological process and prognosis.

Brain↗
PubMed1992

Progression of carotid atherosclerosis in Japanese patients with coronary artery disease.

BACKGROUND AND PURPOSE: Along with the recent changes in lifestyle in Japan, the incidence of coronary artery disease has increased while the incidence of stroke appears to be decreasing. We investigated the relation between the progression of carotid atherosclerosis and the severity of coronary artery disease in the Japanese population. METHODS: The 2-year change in extracranial carotid atherosclerosis in 50 Japanese patients who underwent coronary angiography was evaluated using carotid echotomography. To quantify the extent of carotid atherosclerosis, the maximal thickness measurements of all plaques were summed for an individual plaque score, except for new plaques found on reexamination. Carotid disease progression was evaluated by the sum of plaque score change and the thickness of the new plaque found on reexamination. RESULTS: The plaque score changed by -3.2 to 10.1 mm (mean +/- SD, 1.06 +/- 2.42 mm). The extent of coronary atherosclerosis (p less than 0.02) and serum total cholesterol level (p less than 0.01) were different between the progressing (n = 17) and the nonprogressing (n = 30) groups of carotid atherosclerosis when the progressing group included the patients with a delta plaque score of greater than or equal to 1.0 mm. Neither age, serum triglyceride level, serum high-density lipoprotein cholesterol level, pack-years of smoking, percentage of smokers, percentage of hypertensive patients, nor percentage of diabetic patients was different between the two groups. Carotid disease progression was significantly higher in patients with three-vessel coronary disease than in patients without significant coronary artery disease (p less than 0.005). There was a significant positive linear correlation between carotid disease progression and Gensini's coronary artery disease score (R = 0.411, p less than 0.005). CONCLUSIONS: Our data showed that severe coronary artery disease and a high serum total cholesterol level were strong predictors for carotid disease progression in Japanese patients with high rates of coronary artery disease.

Carotid Artery Diseases↗
PubMed1992

Neurokinin A-stimulated phosphoinositide breakdown in rabbit iris sphincter muscle.

Specific [3H]-substance P binding was saturable and of high affinity (KD = 2.5 nM) with a Bmax of 725 fmol/mg protein in the isolated rabbit iris sphincter muscle. The competition for [3H]-substance P binding was in the order of eledoisin greater than substance P greater than kassinin greater than neurokinin B greater than neurokinin A greater than physalaemin. In the same preparation, neurokinin A, as well as substance P induced a concentration-related accumulation of [3H]-inositol phosphates (IPs), and the maximum increase was about 200% of the control at 10(-4) M. [D-Arg1, D-Trp7,9, Leu11]-substance P (SP) and [D-Pro2, D-Trp7,9]-SP (10(-3) M) inhibited substance P or neurokinin A (10(-4) M)-induced phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis significantly. [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP (10(-3) M) also inhibited neurokinin A (10(-4) M)-induced PIP2 hydrolysis significantly. Neurokinin A and substance P produced concentration-related contractions in normal Ca(2+)-containing medium. The contractile response was weaker in Ca(2+)-free medium, and there was no response in 0.2 mM EGTA medium. In Ca(2+)-free medium, the basal level of [3H]-IPs accumulation was smaller than that in normal medium, and neurokinin A and substance P significantly increased PIP2 hydrolysis. In the 0.2 mM EGTA containing medium, neurokinin A and substance P did not stimulate the PIP2 hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Bone modulation in sustained hematopoietic stimulation in mice.

To understand the etiology of bone modulation and hypercalcemia observed in granulocytosis of a tumor-bearing animal model and to gain insight into the implication of sustained hematopoietic stimulation on the bone tissue, in vivo responses of normal mouse hematopoietic and bone tissues to long-term injections of recombinant human and murine granulocyte colony-stimulating factor (G-CSF), murine granulocyte-macrophage CSF (GM-CSF), and human erythropoietin were quantitatively analyzed. Osteoclast activation was estimated by the osteoclast-endosteal ratio, determined by morphometric analyses of femoral sections. Medullary and bone areas were measured on transverse ground bone sections of the tibia. Recombinant murine G-CSF provoked marked granulocytosis associated with significant increases in the number of marrow granulocytes and their progenitors, and caused expansion of granulopoietic marrow into fatty marrow. The bone of G-CSF-treated mice showed a significant increase in endosteal osteoclast numbers with medullary area enlargement and a reduction in the bone thickness; indicative of endosteal bone resorption. Although GM-CSF had little effect on granulopoiesis, it caused peritoneal macrophages to increase and induced similar bone changes as those observed in G-CSF treatment. Enhanced erythropoiesis stimulated by erythropoietin was also associated with evidence of endosteal bone resorption. Bone changes induced by these growth factors were not associated with hypercalcemia. These animal studies document association of bone modulation in sustained stimulation of hematopoiesis, and implicate important physiologic effects of hematopoietic growth factors on skeletal tissue in vivo.

Animals↗
PubMed1991

Premature expression of the macrophage colony-stimulating factor receptor on a multipotential stem cell line does not alter differentiation lineages controlled by stromal cells used for coculture.

We are interested to know whether expression of a lineage-specific growth factor receptor is deterministic to lineage commitment during hematopoiesis. For this purpose, we introduced the human c-fms gene into the multipotential stem cell clone LyD9 and two myeloid progenitor clones, L-GM3 and L-G3, cells that differentiate in response to granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte (G)-CSF, respectively. Although LyD9 cells have differentiation potential to become macrophages, c-fms transfectants of LyD9 and L-GM3 cells did not differentiate in response to human macrophage (M)-CSF. However, c-fms transfectants of L-G3 cells differentiated to neutrophils in response to human M-CSF. These results indicate that the M-CSF receptor requires a specific signal transduction pathway to exert its differentiational and proliferative effects. Furthermore, the M-CSF receptor can convey a granulocyte-type differentiation signal possibly by cooperating with the G-CSF receptor signal transduction pathway. The c-fms-transfected LyD9 cells as well as the original LyD9 cells differentiated predominantly into GM-CSF- and G-CSF-responsive cells by coculturing with PA6 and ST2 stromal cells, respectively. The results indicate that differentiation lineage is not affected by premature expression of the M-CSF receptor. Instead, the stromal cell used for coculture apparently controls lineage-selective differentiation of the multi-potential stem cell line.

Animals↗
PubMed1991

Functional domains of the granulocyte colony-stimulating factor receptor.

The granulocyte colony-stimulating factor (G-CSF) receptor has a composite structure consisting of an immunoglobulin(Ig)-like domain, a cytokine receptor-homologous (CRH) domain and three fibronectin type III (FNIII) domains in the extracellular region. Introduction of G-CSF receptor cDNA into IL-3-dependent murine myeloid cell line FDC-P1 and pro-B cell line BAF-B03, which normally do not respond to G-CSF, enabled them to proliferate in response to G-CSF. On the other hand, expression of the G-CSF receptor cDNA in the IL-2-dependent T cell line CTLL-2 did not enable it to grow in response to G-CSF, although G-CSF could transiently stimulate DNA synthesis. Mutational analyses of the G-CSF receptor in FDC-P1 cells indicated that the N-terminal half of the CRH domain was essential for the recognition of G-CSF, but the Ig-like, FNIII and cytoplasmic domains were not. The CRH domain and a portion of the cytoplasmic domain of about 100 amino acids in length were indispensable for transduction of the G-CSF-triggered growth signal.

Amino Acid Sequence↗
PubMed1991

Assignment of the human granulocyte colony-stimulating factor receptor gene (CSF3R) to chromosome 1 at region p35-p34.3.

The gene for the granulocyte colony-stimulating factor (G-CSF) receptor (CSF3R) was localized on the p35-p34.3 region of human chromosome 1 by in situ hybridization using human G-CSF receptor cDNA as the probe. Polymerase chain reaction using oligonucleotides specific for the human CSF3R produced a specifically amplified DNA fragment with DNA from mouse A9 cells that contained human chromosome 1 but not other human chromosomes. Localization of the CSF3R on chromosome 1 was further confirmed by the spot-blot hybridization of sorted human chromosomes.

Animals↗
PubMed1991

Granulocyte colony-stimulating factor and its receptor.

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein of Mr of about 20,000, which stimulates proliferation and differentiation of progenitor cells of neutrophils. Recent clinical application of G-CSF has proven that this hormone is effective in treatment of patients suffering from neutropenia. In the last few years, the biochemical and molecular nature of the G-CSF receptor has been characterized. The G-CSF receptor is a glycoprotein of Mr 100-130,000, and is expressed on the cell surface of various myeloid cells. A homodimer of this polypeptide can bind G-CSF with a high affinity, and transduce G-CSF-triggered growth signals into cells. Its extracellular domain contains a sequence of about 200 amino acids which can be found in various cytokine receptors. In addition, it contains an immunoglobulin-like domain and three fibronectin type III domains. The overall structure of the beta-chain (gp130) of the interleukin 6 receptor was found to be very similar to that of the G-CSF receptor.

Amino Acid Sequence↗
PubMed1991

Hyperthermia-induced neuronal protection against ischemic injury in gerbils.

We investigated the effect of hyperthermic pretreatment before induction of ischemia using a gerbil model of 5-min forebrain ischemia. A single hyperthermic treatment 18 h before ischemia exhibited a partial protective effect, and repetitive hyperthermic pretreatments at 18-h intervals before ischemia showed clear protection against neuronal death in the CA1 area of the hippocampus, whereas single hyperthermic treatment 3, 6, 24, or 50 h before ischemia exhibited little protective effect. This transient and cumulative neuroprotective effect of hyperthermic pretreatment strongly suggested the involvement of stress reactions after hyperthermia in the protective mechanism against ischemic neuronal death.

Animals↗
PubMed1991

Reassessment of [3H]glutamate binding to human brain membrane preparations.

We studied [3H]glutamate binding to human brain membrane preparations. We found that the binding assay of [3H]glutamate should be done at 4 degrees C using glass-fiber filters pretreated with polyethyleneimine, sterile incubation buffer, and membrane preparations pretreated with a detergent. Under these assay conditions, we have characterized the three subtypes of glutamate receptors: N-methyl-D-aspartate-, quisqualate- and kainate-sensitive binding sites. Scatchard analysis revealed that the N-methyl-D-aspartate-sensitive [3H]glutamate binding sites consisted of a single component with a dissociation constant (Kd) of 28.2 +/- 2.8 nM and total concentration (Bmax) of 36.2 +/- 3.6 fmol/mg protein (N = 8). These data were much different from those presented in previous studies.

Aged↗
PubMed1991

Effects of chronic administration of carteolol on beta-adrenoceptors in spontaneously hypertensive rat heart.

We studied the effects of chronic administration of beta-adrenoceptor antagonists with and without intrinsic sympathomimetic activity (ISA): carteolol (with ISA) and propranolol (without ISA), respectively, on the heart of spontaneously hypertensive rat (SHR) and Wistar Kyoto rat (WKY). Six-week-old SHRs and WKYs were orally given carteolol or propranolol for ten weeks. The heart rate was reduced in propranolol-treated SHR, but not in carteolol-treated ones. In WKY, carteolol-treatment increased the heart rate. The number and affinities of beta-adrenoceptors were analyzed using [3H]dihydroalprenolol as a ligand. Propranolol at 30 mg/kg increased the number of cardiac beta-adrenoceptors in both SHR and WKY. In contrast, 10 mg/kg carteolol significantly decreased the number of cardiac beta-adrenoceptors in SHR, but not in WKY. These data indicate that carteolol, a beta-adrenoceptor antagonist with ISA, does not cause up-regulation of the number of cardiac beta-adrenoceptors in the rat and suggest that this fact is related to a possible lack of "rebound phenomena" after sudden discontinuation of chronic carteolol-therapy in humans.

Aging↗
PubMed1990

'Ischemic tolerance' phenomenon found in the brain.

We investigated the possibility that neuronal cells given a mild ischemic treatment sufficient to perturb the cellular metabolism acquired tolerance to a subsequent, and what would be lethal, ischemic stress in vivo. Cerebral ischemia was produced in the gerbils by occlusion of both common carotids for 5 min, which consistently resulted in delayed neuronal death in the CA1 region of the hippocampus. Minor 2-min ischemia in this model depletes high-energy phosphate compounds and perturbs the protein synthesis, but never causes neuronal necrosis, and therefore was chosen as mild ischemic treatment. Single 2-min ischemia 1 day or 2 days before 5 min ischemia exhibited only partial protective effects against delayed neuronal death. However, two 2-min ischemic treatments at 1 day intervals 2 days before 5 min ischemia exhibited drastically complete protection against neuronal death. The duration and intervals of ischemic treatment, enough to perturb cellular metabolism and cause protein synthesis, were needed respectively, because neither 1-min ischemia nor 2-min ischemia received twice at short intervals exhibited protective effects. This 'ischemic tolerance' phenomenon induced by ischemic stress--which is unquestionably important--and frequent stress in clinical medicine, is intriguing and may open a new approach to investigate the pathophysiology of ischemic neuronal damage.

Animals↗