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Biomedical subjects

Yasuo Katayama

Publications and source records attributed to Yasuo Katayama.

At least 19 recordsLinked to original sources

Upregulation of GluR2 decreases intracellular Ca2+ following ischemia in developing gerbils.

Developing animals are known to be resistant to cerebral ischemia. To investigate the mechanisms by which developing animals exhibit ischemic resistance, we examined the changes in intracellular calcium ([Ca2+]i) after oxygen-glucose deprivation (OGD) using hippocampal slices from gerbils. We found that increases of [Ca2+]i in hippocampal CA1 neurons is significantly less after OGD in developing gerbils than in adults. Western blot analysis of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptors (AMPARs) showed that GluR2 expression, but not that of the other AMPARs is significantly higher in developing gerbils than in adults. Expression of the anti-apoptotic proteins such as HSP70, Bcl-XL, and plasma membrane Ca2+-ATPase type1 (PMCA1) are not higher in the developing gerbils than in adults. These results suggest that the higher expression of GluR2 is important for the smaller increases in [Ca2+]i and enhanced resistance to ischemia-induced neuronal damage in developing animals.

Aging↗

Mild hypothermia enhances the neuroprotective effects of FK506 and expands its therapeutic window following transient focal ischemia in rats.

FK506 (tacrolimus), an immunosuppressant, reportedly reduces ischemic brain injury following transient middle cerebral artery occlusion (MCAO) in rats. The authors previously reported that the therapeutic window of FK506 in this model is more than 1 h, but less than 2 h. The aim of the present study is to determine whether mild hypothermia (35 degrees C) enhances the neuroprotective effects of FK506 and expands its therapeutic window. Sprague-Dawley rats were subjected to 2 h MCAO followed by 24 h reperfusion. Animals were randomly divided into four groups: (I) vehicle-treated normothermic group; (II) FK506-treated normothermic group; (III) vehicle-treated hypothermic group; (IV) FK506-treated hypothermic group. Animals received a single injection of FK506 (0.3 mg/kg) or vehicle intravenously at 2 h after ischemic induction. During ischemia, temporal muscle and rectal temperatures were maintained at 37 degrees C in the normothermic animals and at 35 degrees C in the hypothermic animals. Infarct volumes and neurological performance were evaluated at 24 h after reperfusion. The combination of FK506 and mild hypothermia significantly reduced infarct volume (cortex, -61%; striatum, -31%) and edema volume (cortex, -57%; striatum, -41%), while mild hypothermia or FK506 alone failed to improve ischemic brain damage. Furthermore, this combination also provided for the best functional outcome. These results demonstrate that the combination of FK506 and mild hypothermia significantly reduces ischemic brain damage following transient MCAO in rats, and expands the therapeutic window for FK506. This therapy may be a new approach for treatment of acute stroke.

Animals↗

Crossed cerebellar diaschisis in patients with cortical infarction: logistic regression analysis to control for confounding effects.

BACKGROUND AND PURPOSE: Crossed cerebellar diaschisis (CCD) refers to reduced metabolism and blood flow in the cerebellar hemisphere contralateral to a cerebral lesion. Many cortical areas have been reported to cause CCD without consideration of confounding factors. We performed single-photon emission computed tomography (SPECT) in patients with cortical infarction to identify regions independently related to CCD, controlling for possible confounding effects. METHODS: Patients with unilateral cortical infarction (n=113; 75 male, 38 female; mean+/-SD age, 66+/-13 years) underwent SPECT of the brain with N-isopropyl-p-[(123)I]iodoamphetamine ((123)I-IMP). Regional cerebral blood flow was measured autoradiographically. Asymmetry indices (AIs) were calculated on the basis of ratios representing symmetrical regional cerebral blood flow in the cerebellum and 16 cerebral regions. CCD was defined as AI for cerebellum >0.1. AIs for 16 cortical regions were considered for both dichotomous and continuous variables for analysis of CCD occurrence by means of backward logistic regression. RESULTS: For dichotomized variables, hypoperfusion of postcentral (odds ratio [OR]=7.607; 95% CI, 2.299 to 25.174) and supramarginal (OR=3.916; 95% CI, 1.394 to 11.003) regions independently influenced CCD. For continuous variables, hypoperfusion of postcentral (OR=1.044; 95% CI, 1.019 to 1.068) and supramarginal (OR=1.021; 95% CI, 1.001 to 1.041) regions (and, as a negative factor, medial occipital regions; OR=0.942; 95% CI, 0.895 to 0.991) independently influenced CCD. CONCLUSIONS: Many cortical areas apparently do not contribute to CCD. Correspondence of CCD between dichotomized and continuous analyses suggests that location of a lesion, not severity, is the main determinant of CCD.

Adult↗

Membranous nephropathy complicated by renal cell carcinoma.

We experienced a patient with membranous nephropathy (MN) and renal cell carcinoma (RCC). Although MN is known to be commonly associated with malignant tumors, association with RCC is rare. In our patient, no malignant focus was found in the major organs examined, except for a small lesion in the right kidney. Diagnosis of a small RCC (1.6 x 1.6 cm), which was made by renal biopsy and histology, was impossible by other, imaging, methods. As surgical treatment for the patient, laparoscopic partial nephrectomy was performed successfully, alleviating the symptoms of nephrotic syndrome for up to 21 months.

Biopsy↗

Aneurysmal subarachnoid hemorrhage in a patient with Wegener's granulomatosis.

A 34-year-old Japanese man admitted to hospital with pneumonia had previously undergone surgery for paranasal sinusitis and also for the clipping of an aneurysm at the origin of the anterior choroidal artery after subarachnoid hemorrhage. Laboratory tests performed at the present admission showed renal insufficiency and serological findings of raised proteinase 3 antineutrophil cytoplasmic antibody level. A renal biopsy was performed that showed diffuse necrotizing glomerulonephritis with fibrocellular crescents. The diagnosis of Wegener's granulomatosis(WG) was confirmed on the basis of the clinical picture, laboratory findings, and biopsies of renal tissues. The disease responded to prednisolone and cyclophosphamide. The association of WG with a ruptured intracranial aneurysm is rare and has not previously been confirmed.

Adult↗

Hypercholesterolemia associated with splice-junction variation of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) gene.

Factors predisposing to the phenotypic features of higher total cholesterol (T-Cho) have not been clearly defined. Here we report an association between a C/T single nucleotide polymorphism at IVS17+8 in the inter-alpha-trypsin inhibitor heavy chain 4 gene (ITIH4) and plasma total cholesterol levels in 351 adult individuals from an east-central area of Japan. Age and gender-adjusted levels of plasma T-Cho, LDL-cholesterol, triglyceride, and HDL-cholesterol were analyzed. When we separate the subjects into two genotypic groups regarding this single nucleotide polymorphism (SNP), those who lack the T-allele had significantly higher plasma T-Cho levels than the others who bear T-allele (mean 252.3 mg/dl versus 241.7 mg/dl; p=0.009). Of the 309 individuals without the T-allele, approximately 90% presented with hypercholesterolemia, whereas only 10% were hypercholesterolemic among 42 individuals with the T-allele (p <0.0001). These data suggest that genetic variation at ITIH4 locus is one of the likely candidate determinants for plasma cholesterol metabolisms.

Aged↗

Growth hormone receptor variant (L526I) modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia: intra-familial association study in an eight-generation hyperlipidemic kindred.

Defect of growth hormone receptor (GHR) is classically known to cause Laron syndrome, characterized by short stature, specific facial appearance, elevated serum growth hormone levels, and decreased insulin-like growth factor I levels. In addition, an increased cardiovascular risk due to elevated plasma total and LDL cholesterol levels marks another feature of the disease. Growth hormone (GH) plays an important role in the regulation of lipoprotein metabolism. GH status was found to be an independent determinant of plasma total cholesterol and triglyceride levels in humans. We studied a total of 207 members of eight-generation extended family of familial hypercholesterolemia (FH) in which affected members presented with various lipoprotein phenotypes. Intra-familial correlation analysis of a modifier effect of a Leu526Ile substitution in GHR gene was carried out among 95 carriers for LDL receptor gene (LDLR) mutation and 112 non-carriers. When plasma high-density lipoprotein cholesterol (HDL-c) levels in the LDLR-mutation carriers were compared, a significant lowering effect of HDL-c was observed with the Leu allele; the values were lowest among Leu/Leu homozygotes (mean +/- SD = 37 +/- 2 mg/dl), highest in Ile/Ile homozygotes (50 +/- 4 mg/dl), and intermediate among Leu/Ile heterozygotes (41 +/- 2 mg/dl) (P = 0.0021). The results indicate a significant modification of the phenotype of FH with the defective LDLR allele, by GHR Leu variation in the kindred studied.

Adult↗

Hypertriglyceridemia associated with amino acid variation Asn985Tyr of the RP1 gene.

Factors predisposing to the phenotypic features of hypertriglyceridemia have not been clearly defined. Here we report an association between a missense coding region polymorphism Asn985Tyr in the retinitis pigmentosa 1 gene ( RP1) and plasma triglyceride (TG) levels in 332 adult individuals from an east-central area of Japan. Age and gender-adjusted levels of LDL-cholesterol, TG, and HDL-cholesterol were analyzed. When we separate the subjects into two genotypic groups regarding this amino acid variation, those who lack the 985-Asn allele (asparagine at residue 985) had significantly higher plasma TG levels than the others who had at least one 985-Asn allele (mean: 175.8 mg/dl vs 123.3 mg/dl; P=0.0006, Mann-Whitney test). Similarly, the former subjects had significantly lower HDL-cholesterol levels than the latter (mean: 48.0 mg/dl vs 53.8 mg/dl; P=0.038). Of the 280 individuals without a 985-Asn allele, approximately half of the individuals presented with hypertriglyceridemia, whereas only a quarter were hypertriglyceridemic among 52 individuals with the 985-Asn allele ( P=0.04). Although this SNP marker may itself be in linkage disequilibrium with other unexamined functional variants within this locus, our data suggest that genetic variation at the RP1 locus is one of the likely candidate determinants for plasma triglyceride and HDL-cholesterol metabolisms.

Aged↗

Effect of glycerol on ischemic cerebral edema assessed by magnetic resonance imaging.

The aim of this study is to assess the anticerebral edema effect of glycerol on a large cerebral infarction with magnetic resonance imaging (MRI). Glycerol, which is widely used as an osmotic agent against cerebral edema, could exacerbate brain tissue shift, since it has been suggested that glycerol might shrink a noninfarcted hemisphere and worsen the mass effect after a large hemispheric cerebral infarction. To investigate these issues, changes in a large hemispheric infarction with cerebral edema were studied using MRI before and after glycerol administration. Infarct volumes, normal brain tissue volumes and lateral ventricle volumes, in addition to signal intensities of T(2)-weighted images, were measured in six patients before and after administration of 300 ml of glycerol. Ventricle volumes were significantly increased (p=0.0015) and the T(2) signal intensity of the post-treatment ischemic region decreased after glycerol administration. In contrast, no significant differences in either cerebral volume or T(2) signal intensity were seen in the noninfarcted hemisphere before and after administration. Our data suggest that glycerol does not exacerbate the mass effect on a large hemispheric infarction.

Aged↗

Neuroprotective effect of NS-7, a novel Na+ and Ca2+ channel blocker, in a focal ischemic model in the rat.

NS-7 is a novel, voltage-dependent Na(+) and Ca(2+) channel blocker. This study evaluated the in vivo neuroprotective effect of NS-7 in a rat transient focal ischemic model when administered during occlusion. Left middle cerebral artery occlusion was induced in adult male Sprague-Dawley rats for 120 min using an intraluminal thread method. The rats received a single intravenous injection of NS-7 or saline (control group) just after the onset of ischemia, and at 30, 60 and 120 min after ischemia. Their brains were removed after 48 h reperfusion, sectioned, and stained with hematoxylin and eosin. Animals were evaluated by neurological examination at 120 min ischemia and 48 h reperfusion. Infarcted cortex and striatum were measured quantitatively and infarction volumes were calculated. Cortical infarction volumes were 128+/-74 (NS-7) and 214+/-64 mm(3) (control) immediately after the ischemia group, 155+/-48 (NS-7) and 225+/-12 mm(3) (control) after the 30 min group, 160+/-54 (NS-7) and 225+/-48 mm(3) (control) after the 60 min group, and 176+/-43 (NS-7) and 223+/-38 mm(3) (control) after the 120 min group. Cortices in NS-7-treated groups were significantly less infarcted than in control groups at all treatment times. There was no significant difference in the striatal infarction volume between the treatment and control groups. Neurological examination showed that hemiparesis and abnormal posture of the NS-7 groups were significantly more improved at 48 h reperfusion than those of the control groups without posture examination in the 120 min group. These observations suggest that NS-7 may be a new potential therapeutic agent for the acute phase of cerebral infarction.

Animals↗

Distinct patterns of gene transfer to gerbil hippocampus with recombinant adeno-associated virus type 2 and 5.

Genetic modification of the gerbil hippocampal neuronal cells in vivo helps us understand the mechanisms of neuronal function under various circumstances such as ischemic insult. In this study, we examined the distinct distribution of the recombinant adeno-associated virus type 2 (rAAV2) and rAAV5 vectors for gene delivery to primary cultured cells and the gerbil hippocampus. Mixed cortical cultures containing both neurons and astrocytes from E17 rat embryos were infected with rAAVs containing the Cytomegalovirus virus (CMV) promoter. rAAV2 was preferably transduced to neurons, whereas rAAV5 was inclined to be transduced to astrocytes in vitro. rAAV2 and rAAV5 vectors, each with the CMV or Rous sarcoma virus (RSV) promoter, were injected into the gerbil hippocampus using a stereotaxic apparatus. Five days after injection, transgene expression was analyzed with X-gal staining. In the gerbil hippocampus, rAAV5 with the CMV promoter achieved a higher overall transgene expression than rAAV2 with the CMV promoter. The transgene expression of rAAV2 with the RSV promoter was found in the pyramidal and granular cells, while the transgene expression of rAAV5 with the RSV promoter was preferentially found in the granular cells. These findings would be valuable in optimizing rAAV-mediated gene transfer to the gerbil hippocampus.

Animals↗

Acute posterior leukoencephalopathy in a patient with nephrotic syndrome.

Reversible posterior leukoencephalopathy syndrome is one of the most serious complications of immunosuppressive therapy. The clinical features include headache, altered mental functioning, seizures, cortical blindness and other visual disturbances, with hypertension. The neuroimaging studies reveal predominant posterior leukoencephalopathy. Usually, antihypertensive therapy and reduction or withdrawal of immunosuppressive agents have been reported to resolve the neurological deficits and imaging abnormalities within a few weeks. We discuss here a 51-year-old woman with nephrotic syndrome who developed acute leukoencephalopathy during combination therapy with prednisolone and cyclosporine. She developed severe headache, visual disturbance, consciousness disturbance, and generalized tonic clonic convulsion. A computed tomography scan (CT) revealed low-density areas in the subcortices of the parietal and occipital lobes. Magnetic resonance imaging (MRI) disclosed a high signal intensity area on T2-weighted images and a low signal intensity area on T1-weighted images in the same lesions. Follow-up brain CT and MRI were performed several times. Three weeks after the first study, these lesions had completely resolved, but she had persistent altered consciousness for more than 1 year.

Brain Diseases↗

Increased regional cerebral blood flow but normal distribution of GABAA receptor in the visual cortex of subjects with early-onset blindness.

Before the completion of visual development, visual deprivation impairs synaptic elimination in the visual cortex. The purpose of this study was to determine whether the distribution of central benzodiazepine receptor (BZR) is also altered in the visual cortex in subjects with early-onset blindness. Positron emission tomography was carried out with [(15)O]water and [(11)C]flumazenil on six blind subjects and seven sighted controls at rest. We found that the CBF was significantly higher in the visual cortex for the early-onset blind subjects than for the sighted control subjects. However, there was no significant difference in the BZR distribution in the visual cortex for the subject with early-onset blindness than for the sighted control subjects. These results demonstrated that early visual deprivation does not affect the distribution of GABA(A) receptors in the visual cortex with the sensitivity of our measurements. Synaptic elimination may be independent of visual experience in the GABAergic system of the human visual cortex during visual development.

Adult↗

Long-term measurement of cerebral blood flow and metabolism in a rat chronic hypoperfusion model.

1. Rat bilateral common carotid artery occlusion (BCAO) was used as a chronic cerebral hypoperfusion model. We observed autoradiographically the long-term changes in regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCGU) after 2 days and 1, 4 and 8 weeks of BCAO and in controls. Regions evaluated included the cerebral cortex, white matter and basal ganglia. Pathological changes were also observed with Klüver-Barrera and haematoxylin-eosin staining. 2. After 2 days, rCBF was significantly reduced to 33-58% in the cortex, white matter and amygdala and similar reductions were observed after 1 week. 3. After 4 weeks, rCBF recovered; however, rCBF remained significantly reduced in the occipital cortex, white matter, globus pallidus and substantia nigra. 4. After 2 days, rCGU was mostly maintained but, after 1 week, rCGU was reduced significantly to 40-70% in the cortex, white matter, basal ganglia and thalamus. Four weeks later, these reductions were no longer seen. 5. Rarefaction of the white matter was observed from 1 week. 6. These results showed that the BCAO in rats is an appropriate model for chronic cerebral hypoperfusion and that uncoupling of rCBF and rCGU was observed from 2 days until 4 weeks in the white matter.

Animals↗

Effects of FK506 on the translocation of protein kinase C and CaM kinase II in the gerbil hippocampal CA1 neurons.

To explore biochemical basis for cerebroprotective effect of immunosuppressant FK506, we studied changes in subcellular distribution of protein kinase C gamma (PKC gamma) as well as calcium/calmodulin-dependent protein kinase II (CaMKII) after ischemia. Male Mongolian gerbils were subjected to 5 min forebrain ischemia. FK506 (1 or 3 mg kg-1) was administered at 1 min after recirculation, which was confirmed to be cerebroprotective by histological examination at seven days after ischemia. At the designated time points (before ischemia, 5 min ischemia, 1 and 24 h recovery), heads were frozen and samples were taken from CA1 subfield of hippocampus. Western blot analysis was carried out. Persistent translocations of PKC gamma and CaMKII to synaptosomal P2 fraction were observed in vehicle-treated group. FK506 significantly decreased levels of PKC gamma and CaMKII in P2 fraction at 24 h of recovery. The present results suggest FK506 downregulates translocated PKC gamma and CaMKII, which may contribute to its survival promoting effect after cerebral ischemia.

Animals↗

[Post-stroke depression].

The frequency of post-stroke depression (PSD) was evaluated in an ischemic stroke cohort four weeks after onset, and the relationship between self-rating depression scale (SDS)/and infarct size, number and location of the ischemic brain lesions was also studied. The effects of a newly developed antidepressant SSRI (selective serotonin reuptake inhibitor), fluvoxamine maleate, on PSD and cerebral blood flow (CBF) was investigated in other ischemic stroke patients. The frequency of patients who had more than 40 on SDS score was 46% (18/39), and that of patients who had more than 50 was 13% (5/39). There were no differences in SDS score in infarct size, number and location of ischemic brain lesions, however there were significant differences in the lesion side. The score of the patients who had lesions in the left hemisphere was significantly higher than that of those who had them in the right. Administration of fluvoxamine maleate for four weeks improved the score on the Hamilton rating scale for depression (HAM-D) from 16.6 +/- 4.7 (n = 5) to 8.4 +/- 4.3 (n = 5), however it did not influence the mean cortical CBF. This study shows that the patients frequently had depression after ischemic stroke, and that left side lesion had a significant relationship with PSD. Therefore it is important that psychiatric examination of post-stroke patients is conducted. This study also shows that a newly developed antidepressant, fluvoxamine maleate, was effective for PSD.

Aged↗