Biomedical subjects
T Asano
Publications and source records attributed to T Asano.
[Clinical study of 18 pediatric cadaveric renal transplantations: organ sharing in pediatric renal transplantation after enforcement of the organ transplant law in Japan].
Renal transplantation is considered to be the optimal replacement therapy for children with end-stage renal disease. However, the number of pediatric renal transplants in Japan is much lower than in the USA and/or Europe. Since October 1997, pediatric(< 15 years) recipients are given priority over adult recipients for organ sharing, only if one or two HLA-DR antigen(s) are matched between the recipient and pediatric(< 15 years) donor. However, the number of pediatric transplants is not increasing. One hundred and twenty-four pediatric renal transplantations were performed in Tokyo Women's Medical University between 1983 and 1999, of which 18(14.5%) were cadaveric transplants and the others (106, 85.5%) were living-related transplants. We examined 18 pediatric cadaveric renal transplantations. Seven patients received their graft from pediatric donors less than 15 years of age and 11 from adult donors. The mean age at transplantation was 13.2 years (range 4.5-18.7 years). Major etiologies of renal disease are hereditary renal disease(38.8%), chronic glomerulonephritis(33.3%), and focal segmental glomerulosclerosis[FSGS] (16.7%). Zero matches in HLA-DR locus were observed in 72.2%. Patient survival rate was 100%. Graft survival rates at 1 and 5 years after transplantation were 83% and 64% successively. There was no significant difference between the graft survival of cadaveric and living-related transplantation at 1 and 5 years. All 5 patients who received their graft between 1994 and 1998 have maintained normal graft function. Causes of their graft loss were chronic rejection in 3, recurrence of FSGS in 2, primary non-function in 1, and graft thrombosis in 1. Donor age and HLA-DR mismatching did not affect the outcome. We propose that pediatric renal grafts should be provided to children with priority, regardless of their HLA-A, B and HLA-DR matching.
Magnetization transfer measurements of the hippocampus in patients with Alzheimer's disease, vascular dementia, and other types of dementia.
BACKGROUND AND PURPOSE: Although atrophy of structures in the medial temporal lobe has been considered an indication of Alzheimer's disease (AD), atrophic changes on MR images have also been associated with other dementing diseases and are not specific to AD. This study was undertaken to determine whether characteristic alterations in the hippocampus of patients with AD are detectable with magnetization transfer (MT) imaging. METHODS: Coronal MT imaging was performed in 35 patients with probable AD, in 14 patients with vascular dementia, in 13 patients with other types of dementia, and in 23 control subjects to measure MT ratios of the hippocampus. Medial temporal lobe atrophy was graded subjectively on a five-point scale. RESULTS: Scores of medial temporal lobe atrophy in all dementia groups were significantly higher than those in control subjects, but no differences were found among the dementia groups. MT ratios in the hippocampus were significantly lower in patients with AD than in those with non-AD dementia and in the control subjects; however, no differences were found between the non-AD dementia patients and the control subjects. MT ratio measurements were better than visual analysis of atrophy for differentiating AD patients from those with non-AD dementia (an overall discrimination rate of 77% versus 65%). MT ratios significantly correlated with scores on the Mini-Mental State Examination and with medial temporal lobe atrophy in AD patients but not in patients with non-AD dementia. CONCLUSION: MT measurements may be more specific than visual analysis in detecting structural damage of the hippocampus in AD patients and might be useful in discriminating AD from vascular dementia and other types of dementia.
Navigation system for neurosurgery with PC platform.
This paper presents a navigation system for a surgical microscope and an endoscope which can be used for neurosurgery. In this system, a wireframe model of a target tumor and other significant anatomical landmarks are superimposed in real-time onto live video images taken from the microscope and the endoscope. The wireframe model is generated from a CT/MRI slice images. Overlaid images are simultaneously displayed in the same monitor using the picture-in-picture function so that the surgeon can concentrate on the single monitor during the surgery. The system measures the position and orientation of the patient using specially designed non-contact sensing devices mounted on the microscope and the endoscope. Based on this real-time measurement, the system displays other useful information about the navigation as well as the rendered wireframe. The accuracy of registration between the wireframe model and the actual live view is less than 2 mm. We tested this system in actual surgery several times, and verified its performance and effectiveness.
Ketoacidosis accompanied by epileptic seizures in a patient with diabetes mellitus and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).
We herein report a rare case of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and diabetes mellitus with ketoacidosis. An 18-year-old female patient was diagnosed to have diabetes mellitus and insulin therapy was thereafter initiated. At 26 years of age, she was hospitalized for diabetic ketoacidosis, soon followed by a loss of consciousness, left-sided dysmetria, and ataxic speech. MELAS was diagnosed because of the presence of ragged red fibers in a muscle biopsy. At 33 years of age, she was admitted to our hospital because of ketoacidosis and partial status epilepticus. A blood gas examination revealed as follows; arterial pH, 6.88; bicarbonate, 2.1 mmol/l; base excess - 29.8 mmol/l. The serum level of glucose had also increased to 30 mmol/l. The serum levels of lactate and B-hydroxybutyrate were elevated to 11.4 mmol/l and 1,990 micromol/l, respectively. Ketoacidosis improved by fluid replacement and continuous intravenous insulin infusion. A brain MRI demonstrated hyperintensity areas on FLAIR images in the bilateral temporal lobes and the cerebellum. A proton MRS demonstrated the abnormal lactate accumulation in the bilateral temporal and occipital lobes. Since epileptic seizures are rare in patients with diabetic ketoacidosis, such seizures may indicate the existence of MELAS syndrome.
Hyperglycemia impairs the insulin signaling step between PI 3-kinase and Akt/PKB activations in ZDF rat liver.
Akt/PKB activation is reportedly essential for insulin-induced glucose metabolism in the liver. During the hypoinsulinemic and hyperglycemic phase in the Zucker diabetic fatty (ZDF) rat liver, insulin-induced phosphorylations of the insulin receptor (IR) and insulin receptor substrate (IRS)-1/2 were significantly enhanced. Similarly, phosphatidylinositol (PI) 3-kinase activities associated with IRS-1/2 were markedly increased in ZDF rat liver compared with those in the control lean rat liver. However, interestingly, insulin-induced phosphorylation and kinase activation of Akt/PKB were severely suppressed. The restoration of normoglycemia by sodium-dependent glucose transporter (SGLT) inhibitor to ZDF rats normalized elevated PI 3-kinase activation and phosphorylation of IR and IRS-1/2 to lean control rat levels. In addition, impaired insulin-induced Akt/PKB activation was also normalized. These results suggest that chronic hyperglycemia reduces the efficiency of the activation step from PI 3-kinase to Akt/PKB kinase and that this impairment is the molecular mechanism underlying hyperglycemia-induced insulin resistance in the liver.
Characterization of N-acylation of Go alpha purified from bovine retinas.
Heterogeneous N-terminal acylation has been identified in several retinal proteins localized predominantly in the outer segments of the photoreceptor cells, but it is still unclear whether such a unique heteroacylation is determined by a photoreceptor cell-specific factor or not. Here, we characterized the N-terminal modification of bovine retinal Go alpha, which seems to be involved in the neural activities and is not detected in the photoreceptor outer segments. In the proteolytic fragments of immunoaffinity-purified retinal Go alpha, we found a single N-terminal peptide modified with myristate, and concluded that retinal Go alpha is purely myristoylated, just like brain Go alpha. This result indicates that the heteroacylation has a more restricted origin in the retina, and supports the idea that it is a photoreceptor cell-specific modification.
Oxyhemoglobin as the principal cause of cerebral vasospasm: a holistic view of its actions.
While oxyhemoglobin (oxyHb) is deemed to be the principal cause of cerebral vasospasm following subarachnoid hemorrhage, the mechanism(s) whereby it leads to vasospasm is by no means clear. Of importance is the fact that prolonged contraction of arterial smooth muscle is not the sole feature of cerebral vasospasm, particularly in humans. Vasospasm is also associated with the occurrence of organic changes in the arterial wall as well as the derangement of cerebral microcirculation. These additional features may play a pivotal role when vasospasm in the proximal arteries incurs delayed ischemic neurological deficits and cerebral infarction. The question then arises as to whether or not all the features of vasospasm are attributable to the actions of oxyHb. In this regard, owing to the recent advances in vascular physiology, it has become clear that the cerebral vasculature should be regarded as an organ, not a mere conduit, in which all intracellular mechanisms are functionally integrated for the maintenance and regulation of cerebral blood flow (CBF). In the sense that the arterial function is not simply a sum of the individual cellular functions, it may be described as "holistic". According to extant literature, oxyHb has multifarious actions that can be divided into the following three categories: (1) scavenging of nitric oxide (NO), (2) generation of reactive oxygen species (ROS), (3) activation of the tyrosine kinase/mitogen-activated kinase (TK/MAPK) pathway. Based on such knowledge, the present review aims at a speculative synthesis in terms of how oxyHb pertains to the occurrence of vasospasm, in which the highly integrated, holistic mechanisms within the cerebral artery are perturbed for a prolonged period.
Diffusion-weighted and magnetization transfer imaging of the corpus callosum in Alzheimer's disease.
We investigated structural changes of the corpus callosum in patients with Alzheimer's disease (AD) using sagittal diffusion-weighted (DW) and magnetization transfer (MT) imaging. Patients with AD (n=23) had a significantly decreased area only in the posterior portion of the corpus callosum. Apparent diffusion coefficient (ADC) values perpendicular to the commisural fiber orientation were significantly higher in the anterior portion of the corpus callosum without definite atrophy, as well as in the posterior portion with significant atrophy, in patients with AD than in controls (n=16) and thus diffusion in these regions showed a significantly lower degree of anisotropy in patients than in controls. MT ratios were also significantly lower in patients with AD in the anterior and posterior portions of the corpus callosum than in controls. These findings probably reflect structural changes in the corpus callosum including axonal loss and/or demyelination. DW and MT imagings may be useful in detecting degeneration of the corpus callosum in AD.
p85/p110-type phosphatidylinositol kinase phosphorylates not only the D-3, but also the D-4 position of the inositol ring.
Activation of p85/p110-type phosphatidylinositol (PI) kinase has been implicated in various cellular activities. This PI kinase phosphorylates the D-4 position with a similar or higher efficiency than the D-3 position when trichloroacetic acid-treated cell membrane is used as a substrate, although it phosphorylates almost exclusively the D-3 position of the inositol ring in phosphoinositides when purified PI is used as a substrate. Furthermore, the lipid kinase activities of p110 for both the D-3 and D-4 positions were completely abolished by introducing kinase-dead point mutations in their lipid kinase domains (DeltaKinalpha and DeltaKinbeta, respectively). In addition, both PI 3- and PI 4-kinase activities of p110alpha and p110beta immunoprecipitates were similarly inhibited by either wortmannin or LY294002, specific inhibitors of p110. Insulin induced phosphorylation of not only the D-3 position, but also the D-4 position. Indeed, overexpression of p110 in Sf9 or 3T3-L1 cells induced marked phosphorylation of the D-4 position to a level comparable to or much greater than that of D-3, whereas inhibition of endogenous p85/p110-type PI kinase via overexpression of dominant-negative p85alpha (Deltap85alpha) in 3T3-L1 adipocytes abolished insulin-induced synthesis of both. Thus, p85/p110-type PI kinase phosphorylates the D-4 position of phosphoinositides more efficiently than the D-3 position in vivo, and each of the D-3- or D-4-phosphorylated phosphoinositides may transmit signals downstream.
Selective association of G protein beta(4) with gamma(5) and gamma(12) subunits in bovine tissues.
The beta and gamma subunits of G proteins are tightly bound under physiological conditions, and so far, seven beta and 11 gamma subunit isoforms have been found. The relative abilities of the beta and gamma subunits to associate with each other have been studied using transfected cell assays, in vitro translation and the yeast two-hybrid system, but have not been fully characterized in various tissues. In the present study, we demonstrated the selectivity of association of the beta with gamma isoforms in bovine tissues. Immunoprecipitation of betagamma complexes from tissue extracts with antibodies against various gamma subunits and subsequent analyses revealed that beta(4) associated with the gamma subunits with the following rank order of selectivity: gamma(5) > gamma(12) > gamma(2) > gamma(3), while beta(2) bound to gamma(2), gamma(3), and gamma(12) more selectively than to gamma(5). By contrast, beta(1) associated with all gamma subunits without significant selectivity. Analyses of purified betagamma complexes containing various gamma isoforms revealed beta subunit compositions similar to those found in the immunoprecipitates. Particular combinations of beta and gamma subunit isoforms may contribute to maintaining efficient and specific signal transduction mediated by G proteins.
Pharbin, a novel inositol polyphosphate 5-phosphatase, induces dendritic appearances in fibroblasts.
We have cloned a cDNA encoding a novel protein pharbin with a homology to inositol polyphosphate 5-phosphatases. Pharbin contains relatively well-conserved catalytic motifs for 5-phosphatase, a proline-rich sequence corresponding to the SH3-binding motif, and a sequence consistent with the CaaX motif at the C-terminus. COS-7 cells transfected with pharbin exhibited elevated hydrolytic activity on the 5-phosphate group of inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, and phosphatidylinositol 4, 5-bisphosphate. Thus, pharbin indeed serves as an inositol polyphosphate 5-phosphatase. When pharbin was transfected to C3H/10T1/2 fibroblasts, it was located to the plasma membrane-associated structures including membrane ruffles. The cells were converted to dendritic forms within 24 h. The protein with deleted or point-mutated CaaX motif hardly induced the dendritic forms but remained associated with the membranes. These results imply that the CaaX motif is required for the morphological alteration but that some other structural element is likely to also be responsible for the membrane localization.
Magnetization transfer ratio in cerebral white matter lesions of Binswanger's disease.
We measured the magnetization transfer (MT) ratios in white matter lesions of Binswanger's disease (BD) and compared them with BD and with similar-appearing changes in non-demented elderly subjects and cerebral infarction. Four subject groups were studied: 30 patients with BD and periventricular hyperintensity (PVH) on MRI, 29 patients with ischemic cerebrovascular event with PVH but no dementia, 17 patients with old cerebral infarction, and 26 elderly control subjects. MT ratios were calculated for areas of PVH in BD and non-demented subjects, of infarction, and of normal-appearing white matter in controls. The decrease in MT ratios for areas in PVH of non-demented subjects and BD and in infarction compared with normal white matter in controls was 12, 20, and 35%, respectively. The MT ratio in PVH of BD was significantly lower than that in PVH of non-demented subjects, but not to the levels seen in areas of infarction. There was a significant high correlation between the Mini-Mental State Examination score and MT ratio for area of PVH (r = 0.790). MT ratio distinguishes PVH in BD patients from those in non-demented subjects, suggesting underlying histopathological differences. Tissue damage in white matter lesions of BD may be more severe than that in non-demented subjects, but not as much as with complete infarction.
[Chronic hepatic dysfunction with fatal outcome due to Vibrio septicemia: report of 3 cases].
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Phosphorylation of F-actin-associating G protein gamma12 subunit enhances fibroblast motility.
Eleven isoforms of G protein gamma subunit have been found thus far, but the precise roles of individual gamma subunits are not known. The gamma12 subunit has two unique properties: phosphorylation by protein kinase C and association with F-actin. To elucidate the role of gamma12, we overexpressed gamma12 and other gamma subunits in NIH 3T3 cells together with the beta1 subunit. The overexpressed gamma12 as well as endogenous gamma12, but not gamma2, gamma5, and gamma7 subunits, associated with cytoskeletal components. Expression of gamma12 induced remarkable changes including cell rounding, disruption of stress fibers, and enhancement of cell migration, but expression of other gamma subunits did not induce significant changes. Deletion of the N-terminal region of gamma12 decreased the abilities of gamma12 to associate with cytoskeletal fractions, to induce cell rounding, and to increase cell motility. Replacement by alanine of Ser2 of gamma12 (Ser1 of a mature gamma12 protein), a phosphorylation site for protein kinase C, eliminated these effects of gamma12, whereas a mutant in which Ser2 was replaced with glutamic acid showed effects equivalent to wild-type gamma12. These results indicate that phosphorylation of gamma12 at Ser2 enhances the motility of cells.
Cyclosporine induces cancer progression by a cell-autonomous mechanism.
Malignancy is a common and dreaded complication following organ transplantation. The high incidence of neoplasm and its aggressive progression, which are associated with immunosuppressive therapy, are thought to be due to the resulting impairment of the organ recipient's immune-surveillance system. Here we report a mechanism for the heightened malignancy that is independent of host immunity. We show that cyclosporine (cyclosporin A), an immunosuppressant that has had a major impact on improving patient outcome following organ transplantation, induces phenotypic changes, including invasiveness of non-transformed cells, by a cell-autonomous mechanism. Our studies show that cyclosporine treatment of adenocarcinoma cells results in striking morphological alterations, including membrane ruffling and numerous pseudopodial protrusions, increased cell motility, and anchorage-independent (invasive) growth. These changes are prevented by treatment with monoclonal antibodies directed at transforming growth factor-beta (TGF-beta). In vivo, cyclosporine enhances tumour growth in immunodeficient SCID-beige mice; anti-TGF-beta monoclonal antibodies but not control antibodies prevent the cyclosporine-induced increase in the number of metastases. Our findings suggest that immunosuppressants like cyclosporine can promote cancer progression by a direct cellular effect that is independent of its effect on the host's immune cells, and that cyclosporine-induced TGF-beta production is involved in this.
Intraluminal increase of superoxide anion following transient focal cerebral ischemia in rats.
Using a modification of Karnovsky's Mn2+/diaminobenzizine (DAB) technique, we examined the production of superoxide anion (.O-2) in the vascular lumen following transient occlusion and reperfusion of the left middle cerebral artery (MCA) in Sprague-Dawley rats. The MCA was occluded for 2 h using an intraluminal suture method. Zero, 15, 30, and 60 min after reperfusion, animals were perfused transcardially with buffer containing Mn2+ and DAB, and brain samples were prepared for light and electron microscopic examination. The amber reaction deposits of.O-2 were observable to the naked eye along the major cerebral vessels of the ischemic hemisphere after each reperfusion period. Upon microscopic examination the deposits were revealed to be within arterial, capillary, and venular lumen. The amount of reaction deposits in the ischemic hemisphere corresponded to the duration of reperfusion. The formation of.O-2 was suppressed when the perfusate contained superoxide dismutase and when either Mn2+ or DAB was omitted, confirming that the reaction products produced are due to the enhanced production of.O-2. These results show that there is a progressive increase in intraluminal. O-2 during reperfusion following an ischemic insult which may participate in the aggravation of cerebral damage.
Enhanced phosphoinositide hydrolysis via overexpression of phospholipase C beta1 or delta1 inhibits stimulus-induced insulin release in insulinoma MIN6 cells.
To study the effects of enhanced phosphoinositide hydrolysis on insulin secretion, phosphoinositide-specific phospholipase Cbeta1 (PLCbeta1) or PLCdelta1 was overexpressed in insulinoma MIN6 cells via adenoviral vectors. Inositol phosphate production stimulated by NaF (with AlCl3) in PLCbeta1-overexpressing cells and that stimulated by KCl or glucose in both PLCbeta1- and PLCdelta1-overexpressing cells were greater than that in control cells. In addition, reduced phosphatidylinositol-4,5-bisphosphate levels were observed in these cells stimulated by NaF or KCl. The greater phosphoinositide hydrolysis was accompanied by 25-45% inhibition of insulin secretion. These data suggest that excessive phosphoinositide hydrolysis inhibits secretagogue-induced insulin release in MIN6 cells.