NMDA-associated glycine binding site increases in schizophrenic brains.
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Biomedical subjects
Publications and source records attributed to M Ishimaru.
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The binding of alpha-[3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]AMPA), a selective ligand for the ion channel-linked quisqualate receptor, was evaluated in Triton X-100-treated membranes of human cerebral cortex. The presence of chaotropic ions produced divergent effects on specific [3H]AMPA binding: A twofold increase in the binding was observed with thiocyanide at 100 mM, although iodide (100 mM) and perchlorate (100 mM) reduced the binding. Chemical modifications of the sulfhydryl group with p-chloromercuriphenylsulfonic acid (PCMBS) produced threefold increases in specific [3H]-AMPA binding in the absence of KSCN as well as in the presence of KSCN. Treatment with dithiothreitol restored the enhanced specific [3H]AMPA binding by PCMBS to the basal level. Although specific [3H]AMPA binding in the absence of KSCN showed a single site (KD = 220 nM, Bmax = 235 fmol/mg of protein), curvilinear Scatchard plots of specific [3H]AMPA binding in the presence of 100 mM KSCN can be resolved into two binding sites with the following parameters: KD1 = 5.82 nM, Bmax1 = 247 fmol/mg of protein; KD2 = 214 nM, Bmax2 = 424 fmol/mg of protein. Quisqualate and AMPA were the most potent inhibitors of the [3H]AMPA binding in the presence of KSCN. Potent inhibitors of the binding included beta-N-oxalylamino-L-alanine (L-BOAA), cysteine-S-sulfate, L-glutamate, 6-cyano-7-nitroquinoxaline-2,3-dione, and 6,7-dinitroquinoxaline-2,3-dione. Kainate, L-homocysteine sulfinic acid, and L-homocysteic acid were active with an IC50 value of a micromolar concentration, whereas L-cysteic acid and L-cysteine sulfinic acid were weakly active.(ABSTRACT TRUNCATED AT 250 WORDS)
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Effective utilization of nonheartbeating cadaver donor organs is limited by the time required to obtain the necessary family consent prior to organ retrieval (a delay of at least 4-6 hr); this exceeds by far the maximum tolerance of kidneys to warm ischemia. Measures that could theoretically permit use of such organs include: (1) rapid in situ flush cooling; (2) continued in situ kidney cooling until permission for donation is secured; and (3) cell-membrane stabilization of vital organs, with only minimal invasion of the donor body. These measures were tested experimentally in dogs. Hemorrhagic shock was produced in mongrel dogs. One hour after cessation of heartbeat, a rapid perfusion tube was placed into the femoral artery; it was advanced, and its balloon was inflated in the aorta above the renal vessels. The kidneys were then flushed in situ with 1000 cc of cold preservation solution containing a calmodulin inhibitor, trifluoperazine. Two other catheters were inserted percutaneously into the peritoneal cavity for continuous intraperitoneal cold perfusion. Core temperatures of 4 degrees C were maintained in situ in the kidneys for 5 hr. Six hours after cardiac arrest, the kidneys were removed and preserved ex vivo at 4 degrees C for 24 hr, and were then transplanted into their respective hosts (n = 11), where they sustained life uneventfully. This method requires a 2-inch incision in the groin of the prospective donor, and two small stab wounds of the abdomen; i.e., semi-invasive procedures which are commonly performed in emergency rooms. The perfused body could then be released to the family if donation is denied. The recently documented increased willingness of the public to donate organs when the termination of life support is not an issue, and court decisions that have authorized the performance of nondeforming diagnostic procedures in cadavers without consent, suggest that the salvage of transplantable semi-invasive procedures described in this study may be useful in helping to alleviate the current shortage of transplantable organs. This technique can provide the time needed for families to consider the option of organ donation from nonheartbeating cadaver donors in an unhurried and unpressured manner, while preserving the viability of vital organs during the decision-making process.
Previous studies have shown a protective effect of trifluoperazine (TFP), a calmodulin inhibitor, upon the microcirculation of cold-stored kidneys. The present study points to similar beneficial effects of TFP on the microcirculation of cold-stored livers; 25 canine livers were preserved for 24 hr with Euro-Collins' solution (EC) (n = 8), University of Wisconsin solution (UW) (n = 7), or UW + TFP (n = 10). The stored livers underwent heterotopic transplantation (HLTX); hepatic-artery and portal-vein pressure and flow were monitored; oxygen consumption and extraction were measured before HLTX and at 15-min intervals after reperfusion, for 1 hr. Mean hepatic-artery and portal-vein flow (HAF & PVF) prior to donor hepatectomy were 172 and 530 cc/min, respectively. Poor HAF and PVF occurred in EC-HLTX (mean 35, 175 cc/min, respectively). The damaged EC-flushed livers could not compensate to the decreased hepatic blood flow by increased oxygen extraction (oxygen consumption and extraction, 8.7 vol.% and 48%, respectively). Light and electron microscopy showed severe liver necrosis and periportal hemorrhages. Improved hepatic-artery and portal-vein flows were seen in UW HLTX (105 and 254 cc/min), and oxygen consumption and extraction were 16.4 vol.% and 66%, respectively. Liver biopsy taken just before reperfusion revealed well-preserved liver architecture. Liver biopsy obtained 1 hr after reperfusion revealed marked edema of the portal triad, sinusoid congestion, and hemorrhage. Electron-microscopy biopsies obtained during reperfusion at 15-min intervals revealed severe vasospasm of the terminal hepatic arterioles and progressive damage to the liver microcirculation. The addition of TFP to the UW-flush solution resulted in excellent protection of the liver microcirculation. Marked increase in hepatic-artery and portal-vein blood flow was noted after reperfusion (mean 167 and 421 cc/min, respectively (P 0.02 vs. UW: P 0.001 vs. EC). The recovery of metabolic activity was evident by the high oxygen consumption and extraction (25.8 vol.% and 80%, respectively). And serial liver biopsies obtained after reperfusion have shown excellent protection of liver architecture and the absence of hepatic arteriolar vasospasm. Taken together, these data suggest that the addition of TFP to the UW solution protects the liver microcirculation by rendering the hepatic microcirculation insensitive to vasospastic stimuli during reperfusion, thus permitting better metabolic recovery after transplantation.
This study was conducted to investigate some biochemical characteristics of compound odontoma obtained from three cases, all found in the mandible. The results were compared with data obtained from deciduous teeth (3) and permanent teeth (3). The mole ratios of calcium to inorganic phosphorus (Ca/P) among three groups were deviated between 1.67 and 1.68 in the enamel extracts and between 1.65 and 1.69 in the dentine extracts. No significant differences were found in each case. Amino acid analysis of dentine showed apparent differences among these groups in the degrees of hydroxylation of proline (Hyp/Pro + Hyp) and of lysine (Hyl/Lys + Hyl). Hydroxylation rates of proline were 43.1 +/- 0.98% for the permanent teeth, 44.4 +/- 0.47% for the deciduous teeth and 40.9 +/- 0.44% for the odontoma. Hydroxylation rates of lysine were 32.0 +/- 0.67% for the permanent teeth, 27.3 +/- 0.0% for the deciduous teeth and 26.5 +/- 0.46% for the odontoma. T-test confirmed the significance of the differences between the permanent teeth and odontoma in the case of lysine (p less than 0.5%) and between the deciduous teeth and odontoma in the case of proline (p less than 0.5%). These results suggest the differential organization of dentine matrix between human permanent teeth, deciduous teeth and compound odontoma.
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This study was undertaken in order to determine whether the administration of nifedipine, a calcium channel blocker, could protect the liver from ischemic damage and to investigate its effect on the hepatic cellular energy status and cardio-vascular system after 60 minutes of hepatic ischemia in dogs. The ischemia was induced by temporarily clamping the portal vein and hepatic artery. One group of animals (n = 17) received nifedipine (5 micrograms/kg body weight) intravenously 15 minutes before the induction of liver ischemia, which was continued at a dose of 0.2 microgram/kg body weight/min throughout the ischemic period, and for an additional 30 minutes afterwards. Control dogs (n = 16) were not given nifedipine and survival was observed over seven days. The survival rate was 83 per cent in the nifedipine treated animals and 0 per cent in the control animals. Serum glutamic oxaloacetic transaminase levels were greatly increased following ischemia, and they were significantly lowered with the nifedipine treatment. The hepatic energy charge decreased remarkably during the hepatic ischemia, however it increased gradually after declamping but did not returned to its preoperative value in either group until one hour later and then it was higher in the nifedipine treated animals than in the control animals. Cardiac index and portal venous blood flow ratio remained higher in the nifedipine treated animals than in the control animals, after the ischemic period. These results suggest that nifedipine may have a powerful cytoprotective effect and that the period of warm hepatic ischemia could be prolonged with its use.
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The approach to the treatment of unresectable liver tumor involves immunotherapy. Systemic administration of OK432 has been widely used in the treatment of malignant neoplasms. However, the most potent antitumor activity of the drug may be expected when it is administered intratumorally. The author evaluated the effect of intratumoral injection of OK-432 on the survival time, the immunological parameters (such as the NK activities of spleen cells and peritoneal exudate cells and the interferon production by spleen cells) and the tumor infiltrating lymphocytes (TIL) in the rats with liver tumor induced by feeding the hepatocarcinogen, 3'-methyl-4-di-methyl-aminoazobenzene. The mean survival time was significantly longer in the rats injected with OK432 intratumorally (I.T. group) than in the rats injected with OK432 intraperitoneally only (I.P. group) and in the rats injected with normal saline intratumorally (Control group). The immunological parameters significantly improved in the rats of I.T. group than in the controls. Intratumoral injection of OK432 increased the number of TIL, especially NK cells and suppressor/cytotoxic T cells. These beneficial effects could be responsible for the better survival time in the rats of I.T. group. The author concluded that the intratumoral OK432 administration therapy is effective for the treatment of the patients with unresectable liver tumor.
Following transection of a nerve, strychnine (1 mg/kg per day) was intraperitoneally injected for 3-23 days at various post-transectional intervals and the medullary and spinal dorsal horns were histologically examined. Strychnine-enhanced transsynaptic destruction was seen when the inferior alveolar nerve was transected and the proximal stump was left in situ in the mandibular canal. Pyknotic neuronal cell bodies were observed in the dorsal half of the medullary dorsal horn ipsilateral to the nerve transection, an area which is known to receive dense innervation from the ipsilateral inferior alveolar nerve. Three days of strychnine treatment revealed pyknotic cells when the experiment was terminated between 18 and 30 days postoperatively. A longer period of strychnine treatment had a tendency to produce more pyknotic cells. Transection of neither mental, lingual, auriculotemporal nor infraorbital nerve induced strychnine-enhanced transsynaptic destruction in the medullary and spinal dorsal horns which are known to receive primary input from the severed nerves. Strychnine-enhanced transsynaptic destruction following transection of the inferior alveolar nerve was effectively prevented by placing the proximal stump outside the mandibular canal.
Cell bodies of primary afferent neurons comprizing individual peripheral branches of the rat mandibular nerve were labeled by retrograde transport of HRP and their sizes were measured. Approximately 60% of cell bodies of primary neurons innervating the intra and perioral structures through the inferior alveolar, lingual, mental, and buccal nerves were in the range between 300 and 600 micron 2 in cross-sectional area: mean +/- SD 509 +/- 243 micron 2, 420 +/- 181 micron 2, 469 +/- 200 micron 2, and 444 +/- 186 micron 2, respectively. Sixty-five percent of cell bodies of primary neurons innervating the periphery of the face through the cutaneous branch of the mylohyoid and auriculotemporal nerves were smaller than 300 micron 2 in cross-sectional area: 285 +/- 170 micron 2 and 286 +/- 172 micron 2, respectively. The data suggest that the intraoral/perioral region is different from the skin in the peripheral region of the face in terms of the mechanism by which sensory information is transmitted to the central nervous system. This difference may explain some of the formerly enigmatic phenomena such as the differential effects of spinal trigeminal tractotomy.
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Amberlite XE-64 and bovine serum albumin-treated rickettsia suspension, which was prepared from the chicken yolk sacs infected with each of 3 reference strains of Rickettsia orientalis, Karp, Gilliam and Kato, was sonicated at 10 KC for 15 min at 4 degrees C and centrifuged at 10,000 rpm for 40 min at 0 degrees C. The supernatant was used to sensitize the formalinized and tanned sheep red blood cells (SFTSRC). This antigen (2.5%) could be preserved for at least 1 wk at 4-8 degrees C and at least a month, if merthiolate (1:10,000) was added. Each SFTSRCP of 3 reference strains was found to be specific in indirect hemagglutination (IHA) reaction with each homologous immune serum and there was little cross reaction with the heterologous one. This minor cross reaction might be due to the presence of a small amount of soluble antigen in SFTSRC. No cross IHA reaction with the typhus fever immune serum was observed. The IHA test was considered to be useful for the diagnosis of scrub typhus.