Biomedical subjects
Publications and source records attributed to K Matsuda.
We reported the rare case of a successful treatment of descending aortic aneurysm which causes syncopal attack. The patient, 75-years-old woman, underwent the descending aortic aneurysmectomy and the graft replacement. Three years has passed since the operation, and patient is leading a normal life without any syncopal attack.
Iomazenil (IMZ) is a partial inverse agonist of central-type benzodiazepine receptors (BZR) which binds specifically to BZR with high affinity. The safety and clinical effectiveness of 123I-IMZ SPECT in the diagnosis of brain diseases were evaluated in 655 patients with various brain diseases, such as epilepsy, cerebrovascular diseases, degenerative diseases and mental disorders relating to BZR. This was a Phase 3 study conducted as a multicenter trial at 52 collaborating institutions. There was no significant adverse reactions in the clinical symptoms or abnormal laboratory test values. The investigators judged 123I-IMZ SPECT to be effective in 95% of 638 analyzed cases. The injected dose did not correlate with the image quality or the clinical effectiveness of 123I-IMZ SPECT, suggesting that these items depend largely on the characteristics of the apparatus used, the disease or pathology of the patients, rather than the dose. We conclude that 123I-IMZ imaging is safe and provides effective information based on BZR binding which is useful in the diagnosis of various brain diseases.
Iomazenil (IMZ) is a partial inverse agonist of central-type benzodiazepine receptors (BZR) which binds specifically to BZR with high affinity. A multi-center Phase 3 clinical study was performed to evaluate the clinical usefulness of 123I-IMZ-SPECT in the diagnosis of brain disorders in 169 patients with degenerative neurological diseases and 37 patients with mental disorders such as neurotic, stress-related and somatoform disorders. In dementia, the decrease in activity in late images, obtained three hours after administration of 123I-IMZ, correlated negatively with the dementia score. In Parkinson's disease and spinocerebellar degeneration. 123I-IMZ showed a more profound decrease in uptake in late images than seen in the cerebral blood flow (CBF) images, and this decrease was in proportion to the duration and severity of the illness. In mental disorders, the ratio of the late to early image counts showed a negative correlation with Hamilton's anxiety scale in all regions in the brain cortices. In panic disorders, the ratio of the cerebral count to the cerebellar count in the late images correlated negatively with the severity of the attack in the frontal, temporal and parietal cortices. These results suggest that 123I-IMZ-SPECT enables us to evaluate the neuronal damage in degenerative diseases and the decrease in the BZR binding potential in mental disorders.
A Phase 3 clinical trial of 123I-Iomazenil (IMZ), a tracer which binds specifically to central-type benzodiazepine receptors (BZR), was performed, and the clinical usefulness of IMZ was evaluated in 121 patients with epilepsy (106 cases with partial epilepsy and 15 cases with generalized epilepsy). A regional abnormality in the BZR distribution was detected in late IMZ images in 20 of 24 cases without abnormal MRI and/or X-ray CT findings. Moreover, only 16 of these 20 cases showed abnormal findings in the cerebral blood flow (CBF) images. In partial epilepsy, abnormal regions in late IMZ images agreed or partially agreed with epileptic foci estimated from the clinical symptoms of epileptic seizures, interictal EEG, and MRI and/or X-ray CT findings in 76%, 70% and 96% of the cases detected. These regions also agreed or partially agreed with the estimated epileptic foci in 92% of the cases with foci estimated by combination of those three methods and in 72% of those estimated by ictal EEG. The agreement or partial agreement rates of late IMZ images with each of the other methods were higher than those of CBF images, although the differences were not significant. For surgically-proven epileptic foci without any abnormality in the CBF image, abnormal regions were detected in late IMZ images. These findings suggest that IMZ SPECT is a useful new tool for detecting epileptic foci based on the distribution of BZR in the brain.
Single photon emission computed tomography (SPECT) using 123I-Iomanzenil (IMZ), a tracer which binds specifically to central-type benzodiazepine receptors, was performed in patients with cerebrovascular diseases (CVD) to determine the clinical signicigance of IMZ SPECT studies in evaluating the pathophysiology of CVD. IMZ SPECT images obtained three hours after administration of the tracer were compared with the images of cerebral blood flow (CBF) studies in 206 cases. In regions with decreased CBF, the uptake of IMZ was relatively preserved in patients with cerebral thrombosis in comparison with cerebral embolism, and in those with perforator branch infarction in comparison with cortical infarction. The uptake of IMZ decreased as a function of both the severity of the decrease in the CBF and the duration of illness in regions with a significantly decreased perfusion reserve. These results suggest that decreased IMZ binding in ischemic stroke reflects the neuronal damage caused by the cerebral ischemia. On the other hand, in patients with intracerebral hemorrhage, the cortical uptake of IMZ was relatively well-preserved in regions with decreased CBF, and the decrease in the uptake of IMZ was more profound as a function of the decrease in the CBF, especially in cases of putaminal hemorrhage. These results also suggest that the decreased cortical CBF is a remote effect caused by a neuronal disconnection, and neuronal damage may occur in regions with severely impaired CBF.
Four patients with upper urinary tract transitional cell carcinoma were treated with bacillus Calmette-Guerin (BCG) via a percutaneous nephrostomy tube or a retrograde ureteral catheter. A 68-year-old female and an 80-year-old male had carcinoma in situ (CIS) in the left upper urinary tract (cases 1 and 2). A man aged 47 had CIS in the left upper urinary tract, bladder, and prostatic urethra (case 3). CIS in the left upper urinary tract was identified in a woman aged 63 with chronic renal insufficiency (case 4). Two patients (cases 1 and 2) responded to this therapy. In the other two patients nephrectomy was performed due to residual tumor. There were extensive tuberculous granulomas in the kidneys. In one resected kidney (case 4) carcinoma had invaded the renal parenchyma. The reviewed literature showed that BCG perfusion therapy was effective in 71% (27 of 38 renal units) for the upper urinary tract tumors and that there were 5 cases of severe complication, including sepsis in 2, high fever in 2, and ureteral stricture in 1. Based on the fact that the kidney receives a profuse blood supply and that the renal pelvis and ureter have a thin wall, careful management is mandatory to prevent severe adverse effects and insidious tumor progression.
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Two cases of metastatic malignant melanoma of the lower limb who were treated successfully with hyperthermic isolated limb perfusion are reported. One patient was infused with cisdiammine (1.1-cyclobutanedicarboxylate) platinum (II) (carboplatin, Paraplatin, Bristol-Myers Squibb Company, New Jersey, USA), and the other was infused with human natural beta-interferon (Feron, Toray, Tokyo, Japan), via the external iliac artery. The first case showed a remarkable suppression of the growth of multiple metastatic melanoma nodules associated with numerous melanophage infiltrations, as shown histopathologically after the operation. The patient's serum level of 5-S-cysteinyl dopa decreased for the two months following the treatment. In the second case, new formation of metastatic melanoma nodules was completely suppressed for up to 12 months following the operation. Analysis of immunological parameters showed that the number of peripheral CD8+ lymphocytes gradually and constantly increased after the operation, while that of CD4+ lymphocytes transiently increased and then returned to the pre-operative level. Natural killer activity transiently decreased to a slight degree 4 days after the operation and then returned to the pre-operative level 21 days after the operation. Side effects, such as nausea, vomiting and leg discomfort, were seen in the patient (Case 1) treated with carboplatin, but were completely reversible. These results suggest that hyperthermic isolated limb perfusion with concomitant infusion of carboplatin or beta-interferon is effective in suppressing the growth of metastatic malignant melanomas of the lower limb.
A phase 2 study of 123I-Iomazenil (IMZ) was performed to evaluate its clinical usefulness in SPECT imaging of central-type benzodiazepine receptors (BZR). A total of 246 patients with various central nervous system disorders [82 with epilepsy, 94 with cerebrovascular disease (CVD), 47 with degenerative disorders, 14 with mental disorders relating to BZR and 9 with other diseases] were intravenously injected with 111-222 MBq of IMZ. Early and late images were obtained 15 min and 180 min after injection as the mid-scan time, respectively. In comparison with regional cerebral blood flow (rCBF) images, the uptake of IMZ in the late images, which reflect the regional distribution of BZR, was relatively preserved compared to the uptake of CBF tracers in most of the patients with CVD. In the area of hyperperfusion in the subacute phase of cerebral infarction, however, the defects of IMZ uptake were accompanied by increased uptake of the CBF tracers. On the other hand, late IMZ uptake in most of the patients with the other diseases was decreased more significantly than the uptake of the CBF tracers, suggesting that cortical neuronal damage is more prominent than rCBF in these diseases compared to the vascular perfusional state. No adverse reactions were recognized relating to the IMZ administration. These results suggest that IMZ may provide us with valuable information for assessing pathophysiological state in the brain, which are difficult to achieve with other imaging modalities.
A phase 2 clinical study of 123I-iomazenil (IMZ) was performed to evaluate its clinical usefulness as central-type benzodiazepine receptor imaging agent in 81 cases with epilepsy, 82 cases with cerebrovascular diseases (CVD), 35 cases with degenerative disorders and 14 cases with mental disorders. In epilepsy, IMZ SPECT images for detection of epileptic foci showed relatively high specificity compared with EEG recording in not only interictal but also ictal state, in spite of the fact that IMZ SPECT images was performed during interictally. It was surmised that IMZ SPECT provides valuable clinical information for detection of epileptic foci which are hard to be diagnosed by EEG. The frequency of abnormal findings by IMZ late images was higher than that by interictal blood flow images and comparable to that by ictal blood flow images. In patients with CVD, different observations were obtained between IMZ late images and blood flow images; for example, in regions of hemodynamic cerebral ischemia, postischemic reperfusion and other pathological perfusion, IMZ late images seemed to reflect the degree of cortical neuronal loss. In patients with degenerative disorders, the binding potential (calculated by a simple quantitative method for IMZ) and other parameters correlated with the dementia score. While the number of examined cases with mental disorders was limited, the frequency of abnormal findings with IMZ imaging was higher than that with morphological imaging.
Lutz et al. made the first report in which ultrasonographic probe could differentiate cystic tumor from solid one. After that, endoscopic ultrasonography (EUS) have advanced rapidly in engineering and clinical application. EUS is the most accurate diagnostic method presently available to determine the depth of gastrointestinal cancer invasion. We have proposed the pattern analysis for the differentiation between cancer invasion and ulcer fibrosis, because fibrosis and cancer invasion have of the same echo level. USP is more useful and easy than EUS in cases with small and flat lesion without ulcer, and EUS should perform in remaining lesions that look like early cancer with ulcer and advanced cancer. Clinically, it is believed that the invasion of early gallbladder cancer limited to the proper muscle, the early pancreas cancer is less than 1 cm. It is also practicable with EUS to detect the these cancer easily and diagnose the local stage of gall bladder and pancreas cancer. Now we are performing IDUS (ER-US, PT-US) and 3D-EUS, and believing that these technics will be used commonly in the near future.
Pathophysiologic concept of SIRS has been proposed for the better management of postoperative severe infection and septic MOF, and the concept has been found to be very useful. It is very important to identify the high risk SIRS patients of the development of septic MOF and to treat those patients aggressively to prevent the development of septic MOF. In the prevention and treatment of septic MOF, the blood purification has been found to be very effective. Among the blood purifications, continuous blood purification, such as continuous hemodiafiltration (CHDF) should be chosen for this purpose. CHDF has been claimed to be very effective to removal of causative humoral mediators from the blood stream. The concept of DIC has been changed recently and the concept of DII (disseminated intravascular inflammation) should be applied instead of DIC, since the main feature of this pathologic condition is the damage of endothelial cells due to extensive systemic inflammation.
Peripheral tolerance is important to prevent autoimmunity of T cells against tissue-specific autoantigens in peripheral organs. In certain pathologic situations, peripheral tolerance breaks for unknown reasons and autoimmune diseases occur. Anergy is one of the mechanisms of peripheral tolerance that down-modulates IL-2 synthesis and IL-4 responsiveness by helper T cell clones. In this report, we utilized a model system in which V beta 8+ CD4 T cells were anergized by administration of high doses of Staphylococcus enterotoxin B (SEB) in vivo and investigated an effect of recombinant human (rh) IL-1 on the tolerance induction. RhIL-1 was used because of its ability to induce IL-4 responsiveness in T cells. When rhIL-1 was administered within 24 h after SEB inoculation, the cytokine interfered with tolerance induction; V beta 8+CD4 T cells from mice that had been treated with both SEB and IL-1 proliferated in response to SEB and produced IL-2, IL-4, and IFN-gamma upon TCR/CD28 cross-linking. Delayed administration of rhIL-1 by 48 h failed to do this; T cells did not proliferate in response to SEB, but they retained an ability to produce IL-4 upon TCR/CD28 cross-linking. Administration of rhIL-1 induced better proliferation of V beta 8+CD4 T cells in response to SEB in vivo but did not prevent cell death after proliferation. These results suggest a potential role of inflammatory cytokine IL-1 in the course of autoimmunity via interference with tolerance.
A toxic substance was purified from larvae of the antilion, Myrmeleon bore, by DEAE Sephacel and Phenyl Superose column chromatography. The substance was a large polypeptide with a molecular weight of about 165-167 kDa. Its paralytic activity measured by injection against German cockroaches was about 130 times higher than that of tetrodotoxin on a molar basis.
A decapeptide called sodefrin was isolated from the abdominal gland of the cloaca of the male red-bellied newt, Cynops pyrrhogaster. The native peptide, as well as the synthetic one, had a female-attracting activity. Sodefrin was found in the apical portion of the epithelial cells of the abdominal gland. Sodefrin is apparently species specific because it did not attract females of Cynops ensicauda. This is the first amphibian pheromone to be identified and the first peptide pheromone identified in a vertebrate.
The transcriptional activity of the hexafluorinated derivative of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 [F6-1,25-(OH)2D3], was examined in cultured cells by a transient expression assay (CAT assay) using expression vectors for the rat nuclear vitamin D3 receptor (VDR) and the rat 9-cis-retinoic acid receptor (RXR beta), and a reporter plasmid containing a consensus vitamin D3 response element (VDRE) consisting of two directly repeated AGGTCA motifs spaced by 3 bp (DR3). At physiological concentrations, the transcriptional activity of F6-1,25-(OH)2D3 was 2-4 times more potent than that of 1,25-(OH)2D3 in both nontarget (HeLa) and target (UMR106) cells for 1,25-(OH)2D3. The transcriptional activity of F6-1,25-(OH)2D3 was also higher when the endogenous target gene (osteopontin), which has a VDRE related to the DR3 in its promoter, was induced. A gel-shift assay using DR3 as a probe and in vitro synthesized receptors showed that the ligand-induced DNA binding of VDR required RXR to form a heterodimer. Moreover, in this assay we found that F6-1,25-(OH)2D3 induced the receptor-DNA complex at a 10-fold lower concentration than 1,25-(OH)2D3 without influencing the dissociation kinetics. However, the binding affinity of F6-1,25-(OH)2D3 for VDR was slightly lower than that of 1,25-(OH)2D3. The increased DNA binding of ligand-bound VDR by introducing hexafluorines into 1,25-(OH)2D3 may potentiate the transcriptional activity. Thus, the higher biological activity of F6-1,25-(OH)2D3 may be exerted at least in part by enhanced transcriptional activity.
Testosterone has been implicated as a risk factor for cardiovascular diseases and thromboxane A2 (TXA2) plays a role in these diseases. We tested the notion that testosterone regulates the expression of TXA2 receptors in platelets and vascular smooth muscle. Testosterone significantly increased the density of TXA2 receptors in cultured rat aortic smooth muscle and human erythroleukemia cells, a megakaryocyte-like cell. Treatment of rats with testosterone resulted in a significant increase in platelet and aortic TXA2 receptor density and increased responsiveness to TXA2 mimetics. We conclude that testosterone regulates the expression of TXA2 receptors.
The present study was undertaken to investigate whether epidermal growth factor (EGF) could stimulate prostaglandin E2 release, and if so, by what mechanism EGF would exert such an effect in gastric mucosal cells. In cultured guinea pig gastric mucous cells, EGF dose-dependently stimulated prostaglandin E2 release, with maximal stimulation observed at 10 ng/ml. EGF stimulated an increase in cyclooxygenase activity, which was reduced by protein synthesis inhibitor, actinomycin D, and cycloheximide. EGF also stimulated the enzyme protein synthesis estimated by Western blot analysis, whereas EGF did not stimulate phospholipase A2 activity. These results suggest that such an effect of EGF of de novo synthesis of cyclooxygenase protein and prostaglandin E2 release may be involved at least in part in the mechanism of EGF-induced local regulation of gastric mucosal integrity.