Biomedical subjects
T Nishimura
Publications and source records attributed to T Nishimura.
[A case of sleep apnea syndrome due to a nasopharyngeal tumor].
Obstructive Sleep Apnea Syndrome (OSAS) is children is commonly caused by upper airway obstruction, such as that caused by adeno-tonsillar hypertrophy. We report a rare case of SAS due to a nasopharyngeal tumor. The patient was a 10-year-old boy who complained of snoring and sleep apnea. The tumor was found in the nasopharynx and mesopharyngeal space. We diagnosed this case as OSAS by overnight sleep study (Apnea Hypopnea Index: AHI = 19.67). The tumor was removed under general anesthesia. Histopathology revealed features of nasopharyngeal angiofibroma. After removal of the tumor, his symptoms resolved completely. A follow-up overnight sleep study confirmed resolution of OSAS. At the last follow up, conducted 17 months after the operation there were no signs of tumor recurrence.
Novel blockade of cell surface expression of virus glycoproteins by leucinostatin A.
The nonapeptide leucinostatin A (LSA) inhibited syncytium formation without profoundly affecting HN glycoprotein synthesis in Newcastle disease virus (NDV)-infected BHK cells. At similar doses of LSA, cytopathic effect and infectious virus production were suppressed in vesicular stomatitis virus (VSV)-infected BHK cells. Blockade by LSA of cell surface expression of NDV-HN and VSV-G glycoproteins was demonstrated, accompanied by intracellular accumulation of these virus glycoproteins. LSA acts as an inhibitor of mitochondrial F-type H(+)-translocating ATPase, a key enzyme in the generation of ATP, but its action against cell surface expression of virus glycoproteins was independent of the depletion of intracellular ATP. LSA also acts as an ionophore, but its action on intoxication by ricin and diphtheria toxin was different from that of monensin. This novel action of LSA is expected to be useful in investigation of the mechanism of intracellular trafficking of proteins.
Maladaptation of vascular response in frontal area of patients with orthostatic hypotension.
UNLABELLED: To clarify the relationship between abnormalities in cerebral blood flow (CBF) and in blood pressure regulation, we performed 99mTc-HMPAO brain SPECT in association with measurement of plasma norepinephrine and blood pressure in both the upright and supine positions. METHODS: We studied six patients with orthostatic hypotension and six normal patients. No patient had any significant stenosis of the carotid arteries on echocardiography-Doppler ultrasound and no abnormalities on brain MRI or CT. Changes in systolic blood pressure were monitored during the upright test, and 8-ml blood samples were taken at baseline and at 1 and 5 min after the upright position. RESULTS: Systolic blood pressure decreased by a mean of 38 +/- 10 and 9 +/- 3 mmHg in the orthostatic hypotension and normal groups, respectively. Compared with baseline values, plasma norepinephrine levels at 1 and 5 min after the upright test did not increase in the orthostatic hypotension group but did increase significantly in the normal group. In the orthostatic hypotension group, 99mTc-HMPAO brain SPECT showed postural cerebral hypoperfusion in the bilateral frontal areas, of which the mean count ratio of the frontal-to-cerebellar area between the upright and supine positions significantly changed from 0.871 +/- 0.029 to 0.942 +/- 0.067 and from 0.881 +/- 0.035 to 0.954 +/- 0.073 in the right and left areas, respectively. No postural change in CBF was evident in other areas in the orthostatic hypotension group. In the normal group, there were no such changes in CBF, blood pressure and plasma norepinephrine levels during the upright test. CONCLUSION: Postural cerebral hypoperfusion in the frontal areas in the orthostatic hypotension group might relate to maladaptation of the vascular response during the upright test.
[A phase 3 clinical trial of 123I-iomazenil, a new central-type benzodiazepine receptor imaging agent (Part 1)--report on clinical usefulness in 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. 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.
[A phase 3 clinical trial of 123I-iomazenil, a new central-type benzodiazepine receptor imaging agent (Part 2)--Report on clinical usefulness in diagnosis of degenerative neurological diseases and mental disorders].
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, a new central-type benzodiazepine receptor imaging agent (Part 3)--Report on clinical usefulness in epilepsy].
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.
[A phase 3 clinical trial of 123I-iomazenil, a new central-type benzodiazepine receptor imaging agent (Part 4)--Report on clinical usefulness in diagnosis of cerebrovascular diseases].
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.
[Neurofibrillary changes and phosphorylated tau of Alzheimer's disease].
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The effects of repetitive mild brain injury on cytoskeletal protein and behavior.
The purpose of this study was to examine the hypothesis if repetition of mild mechanical brain injury induces the pathological process related to Alzheimer's disease. After defining the magnitude of the subthreshold brain injury which does not induce brain tissue damage by a single hit, the subthreshold mild impact (1.0 atm) was repeated 7 times every 24 h. One week after the last impact, abnormal accumulation of microtubule-associated protein 2 (MAP2) and phosphorylated neurofilament 200 kD (p-NFH) was observed in neuronal perikarya and dendrites. One month after percussion, the number of MAP2-and p-NFH-positive neuronal perikarya was increased and observed in remote areas including the contralateral cortex and the hippocampus. Tau-1 immunoreactivity was increased in deep cortical neurons of the ipsilateral side after dephosphorylation, indicating the accumulation of phosphorylated tau in neuronal perikarya. The abnormal accumulation of cytoskeletal proteins in neuronal perikarya may be due to impaired axonal transport caused by mechanical brain injury. The behavioral study revealed that after repetitive mild percussion, rats show less efficient habituation to a new environment. It is suggested that the repetition of subthreshold mechanical brain injury may trigger cytoskeletal alteration related to neuronal degeneration.
[Evaluation of 123I-iomazenil SPECT in patients with ischemic cerebrovascular disease: comparative study with 123I-IMP SPECT].
Clinical evaluation of 123I-iomazenil, a new imaging agent for central-type benzodiazepine receptors with SPECT, was performed in patients with ischemic cerebrovascular disease. We investigated 15 patients with angiographically-proven severe occlusive lesions (occlusion or > 70% stenosis) in the unilateral carotid system. 123I-iomazenil SPECT images were compared with cerebral blood flow (CBF) images and the cerebral perfusion reserve, which were measured using the "split dose 123I-IMP SPECT method" before and after the intravenous injection of 1 g of acetazolamide. For the detection of ischemic lesions, CBF images were superior to 123I-iomazenil images based on visual analysis. Regarding the count ratio of the affected MCA territory to the non-affected (L/N), 123I-IMP was lower than 123I-iomazenil in most of the cases. In five patients showing "crossed cerebellar diaschisis" by 123I-IMP, asymmetry of the cerebellar accumulation was observed in only one patient with 123I-iomazenil, which was less prominent than with 123I-IMP. There was no significant correlation between the L/N ratio with 123I-iomazenil and the cerebral perfusion reserve in the affected MCA territory. However, in some cases showing a decreased L/N ratio (< 90%) with 123I-iomazenil, a decreased CBF with normal perfusion reserve and cerebral hemi-atrophy were observed with 123I-IMP and MRI, which suggested the influence of neuronal loss due to chronic ischemia. These results indicate that 123I-iomazenil SPECT, which provides new information regarding neuronal loss due to ischemic damage to the brain, is useful for the evaluation of ischemic cerebrovascular disease.
[Evaluation of remote effect to supratentorial areas in cerebellar infarction: a semiquantitative analysis using 99mTc-HM-PAO SPECT].
We studied 18 patients with unilateral cerebellar infarction to investigate its remote effect to the supratentorial areas with 99mTc-HM-PAO SPECT. Asymmetry indexes (AI) were calculated in the cerebellum and in seven supratentorial areas (thalamus, basal ganglia, superior and inferior frontal areas, temporal area, parietal area and occipital area). Mean AIs of supratentorial areas ranged from -0.64 +/- 2.74% to +1.04 +/- 2.03%. In cerebellar infarction of acute or subacute phase, the mean AI showed larger values (+1.13%) than that of chronic phase (+0.21%), but this difference did not reach statistical significance. There was no significant difference among supratentorial AIs grouped according to cerebellar infarction size. There was also no significant correlation among AIs of cerebellar and the supratentorial areas (r = -0.32 to +0.38). Crossed hemispheric hypoperfusion is thought to be related to the interruption of cerebellocortical tracts. We concluded that the detection of the remote effect to supratentorial areas in cerebellar infarction was difficult with 99mTc-HM-PAO SPECT.
Development of a centrifugal pump with improved antithrombogenicity and hemolytic property for chronic circulatory support.
A centrifugal pump with a unique structure has been developed for chronic support. The pump is driven by a magnetic coupling and has no rotating shaft, no seal around the rotating part, and a balancing hole at the center of the impeller and the thrust bearing. The pump was improved in stepwise fashion to realize good antithrombogenicity and low hemolysis. The first pump, the National Cardiovascular Center (NCVC)-0, had an impeller with 4 rectangular and curved vanes; 6 triangularly shaped curved vanes were employed in the second model, the NCVC-1, to reduce trauma to the blood. In the third design, the NCVC-2, the central hole was enlarged, and the thrust bearing shoulder was rounded so that blood washing was enhanced around the impeller; stream lines also were smoothed for improved antithrombogenicity. The hemolytic property of the device was evaluated in vitro with heparinized fresh goat blood; hemolysis indexes of the NCVC-0, -1, and -2 were 0.05, 0.01, and 0.006 g per 100 L, respectively. Antithrombogenicity of the pumps was examined in animal experiments as a left heart bypass device in goals weighing 52-75 kg. Six NCVC-0 pumps were driven for 14 to 33 (22.0 +/- 7.6) days in goats receiving the antiplatelet drug cilostazol orally. Four NCVC-1 pumps ran for 1 to 80 (28.5 +/- 30.6) days with the same drug regimen in 2 cases and with no anticoagulation therapy in 2 cases. After 3 preliminary 1-week tests of NCVC-2 pumps in animals, the pump was installed in 3 goats; 2 pumps were still running on the 182nd and 58th pumping day. Intracorporeal implantation also was attempted successfully. The results indicate that this pump has promising features for chronic support although longer term and additional evaluations are necessary.
Tandem operation of a turbo blood pump (BP-80--type centrifugal pump) to reduce hemolysis.
When operating turbo blood pumps in tandem, the strength of shear stress is reduced, but the exposure duration of the stress is increased. The purpose of this experiment was to compare the degree of contribution of these two factors on hemolysis as well as to evaluate the effectiveness of the tandem operation of turbo blood pumps. Tandem operation of two Bio-pumps (BP-80; Medtronics Bio-medicus, Inc., Eden Prairie, Minnesota, U.S.A.) were compared with single operation of a BP-80 in in vitro hemolysis tests in three different driving conditions, that is, pumping heads of 200, 350, and 500 mm Hg under a pump flow rate of 5 L/min. The Allen's hemolytic indexes of the tandem operation at pumping heads of 200, 350, and 500 mm Hg were 0.014, 0.020, and 0.080 mg/dl, respectively. The hemolytic indexes of the single operation at pumping heads of 200, 35, and 500 mm Hg were 0.014, 0.056, and 0.12 mg/dl, respectively. These results indicate that tandem operation is a useful method of reducing hemolysis with the BP-80 under high pumping heads and that the effect on hemolysis of exposure to higher shear stresses may be more serious than that of longer durations of exposure to shear stress in turbo blood pumps.
[Usefulness of 123I-BMIPP scanning for distinction of ischemic from nonischemic dilated cardiomyopathy].
To determine if imaging of blood flow (using 201Tl) and fatty acid (using 123-I-BMIPP) with SPECT can distinguish cardiomyopathy of coronary artery disease from nonischemic dilated cardiomyopathy, 24 patients with severe left ventricular dysfunction were evaluated. The origin of left ventricular dysfunction had been previously determined by coronary angiography to be ischemic (9 patients) or nonischemic (15 patients). Images were visually analyzed by three observers on a graded scale (score 0; normal, 1; mild uptake reduction, 2; severe uptake reduction, and 3; defect) in 20 left ventricular segments revealed higher defect score in ICM compared with NCM for 123I-BMIPP (35.5 +/- 14.4 versus 14.1 +/- 9.3, p <0.0005) and 201Tl (27.6 +/- 14.6 versus 12.1 +/- 7.4, p <0.005). The defect score/segment ratio also revealed higher value in ICM compared with NCM for 123I-BMIPP (2.25 +/- 0.52 versus 1.36 +/- 0.36, p <0.0001) and 201Tl (1.92 +/- 0.51 versus 1.24 +/- 0.42, p <0.005). Myocardium of ICM is more severely damaged than that of NCM. Thus, noninvasive SPECT imaging with 123I-BMIPP is helpful in distinguishing patients with severe left ventricular dysfunction secondary to coronary artery disease from those with nonischemic cardiomyopathy.
[Therapeutic effects of coenzyme Q10 on dilated cardiomyopathy: assessment by 123I-BMIPP myocardial single photon emission computed tomography (SPECT): a multicenter trial in Osaka University Medical School Group].
To evaluate therapeutic effects of Cenzyme Q10 (CoQ10), 15 patients with dilated cardiomyopathy were investigated by 123I-BMIPP myocardial single photon emission computed tomography (SPECT). The BMIPP defect score was determined semiquantitatively by using representative short and long axial SPECT images. Mean BMIPP defect score with CoQ10 treatment was significantly low, 7.7 +/- 6.1 compared to 12.7 +/- 7.4 without CoQ10 treatment. On the other hand, in 8 patients of dilated cardiomyopathy, % fractional shortening using echocardiography was not different before and after CoQ10 treatment. In conclusion, 123I-BMIPP myocardial SPECT was proved to be sensitive to evaluate the therapeutic effects of CoQ10, which improve myocardial mitochondrial function, in the cases of dilated cardiomyopathy.
[Criteria for the clinical evaluation of antimicrobial drugs in neonates].
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General pharmacology of recombinant human basic fibroblast growth factor.
General pharmacological effects of recombinant human basic fibroblast growth factor (bFGF) were investigated. 1. Central nervous system: Basic FGF produced almost no effect on the general symptoms and behaviors of mice. Basic FGF did not influence the spontaneous motor activity, hexobarbital-induced anesthesia, electroshock seizure threshold, pentylenetetrazole-induced seizure in mice and normal body temperature and spinal reflex in rats up to a dose of 1 mg/kg (s.c., i.v.). As regards pain sensation, it inhibited the acetic acid-induced writhing at 1 mg/kg (s.c.). No abnormal waves were observed in spontaneous EEG of the rabbit up to 1 mg/kg (i.v.) of bFGF, but at 0.1 mg/kg it had a slight effect on the ratio of EEG levels and at 1 mg/kg induced an increase in rest period, disappearance in the period of fast wave sleep and a decrease in the period of deep sleep. 2. Somatic nervous system: Basic FGF did not influence the corneal reflex, twitch response of the skin and diaphragm-phrenic nerve preparations. 3. Autonomic nervous system and smooth muscle: Basic FGF showed little effects on the spontaneous movement of the isolated ileum, contraction induced by various agonists in isolated ileum, resting tension and noradrenaline(NA)-induced contraction of the aorta, resting tension and histamine-induced contraction of isolated trachea, spontaneous movement and 5-HT-induced contraction of isolated strips of stomach fundus, NA-induced contraction of isolated vas deferens of the rat up to the concentration of 10(-4) g/ml. Basic FGF augmented the tone of the isolated non-pregnant uterus at the concentrations of 10(-5) g/ml and above and inhibited or tended to inhibit the contractile tension of non-pregnant or pregnant uterus at 10(-4) g/ml, but it did not influence the spontaneous movement of the uterus, either the non-pregnant or pregnant, under in situ conditions even at a dose of 1 mg/kg (i.v.). Basic FGF did not influence the pupil size. 4. Respiratory and circulatory systems: Basic FGF had no effect on the isolated heart. The influence was not exerted on the heart rate for the isolated atria but slight inhibition of contractile force was observed at 10(-4) g/ml. In anesthetized dogs a decrease in blood pressure, a slight increase in heart rate and respiratory rate and a decrease in femoral blood flow were observed at 0.01 and 0.1 mg/kg (i.v.) of bFGF Similarly, a slight increase in heart rate and a slight decrease of blood pressure were observed at 1 mg/kg (s.c.) in conscious rats. 5. Digestive system: Administration of bFGF at 1 mg/kg did not result in changes in the transport capacity within the gastrointestinal tract (s.c., i.v.) and the secretion of the gastric juice (s.c.). 6. Urine output and electrolyte metabolism: Basic FGF produced a decrease in urinary Na+ excretion at 1 mg/kg (s.c.), and showed a tendency to increase in urinary volume at 0.01 and 0.1 mg/kg (i.v.). At 1 mg/kg (i.v.) urinary excretion of Na+ and Cl- was decreased significantly. It had no effect on the ability of rats to excrete PSP (phenol red) up to 1 mg/kg (s.c.). 7. Blood system: Basic FGF did not influence the coagulation time of the whole blood, prothrombin time and activated partial thromboplastin time of rats up to 1 mg/kg (s.c., i.v.). It did not influence the aggregation of rabbit platelets induced by collagen and ADP up to 10(-4) g/ml. Basic FGF at concentration of 10(-4) g/ml exhibited no hemolytic action. 8. Local action: Plantar subcutaneous injection of bFGF at above 0.005 mg/site induced edema by itself on and after the next day, and also reinforced carrageenin-induced edema from 1 day after injection. The results show that bFGF did not produce any acute effects on the somatic nervous system, autonomic nervous system, smooth muscle and blood system. In contrast, bFGF produced slight effects on the circulatory system, central nervous system and kidney function when injected systemically. Subcutaneous administration may produce edema at the s