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Biomedical subjects

I Tokunaga

Publications and source records attributed to I Tokunaga.

At least 19 recordsLinked to original sources
PubMed2001

Neuronal changes in the arcuate and hypoglossal nuclei of brain stem induced by head injury.

In head injury, assessing the damage not only to the cerebrum and the cerebellum but also to the brain stem is very important. In this paper, we report neuronal changes of the arcuate nucleus (ARC) and the hypoglossal nucleus (HN) in the brain stem. We investigated these changes immunohistochemically with antibodies against microtubule-associated protein 2 (MAP2), muscarinic acetylcholine receptor (mAChR), c-fos gene product (c-Fos), and the 72 kD heat-shock protein (HSP70). We measured the percentage of immunopositive neurons among the total neurons of the ARC and the HN. The investigation of neuronal changes in relation to the type of head injury showed different results. In cases of tonsillar herniation, immunoreactivity to MAP2 and mAChR in the ARC was significantly lower than in the HN (p < 0.01). Moreover, MAP2, HSP70 and c-Fos reactivities in the ARC were significantly lower than in other types of head injuries (p < 0.01). In the HN, diffuse axonal injury produced slightly higher immunoreactivity to mAChR and c-Fos (p < 0.1). Our observations indicate that immunohistochemical examination of brain stem nuclei can provide useful information for estimating damage to the brain stem.

Adolescent↗
PubMed2001

Assessment of inpatient treatment of patients with schizophrenia in Japan: implications for practice.

This descriptive study examined a stratified random sample by month of 202 persons with schizophrenia hospitalized on an inpatient unit at a nonprofit hospital located in Tokyo, Japan in 1998. This is one of the first studies reported that evaluates the inpatient care provided to persons with schizophrenia. The average length of stay was 107 days. The master treatment largely focused on medication management with other domains including daily observations and documentation of care not meeting the standard of care. Over 25% of the patients were in restraints during their hospitalization. Two patient deaths were reported. Problematic areas were patient teaching, monitoring of medication side effects, treatment planning, and discharge planning. The study site is fully accredited and attending physicians were all psychiatrists. How pervasive these deficiencies are in other settings is not known. The findings of the study were shared with the professional staff.

Accreditation↗
PubMed2000

Effect of toluene inhalation on astrocytes and neurotrophic factor in rat brain.

Toluene, an abused substance in Japan, is a neurotoxic chemical that has been shown to have neurobehavioral and electrophysiological effects. In previous work, both acute and chronic effects of toluene on cells have been studied extensively. However, although glial cells are thought to play an important role in the survival of neurons in the brain, the effect of toluene on glial cell function has not yet been characterized. To elucidate this, the effect of toluene inhalation on astrocytes in rat brain was examined. Toluene exposure (1500 ppm for 4 h on 4-10 days) augmented glial fibrillary acidic protein (GFAP) immunoreactivity, particularly in the hippocampus and cerebellum. Quantitative analysis showed that toluene inhalation markedly enhanced GFAP expression in the hippocampus and cerebellum. In both regions, proliferating cell nuclear antigen (PCNA) showed no obvious changes, but glutamine synthetase (GS)-immunoreactive cells were markedly increased by toluene exposure. Thus, the elevation of GFAP expression was induced by astrocyte activation rather than by cell proliferation. If toluene exposure activates astrocytes, astrocytes may play a role in the neurophysiological changes observed in toluene intoxication. A neurotrophic factor, basic fibroblast growth factor (b-FGF) was observed immunohistochemically in the capillary vessel walls in the hippocampus and the cerebellum of toluene-intoxicated rats. Basic-FGF may have induced GFAP expression both in the hippocampus and the cerebellum. So, other neurotrophic factors may affect the difference of GFAP elevation between the hippocampus and the cerebellum. These differences may relate to neurobehavioral function of each brain part after toluene exposure.

Acute Disease↗
PubMed2000

Enhancement of glial cell line-derived neurotrophic factor expression in rat adrenal glands by toluene exposure.

Toluene, a widely used industrial organic solvent, has been shown to influence the function of catecholaminergic cells including sympathoadrenergic neurons and adrenal medullary cells. While glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-beta superfamily, has recently been shown to be expressed in rat adrenal glands, and suggested as playing a potential autocrine or paracrine role in development and differentiation of the adrenal medullary cell. Based on these findings, it seemed of interest to examine the effect of toluene exposure on GDNF expression in the adrenal medulla. Toluene inhalation (1500 ppm for 4h on 4-10 days) increased GDNF protein content in rat adrenal glands without any significant change in GDNF mRNA level. Furthermore, toluene exposure failed to cause any notable change in the expression of mRNA encoding phenylethanolamine N-methyltransferase (PNMT), a stress-inducible enzyme in the adrenal medulla. These results suggest that the elevation of GDNF protein expression caused by toluene exposure is likely due to the enhancement of protein synthesis and/or processing rather than the stimulation of GDNF gene transcription in rat adrenal glands, and may not be directly associated with the stress response of adrenal glands during toluene inhalation.

Adrenal Glands↗
PubMed2000

Elevation of steroid 5 alpha-reductase mRNA levels in rat cerebellum by toluene inhalation: possible relation to GFAP expression.

Toluene, a commonly used industrial solvent, is known to be toxic to both neuronal and glial cells, and has been shown to increase the immunoreactivity of glial fibrillary acidic protein (GFAP) in the brain. However, the mechanism of toluene-induced GFAP expression is poorly understood. Recently, GFAP mRNA expression in cultured astrocytes has been shown to be modulated by various steroid hormones, such as progesterone, testosterone, and their 5 alpha-reduced metabolites. Therefore, it seems possible that steroid hormones may play a potential role in the enhancement of GFAP expression observed following toluene exposure. To address this possibility, the effect of toluene inhalation on the expression of mRNAs encoding GFAP and steroidogenic enzymes in rat brain was examined. Toluene exposure increased GFAP protein contents without any significant alteration in GFAP mRNA levels in the hippocampus. In contrast, the elevation of both GFAP protein contents and its mRNA levels was observed in the cerebellum following toluene exposure. Further studies indicated that toluene exposure increased steroid 5 alpha-reductase (5 alpha-R) mRNA levels prior to the elevation of GFAP mRNA in the cerebellum, whereas neither 5 alpha-R nor GFAP mRNA levels in the hippocampus were significantly affected by toluene exposure. These results suggest that toluene inhalation may enhance GFAP gene expression in the rat cerebellum, and propose the possibility that the elevation of 5 alpha-R expression, and hence 5 alpha-reduced metabolites of steroid hormones, is presumably related to toluene-induced GFAP mRNA expression.

3-Hydroxysteroid Dehydrogenases↗
PubMed2000

HSP70 and c-Fos expression of brain stem hypoglossal nucleus in drowning.

The brain stem hypoglossal nucleus (HN) is the center of nerves innervating the upper respiratory tract and is related to control of mastication, deglutition, speech and respiration. To elucidate the relationship between asphyxia and the HN, we investigated the change of hypoglossal neurons in cases of hanging, strangulation, smothering, choking, drowning and respiratory failure. Using immunohistochemical techniques, we observed the brain stem HN with antibodies against microtubule-associated protein 2 (MAP2), muscarinic acetylcholine receptor (mAChR), c-fos gene product (c-Fos) and 72 kD heat-shock protein (HSP70). MAP2, a cytoskeletal protein of the neuron, is a marker of neuronal damage. Muscarinic AChR was used as a marker of neuronal membrane and ACh signaling. We employed both HSP70 and c-Fos as markers of stress- or damage-related events. We measured the percentage of immunopositive neurons in total neurons of HN. Drowning produced higher expression of HSP70 and c-Fos than other causes of asphyxia, suggesting that drowning induces more severe damage in HN neurons. Furthermore, it was suspected that neuronal changes in drowning might relate to functions of the HN. These observations indicate that immunohistochemical examination of the brain stem HN could provide useful information for determining the cause of asphyxia.

Brain Stem↗
PubMed1999

Cytotoxic effect of paraquat on rat C6 glioma cells: evidence for the possibility of non-oxidative damage to the cells.

Although paraquat has been shown to cause oxidative damage to neuronal cells, little is known about its effect on glial cells. Thus the effect of paraquat on glial cells was examined using rat C6 glioma cells as a model system. Paraquat reduced cell viability in a concentration- and time-dependent manner, and this toxic effect was not significantly attenuated by various kinds of antioxidants. Furthermore, paraquat failed to increase 8-hydroxy-deoxyguanosine formation in the cells. These results indicate that paraquat can be toxic to glial cells and suggest that this cytotoxic effect may not be associated with the oxidative damage to the cells.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

[Immunohistochemical studies on neuronal changes in brain stem nucleus of forensic autopsied cases. I. Various cases of asphyxia and respiratory disorder].

Several nuclei in brain stem are well known to play an important role in supporting human life. However, the connection between neural changes of brain stem and the cause of death is not yet fully understood. To investigate the correlation of brain stem damage with various cause of respiratory disorders, neural changes of the arcuate nucleus (ARC), the hypoglossal nucleus (HN) and the inferior olivary nucleus (IO) were examined using immunohistochemical technique. Based on the cause of death, the forensic autopsy cases were divided into 5 groups as follows. Group I: hanging, ligature strangulation and manual strangulation, Group II: smothering and choking, Group III: drowning, Group IV: respiratory failure, control group: heat stroke and sun stroke. Brain was fixed with phosphate-buffer formalin, and the brain stem was horizontally dissected at the level of apex, then embedded in paraffin. The sections were stained with the antibodies against microtubule-associated protein 2 (MAP2), muscalinic acetylcholine receptor (mAChR), c-fos gene product (c-Fos) and 72 kD heat-shock protein (HSP70). Three nuclei showed no obvious morphological changes in all examined groups. However, in case of asphyxia (Group I to III), neurons in HN were positively stained with both HSP70 and c-Fos antibodies. This may indicate that the occlusion of upper airway results in the neuronal damage of HN without their morphological changes. Positive staining of HSP70 and c-Fos in IO was more frequently observed in Group III than other 4 groups. Since IO is involved in maintaining body balance which is often disturbed by drowning, it seems possible that neuronal damage in IO observed in drowning may be related to the disturbance of body balance. These observations indicate that immunohistochemical study on the damage to neurons in brain stem nuclei can provide useful information for determining the cause of death.

Arcuate Nucleus of Hypothalamus↗
PubMed1998

[Immunohistochemical studies on neuronal changes in brain stem nucleus of forensic autopsied cases. II. Sudden infant death syndrome].

Several nuclei in brain stem are well known to play an important role in supporting human life. However, the connection between neural changes of brain stem and the cause of death is not yet fully understood. Previously, in sudden infant death syndrome (SIDS) it has been suggested that impaired cardioventilatory control might contribute to cause of death. So, to investigate the brain stem damage in SIDS, neural changes of the arcuate nucleus (ARC), the hypoglossal nucleus (HN) and the inferior olivary nucleus (IO) was examined using immunohistochemical technique. Brain was fixed with phosphate-buffer formalin, and the brain stem was horizontally dissected at the level of apex, then embedded in paraffin. The sections were stained with the antibodies against microtubule-associated protein 2 (MAP2), muscalinic acetylcholine receptor (mAChR), c-fos gene product (c-Fos) and 72 kD heat-shock protein (HSP70). Morphological changes of neurons in three nuclei were not evident. Moreover, because MAP2 degeneration and expression of HSP70 and c-Fos were not observed, neuronal damage in those nuclei was not suspected. However, although there was no abnormality of mAChR immunostaining in HN and IO, the rate of mAChR-immunopositive neurons in ARC was less than that in control. These observations indicate that immunohistochemical study on the neuronal changes in ARC can provide useful information for diagnosing SIDS.

Arcuate Nucleus of Hypothalamus↗
PubMed1998

Immunohistochemical diagnosis and significance of forensic neuropathological changes.

Immunohistochemistry is very useful when investigating the cause of death. Ischemic cell changes in the hippocampal neurons were not obvious in the brains damaged by hypoxic injury. However, it is suggested that even a moderate hypoxia, which may affect the neuronal proteins and metabolism, induced astrocytosis in the CA3 and CA4 regions, and that in patients with a history of hypoxic attacks neuronal damage may be severe even several hours after ischemic injury. Furthermore, hsp70 expression was found in the CA2, CA3 and CA4 regions of long-term survivors after severe hypoxic/ischemic injury. In forensic practice, detailed information about the duration and extent of a hypoxic/ischemic injury is often unavailable, so that immunohistochemical detection of hsp70 and glial cell staining can be of great value in diagnosing not only the hypoxic/ischemic injury during the process of death but also the victim's past history of hypoxic attacks. In diffuse axonal injury, degeneration of axon and myelin, such as swelling and waving, were observed in survivors of more than 8 hours. Retraction balls appeared in survivors of more than 1 days. In longer term survivors, such as 3 or 5 months, breakdown of myelin and fat-granule cells were observed. In addition, retraction balls were also found. Immunohistochemical staining of 200 kD neurofilament was a very useful method to examine axonal changes, because antisera is specific for degenerative neurofilaments. In our study, all cases which had pathological findings of diffuse axonal injury (DAI) were associated with focal head injuries. From the immunohistochemical staining of neurons in the hippocampus, it was suggested that neurons in the hippocampus were injured by diffuse brain damage. Furthermore, repairing and protective mechanisms occurred especially from CA2 to CA4. It was considered that neuronal damage in diffuse brain injury was elucidated not only morphologically but also functionally. Therefore, in cases of suspected diffuse brain damage, it is recommended to examine the neuronal changes in addition to observing the findings of diffuse axonal injury. Immunohistochemical staining of the carotid body is potentially very useful for necropsy diagnosis, since it provides a method to detect evidence of mechanical asphyxia in suspected cases of manual and/or ligature strangulation.

Biomarkers↗
PubMed1997

Determination of 8-hydroxy-deoxyguanosine formation in rat organs: assessment of paraquat-evoked oxidative DNA damage.

Paraquat has previously been shown to cause the oxidative damage to DNA in variety of cells and tissues. However, although paraquat-evoked strand breaks has been extensively studied to assess the DNA damage, the effect of paraquat on base modifications, another marker for the oxidative damage, has not yet been investigated. To further characterize paraquat-evoked DNA damage, the effect of paraquat on 8-hydroxy-deoxyguanosine (8-OH-dG) formation in various rat organs was examined. Paraquat markedly increased 8-OH-dG contents in various organs, particularly in brain, lung and heart, and this increase reached the maximum levels at 5 days after the drug administration. In contrast, the formation of 8-hydroxy-guanosine (8-OH-G), a marker for the oxidative damage to RNA, was not significantly affected by paraquat. These results indicate that paraquat causes base modifications as well as strand breaks as a consequence of the oxidative damage to DNA.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Experimental studies on effects of barbiturate on electroencephalogram and auditory brain-stem responses.

The effects of pentobarbital on electroencephalogram (EEG) and auditory brain-stem response (ABR) were evaluated in 13 Japanese white male rabbits, divided into two groups, 7 and 6, respectively. After baseline evoked responses were obtained, pentobarbital was infused intravenously at 60 mg/kg/h in both groups. EEGs and ABR were recorded with 15 min intervals. When the blood concentration of pentobarbital reached therapeutic levels (2.0-5.0 mg/dL), cortical and hippocampal EEGs became isoelectric. Although the appearance of ABR waves was significantly delayed, each wave was clearly observed in spite of isoelectric EEG levels. The rabbits in one group were killed at that time, and their brains were removed to determine the concentration of pentobarbital in the brain tissue. In another group, pentobarbital was additionally infused at the rate of 120 mg/kg/h. Although the waves (II-IV) of the ABR gradually disappeared with increasing dosage, wave I was present until just prior to cardiac arrest. It is considered that the persistency of ABR at high doses of barbiturates is characteristic of patients in deep barbiturate coma. Therefore, at the diagnosis of brain death, there is no necessity to consider the half-life of the barbiturate, even if an excessive amount of barbiturate remains in the brain. In this study, pentobarbital concentration in the brain was nearly equal to the concentration in the blood. However, it is estimated that a large amount of barbiturate is accumulated in the brain of a patient after brain death because the blood flow in the brain is stagnant.

Animals↗
PubMed1993

Comparison of postmortem autolysis in cardiac and skeletal muscle.

To understand the mechanism in postmortem autolysis better, processes in the postmortem degradation of myofibril proteins in the presence of protease inhibitors were studied. Male Wistar rats were given injections of the carboxyl-, thiol-, and serine-protease inhibitors, pepstatin, Ep-475[L-transepoxysuccinyl-leucylamide(3-methyl) butane; E-64-C], and chymostatin, via the femoral vein. Control rats were similarly treated with saline. Then, myofibril proteins were isolated from their cardiac and femoral muscles and from those of control animals at various times after death, and degradation of these myofibril proteins with time was examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In cardiac muscle, alpha-actinin was degraded rapidly, followed by the heavy chain of myosin and light chain of myosin (L2). Actin and the light chain of myosin (L1) were degraded slowly. the degradations of the heavy chain of myosin, alpha-actinin, tropomyosin and L2 after 14 days were not inhibited by pepstatin, but were inhibited by Ep-475 and chymostatin. In skeletal muscle, L1 and L2 were degraded rapidly, followed by the heavy chain of myosin and alpha-actinin. Actin was degraded slowly and was still unchanged 2 weeks after death. The degradations of protein components were inhibited by pepstatin, Ep-475 and chymostatin. These results indicated that after death the components of myofibrils are degraded by various proteases at various rates depending on their properties or structures. This degradation is fundamentally the same in cardiac and skeletal muscles, but inhibitors have somewhat different effects on the postmortem degradation processes after death in the two types of muscle.

Animals↗
PubMed1990

Electroencephalographical analysis of acute paraquat poisoning.

The disturbances in the central nervous system of rabbits induced by gramoxon poisoning were studied by examination of subcortical electroencephalograms (EEGs) and power spectral analysis of EEGs. The following results were obtained. Administration of the fatal gramoxon (2.0 ml/kg i.p.) resulted in increases of slow frequency discharges from the reticular formation (RF), and from the hippocampus (Hpc) and sensorimotor cortex (Cm) after about 5 minutes and 20 minutes, respectively, detected by power-spectrum array. After about 30 to 40 minutes, the discharges from the Cm changed to rapid frequency discharges. The discharges from the Hpc and Cm decreased after about 50 to 60 minutes, and increased again in the agonal stage, and then seizure discharges developed. Soon after administration of gramoxon solution, the heart rate and respiratory rate increased and the PCO2, base excess (BE) and [HCO3-] decreased transiently. These findings indicate a shift to acute respiratory alkalosis and thereafter a shift to metabolic acidosis. Subsequently, the blood pressure, heart rate, respiratory rate, pH, BE and [HCO3-] decreased and the PCO2 increased. These findings indicate a shift to respiratory and metabolic acidosis. After about 70 minutes, the EEGs from all leads became almost flat, respiration ceased, and the blood pressure decreased to zero. After administration of gramoxon solution, the paraquat concentration in the blood increased rapidly. These results suggest that rapid increase in the paraquat concentration in the blood after gramoxon administration affects the central nervous system from an early stage.

Acid-Base Equilibrium↗
PubMed1989

Electroencephalographical analysis of acute drug intoxication--SS Bron solution-W.

Disturbances of the central nervous system due to abuse of SS Bron solution-W (B-solution), an antitussive and expectorant containing dihydrocodeine and other constituents, were studied in rabbits. Animals were given 20 ml/kg of B-solution orally at 4 hour intervals for 8 hours or more, and changes in the electroencephalograms (EEGs) from the reticular formation(RF), hippocampus(Hpc) and sensorimotor cortex(Cm) were examined. The following results were obtained. About 3 hours after administration of B-solution, the EEG from the Hpc showed low voltage, slow wave, the heart rate decreased rapidly, and the respiratory rate increased. After about 7 to 7.5 hours, the EEG from the Cm showed slow wave hypersynchrony and stimulation of the RF with square pulses of 2.0 V induced slight arousal reactions in the Cm and Hpc. The blood pressure and respiratory rate decreased, and ECG changes indicated atrial flutter-fibrillation and ventricular tachycardia. Power-spectrum array analysis indicated increase of slow frequency discharges in the EEGs from all regions. The slow wave hypersynchrony of the EEG from the Cm and slow wave, low voltage of the EEG from the Hpc seemed to be associated with hallucination and delusion.

Animals↗
PubMed1986

Fluidity of cadaveric blood after sudden death: Part III. Acid-base balance and fibrinolysis.

In rats, fibrinolytic activity and acidosis increased rapidly after death. Postmortem fibrinolysis and the pH, base excess (BE), and [HCO3-] levels were affected by the method of sacrifice: the lower the pH, BE, and [HCO3-] levels, the higher the fibrinolytic activity. Conversely, in experiments using the vascular perfusion technique, low pH, BE, and [HCO3-] levels of the perfusate induced abundant release of plasminogen activator from the vascular wall.

Acid-Base Equilibrium↗
PubMed1986

Experimental studies on death by fire in automobiles and exhaust gas poisoning.

Studies were made on the acid-base balance, blood gases, and carbon monoxide (CO), cyanide, and sulfur dioxide concentrations in the blood of albino rabbits that died from automobile exhaust gas poisoning (group I) or fires in cars (complete combustion, group II; incomplete combustion, group III). In group I, the temperature and CO concentration increased gradually to 35 degrees C and 5.2% in 70 min. The animals died after 9 min, when the values were 20 degrees C and 5.2%, respectively. In group II the animals died after 9 min, when the values were 55 degrees C and 1.95%, respectively. In group III, the temperature was very high (870 degrees C), but the CO concentration was not (0.6-1.3%) after 4 min. The animals died after 5 min. In all experimental groups, marked acidosis and hypoxemia were seen, but the CO2 tension (PCO2) was high, in contrast to previous studies on pure CO poisoning. In group I, the level of carboxyhemoglobin (CO-Hb) was significantly higher (91.2 +/- 3.4% in arterial blood, 87.5 +/- 8.1% in venous blood; p less than 0.01) than in groups II and III. Although the O2 tensions of venous and arterial blood (PvO2, PaO2) were very low, that of arterial blood was higher, suggesting that O2 was still being utilized in the tissues at the time of death. In group II, CO-Hb was high (57.7 +/- 16.0% in arterial blood, 61.2 +/- 20.6% in venous blood) and the acid-base balance indicated marked acidosis. In group III, the CO-Hb, PCO2 and cyanide levels in the blood were very high.(ABSTRACT TRUNCATED AT 250 WORDS)

Accidents, Traffic↗