Chromosomal duplication and the emergence of the adaptive immune system.
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Animals↗
Biomedical subjects
N Takahata
Publications and source records attributed to N Takahata.
Snake coiled fibres in rat soleus muscle in chloroquine induced myopathy share immunohistochemical characteristics with amyloid depositions in Alzheimer's disease brain tissue.
Pathological and immunopathological studies were carried out on snake coiled fibres (SCF) which occurred in affected soleus muscle in chloroquine treated rats. The SCF began to appear in denervated soleus muscle by 8 days after chloroquine injection. By day 14, typical SCF were observed with an unusual swirling pattern of the myofibrils, presenting a bizarre appearance. By day 21 or later, the SCF became less remarkable, and were fragmented and broken apart to form large vacuoles. Immunopathological studies demonstrated that the amyloid beta (A beta) and N and C-terminal regions of amyloid precursor protein (APP), and the amyloid associated proteins tested, apolipoprotein E (apoE), SP-40,40, alpha 1-antichymotrypsin (alpha 1-ACT), and ubiquitin, which are known to be components of amyloid depositions found in Alzheimer's disease (AD) affected brains, were present in the SCF. ApoE, SP-40,40, alpha 1-ACT, and ubiquitin are induced following certain cell challenges (e.g. heat shock, various drugs and injury). The significance of APP, A beta, and amyloid associated proteins are discussed in respect to snake coiled fibre formations in chloroquine rat myopathy and in the amyloidogenesis of AD.
Alzheimer Disease↗
[Recent advances in Alzheimer's disease research--amyloid precursor protein trafficking, processing, and mutations in Alzheimer's disease linked genes].
Recent advances in Alzheimer's disease (AD) research were briefly reviewed. The AD affected brain is characterized by numerous amyloid plaques, neurofibrillary tangles, and neuronal losses. The amyloid is composed of amyloid beta peptide (A beta), a 40-42 amino acid fragment of large membrane protein, amyloid precursor protein (APP). A beta is cleaved by proteolytic enzyme, beta, and gamma secretase yielding N and C terminus of the A beta. Considerable effort has been directed to identify these enzymes, and to find the intracellular compartments where A beta is generated. Endosome, lysosomal pathway, or related acidic compartment is one of the candidates for A beta generation. Biochemical and immunopathological data implicate that A beta 42 is more important than A beta 40 in the pathogenesis of AD. On the other hand, many missence mutations in APP gene and other gene, S182 (presenilin1), and STM2 (presenilin2) were identified in familial AD. Neuropathology in these FAD appear basically quite similar, and AD is regarded as cerebral A beta amyloidosis. It was established that missense mutations in the genes encoding APP, presenilin1, and presenilin2, all treated APP processing, leading to increased production of A beta 42. AD amyloid is composed of many other proteins than A beta, designated as amyloid associated proteins, It should be a key issue to determine the precise mechanism, by which A beta is generated, and the alteration of APP trafficking resulting in increased A beta 42 generation with these mutant genes.
Alzheimer Disease↗
[The statistics of inpatients at Department of Neuropsychiatry in Sapporo Medical University Hospital (October, 1983 - March, 1996)].
The role of university hospitals should be re-examined considering the recent situation in psychiatrical health care. In this report, we investigated inpatients of neuropsychiatry in Sapporo Medical University Hospital from various aspects. Statistics were gathered on 1) age and sex, 2) address, 3) admission form based on the mental health law, 4) the number of admissions and discharges per year, 5) hospitalization term, 6) diagnostic group, 7) diagnosis, 8) rates of re-admission and re-admission within three months, 9) age and sex of schizophrenia patients and 10) age and sex of patients with affective disorders from October 31, 1983 to March 31, 1996. In our hospital, the rates of the inpatients with dementia and personality disorders are higher than those in other university hospitals. The reason for the high rate of personality disorders is elusive; however, most of the dementia patients enter our hospital mainly because we concentrate on a special research project about dementia. These data indicate that a specific function is required in university hospitals. In recent years, however, the surroundings of people with mental disorders have become more complicated, and the services for them have become diversified. However, it is very difficult for university hospitals to provide them with all such services, as the hospitals fulfill just one specialized function among the necessary services.
Adolescent↗
[The disturbance of reversible operation in space in the early stage of Alzheimer's disease].
Constructional apraxia is one of the neuropsychological findings frequently observed in the early stage of the Alzheimer's disease, which may result from the visuo-spatial disturbances. The visual space consists of a variety of visual information processing, viewer-centered coordinate system, objects-centered coordinate system, integration of both coordinate systems, and verifying visual representation with the knowledge in the memory. The reversible operation in space, or mental rotation appears to play an important role in visuo-spatial functions, which refers to the operation of the visual representation at one orientation in viewer-centered coordinate system to construct the representation in object-centered coordinate system so that one can look like if it were presented at another orientation. To the present, little is known about reversible operation or mental rotation in patients with Alzheimer's disease. In this present paper, we attempted to investigate the ability of reversible operations in space so as to understand the mechanisms underlying constructional apraxia, or visuo-spatial disturbances in the early stage of Alzheimer's disease. The subjects were 12 patients with Alzheimer's disease in early stage (AD group), 12 patients with multi-infarcts dementia as disease control (MID group), 12 age matched persons as healthy control (HC group). In perspective taking tasks, that requires the subjects to imagine the spatial arrangement of the objects at the different view points from the subjects' one, AD group showed more severe deficits than MID group and HC group. Moreover, in a task that the subjects were asked to assume the photo-angle of the photograph taken of the model which was in front of them, AD group was imparied compared to the control groups. These disturbances were closely associated with deficits in Block Design test of WAIS. These results clearly demonstrate that the patients with Alzheimer's disease have disturbance in reversible operation in space and that the disturbance may be responsible for visuo-spatial dysfunctions, not only the constructional apraxia, but also a variety of performance deficits in the early stage of Alzheimer's disease.
Aged↗
Reduced immunoreactivity of adenylyl cyclase in dementia of the Alzheimer type.
The amounts of three adenylyl cyclase (AC) subtypes in membranes from brain obtained post-mortem from patients with dementia of Alzheimer type (DAT) and controls were studied by Western blotting using polyclonal antibodies. AC subtypes were characterized by preabsorption by complementary peptides, species difference, tissue distribution and by using AC-VI-transfected cells. Immunoreactivities of AC-I and AC-II subtypes, which are predominant in brain tissue were decreased 40.5% (p < 0.02) and 52.0% (p < 0.02), respectively in DAT compared with controls. No significant difference in immunoreactivity of AC-V/VI subtypes distributed in various other tissues was observed. Our results are the first to indicate that reduced levels of brain-specific AC subtypes occur in DAT.
Adenylyl Cyclases↗
Effects of ceruletide on perioral movements and the dopamine receptor-adenylate cyclase system in rats chronically treated with fluphenazine.
The effects of repeated administration of ceruletide (100 micrograms/kg/perday, i.p. for 3 days) on perioral movements and the striatal dopamine receptor adenylate cyclase system were examined in rats chronically treated with fluphenazine enanthate (FPZ) (25 mg/kg i.m. every 3 weeks for 30 weeks) and sesame oil-treated (control) rats. After the tenth injection of fluphenazine, the rats started to display five types of perioral movements (teeth chattering, chewing, tongue protrusion, mouth opening and perioral tremors). Moreover, increases in SCH23390 binding and spiperone binding to striatal membranes, were found in the FPZ-treated rats. Furthermore, dopamine receptor-coupled adenylate cyclase activity was potentiated in striatal membranes. High amplitude EMG discharges (8-10 Hz), recorded from the masseter in the FPZ-treated rats occurred concurrently with perioral tremors. Repeated ceruletide (CLT) injections abolished perioral movements, and reversed both the elevated SCH23390 binding and the dopamine stimulated adenylate cyclase (AC) activity to the control level. The effect of CLT on perioral movements, D1 receptors and dopamine-stimulated AC activity continued for 6 days after the final CLT injection. These findings suggest that systemically administered CLT affects the D1 receptor adenylate cyclase system and that an increase of the D1 receptor mechanism may play an important role in the pathogenesis of tardive dyskinesia.
Adenylyl Cyclases↗
Diazepam physical dependence and withdrawal in rats is associated with alteration in GABAA receptor function.
Alteration in the function of the GABAA receptor complex and its relation to changes in withdrawal signs in diazepam (DZP)-dependent rats were studied. Physical dependence on DZP was induced in male F344 rats by using the drug-admixed food method. After cessation of treatment, withdrawal signs such as spontaneous convulsions were observed and withdrawal scores were maximal at 39 approximately 45 hr after the DZP withdrawal. Furthermore, these withdrawal signs almost disappeared by 159 approximately 168 hr after the DZP withdrawal. GABA-stimulated 36Cl- influx into cerebral cortical membrane vesicles was significantly decreased in rats 0 hr after DZP withdrawal and significantly increased in rats 42 hr after DZP withdrawal compared with control rats Flunitrazepam (FZ)-induced potentiation and an antagonistic effect of Ro 15-1788 on GABA-stimulated 36Cl- influx were observed in control rats. No FZ-potentiated GABA-stimulated 36Cl- influx was observed in rats 0 hr after DZP withdrawal: however, such an effect of FZ was recognized in rats 42 hr and 162 hr after DZP withdrawal. No antagonistic effect of Ro15-1788 on the FZ-induced stimulation was recognized in rats 0 hr and 42 hr after DZP withdrawal but was recognized at 162 hr after DZP treatment, although it was not significant. In a [3H]FZ assay of binding to benzodiazepine (BZ) receptors. Bmax values were significantly decreased in rats 0 hr after DZP withdrawal, but increased at 42 hr after DZP withdrawal, compared with control rats Bmax had almost returned to the control level at 162 hr after DZP treatment rats. In conclusion, these results indicate that functional changes in the GABAA/BZ receptor/CI- channel complex, i.e. increased sensitivity in GABAA receptors and impairment in the functional coupling between BZ receptors and GABAA receptors, may possibly be involved in the biochemical mechanism of the severe withdrawal symptoms appearing after chronic treatment with DZP.
Animals↗
Neutral theory of molecular evolution.
DNA sequence data are generally interpreted as favouring Kimura's neutral theory but not without dissent and often with a great deal of controversy with respect to molecular clocks, DNA polymorphism, adaptive evolution, and gene genealogy. Although the theory serves as a guiding principle, many issues concerning mutation, recombination, and selection remain unsettled. Of particular importance is the need for more knowledge about the function and structure of molecules.
Adaptation, Biological↗
Changes in GABAA receptor function and cross-tolerance to ethanol in diazepam-dependent rats.
Changes in gamma-aminobutyric acidA (GABAA) receptor function and their relation to cross-tolerance to ethanol (EtOH) were studied in diazepam (DZP)-dependent rats. Physical dependence on DZP was induced in male Fischer rats by using the drug-admixed food method. The 38Cl- influx into cerebral cortical synaptoneurosomes induced by 10 microM GABA in DZP-withdrawn rats was significantly increased, compared with control and DZP-tolerant rats. Although enhancement of GABA-dependent 38Cl- influx by the addition of EtOH and flunitrazepam (FZ) was recognized in the control, there was no such effect of EtOH or FZ in the DZP-tolerant animals. On the other hand, GABA-dependent 38Cl- influx was enhanced by FZ in the withdrawn group. The addition of picrotoxin and bicuculline inhibited GABA-dependent 38Cl- influx in each group. The stimulatory effect of FZ on GABA-dependent 38Cl- influx was inhibited by the addition of Ro 15-1788 in the control group. However, such an inhibitory effect was not observed in the withdrawn group. The antagonistic effect of Ro 15-4513 on EtOH stimulation of GABA-dependent 38Cl- influx observed in the control was not recognized in the withdrawn group. In a [3H]FZ assay of binding to benzodiazepine (BZ) receptors, Bmax values were significantly increased in DZP-withdrawn animals, but decreased in the DZP-tolerant group, compared with the control. When [3H]muscimol binding was examined, the Kd of high-affinity sites of the GABAA receptor in withdrawn rats was significantly lower than in the control. In low-affinity binding sites, the values of Kd and Bmax were significantly decreased, compared with those in the control. The present study indicates that GABAergic transmission involving the regulation of GABA-dependent chloride channels is altered in DZP-dependent rats. Alterations of the GABAA/BZ/chloride channel complex function may be related to the cross-tolerance between BZ and EtOH.
Alcoholic Intoxication↗
[A case of volatile solvent psychosis accompanied with multiple neurological and psychological symptoms].
A case of psychosis accompanied with variable symptoms induced by chronic volatile solvent inhalation is reported in this study. The patient was a 27-year-old male who had abused volatile solvents for 15 years, and was sent to the hospital because of a tonic-clonic seizure. Severe psychomotor excitement was observed on the first day and the 7th day after admission. After 10 days of admission, we observed visual transformation and hyperthermia, which suggested acute toxic symptoms due to a volatile solvent. Furthermore, symptoms such as incoherence, delusions of persecution, and catalepsy were also observed in this case. There have been few reports of multiple neurological and mental symptoms appearing in cases of volatile solvent psychosis. Although we sometimes experience cases of solvent abuse with acute mental symptoms and recurrent excitement after sedation, such symptoms are not always observed because of flashback in the strict sense. Therefore, careful early treatment should be employed to prevent 'secondary excitement'.
Adult↗
[Changes in platelet adenylyl cyclase system in alcoholics].
Platelet GTP binding protein (G protein) in 25 alcoholics with a first-degree alcoholic relative (family history positive alcoholic; FHP), in 25 alcoholics without alcoholic relatives (family history negative alcoholic; FHN) and in 25 controls without alcoholic relatives was investigated to determine whether this protein is a trait marker for alcoholism. The alcoholic subjects met DSM III-R criteria for alcohol dependence and had been abstinent from alcohol for at least one year. Lowered platelet guanine nucleotide (GppNHp)-stimulated adenylyl cyclase (AC) activity and reduced sensitivity of AC to ethanol were recognized in FHP but not in FHN. Remarkable reduction in ethanol enhancement of functional photoaffinity GTP (azidoanilido GTP; AAGTP) binding to Gs alpha and Gi alpha in platelet membrane was observed in FHP but not in FHN. A quantitative reduction in Gs alpha and GsH alpha (high molecular weight Gs alpha) levels as assessed by immunoblotting was seen in platelet membrane from FHP but not from FHN. These results indicate that the characteristic of platelet G protein may be used as a trait marker for alcoholism.
Adenylyl Cyclases↗
[Closing-in phenomena observed in patients with Alzheimer's disease--analysis of drawing behavior and eye movements].
'Closing-in' symptom is defined as a tendency to close-in on the model while performing constructive tasks. This unique symptom is one of the constructional apraxia often observed in Alzheimer's disease (AD), which is considered to be involved in visuospatial dysfunctions. However, little is known about the nature of the symptom and pathophysiology underlying the symptom. In this study, we examined drawing behavior, eye movements of AD (n = 19), multi-infarct dementia (n = 8) and age matched healthy subjects (n = 10). 1) In AD, contrary to age matched healthy subjects, the patients drew slowly with apparent difficulty and drawing behavior was disorganized. The copied figures were incomplete and often fragmented. The spatial relationships of the parts were lost each other during copying a Necker's cube. 2) The characteristic eye movements were observed in AD patients with apraxia, and closing-in symptom. These were consisted of gaze apraxia, and disorders of visual attention appeared similar to Bàlint's syndrome. 3) The eye movements of the AD patients with closing-in symptoms were classified into wandering of fixation, locking of fixation, and mixed types. The 'closing-in' symptoms in copied figures were classified into three types, overlap, adherent, and near types. Then, the wandering type was seen both in near and adherent types, whereas the fixation type was only found in the overlap type. 4) SPECTs showed reduced RI activities in the parieto-occipital and in the frontal regions of AD patients with apraxia and closing-in symptoms. Our results suggest that AD patients may have a difficulty to create abstract space from concrete space. This may also imply regression to a primitive undifferentiated stage where gnostic and practic behavior is not differentiated in terms of space appreciation.
Aged↗
[Aging brains and the dementias].
Dementia has been defined generally as an acquired persistent impairment of intellectual function caused by organic brain diseases. The rapidly increasing incidence of dementias has been claimed on the basis of epidemic studies in Japan as well as in Western developed countries. These observations are justified by the facts that most dementias are found in people over the age of 65 years, and that the elderly population is increasing rapidly resulting in both absolute numbers and percentage of the population. In Japan, it is estimated that 1.5 million of demented persons are present. The purpose of this paper is to describe clinical manifestations and morphological alterations of aged and demented individuals, diagnostic process to differential diagnosis to provide knowledgeable approach to management, and adequate care of the demented individuals. In aged brain, there are a variety of morphological changes. Some of these are usually observed in aged brains; atrophy of the brains, loss of neurons, accumulations of lipofuscin. Others observed in pathologically aged brains, or accelerated aging brains are Alzheimer's neurofibrillary tangles, senile plaques, and granulovacuolar degeneration. Psychiatric manifestations associated with aging and dementing diseases are described. It should be realized that clinical manifestations of the demented reflect primarily the topography of the organic lesions in the brain, and functional alterations, and are influenced by psychological and socio-environmental factors.
Aging↗
[Biological characteristics of amyloid precursor protein and Alzheimer's disease].
Recent advances in Alzheimer's disease (AD) research were briefly reviewed. AD is the most common cause of progressive intellectual decline in the aged in the Western world and also in Japan. The AD-affected brain is characterized by numerous amyloid plaques, neurofibrillary tangles, and neuronal losses. The amyloid deposition is considered to be more important because it appears first, and is followed by NFTs. The amyloid is composed of amyloid beta peptide (Abeta), a 40 approximately 42 amino acid fragment of the large membrane protein, amyloid precursor protein (APP). Abeta is cleaved by the proteolytic enzymes, beta, and gamma secretase. Considerable effort has been directed to identify these enzymes, and to find the intracellular compartments where Abeta is generated. The lysosome, or related acidic compartment is one of the candidates. The N and C terminis of the Abeta is known to vary slightly. Biochemical and immunopathological studies implicate that Abeta42 is more important than Abeta40 in the pathogenesis of AD. On the other hand, many missense mutations in APP gene and other genes, e.g. S182, and STM 2 have been identified in familial AD. Neuropathologically, AD is regarded as cerebral Abeta amyloidosis. The AD amyloid is composed of many proteins other than Abeta, designated as amyloid associated proteins. These proteins may play important roles in amyloid formation, since Abeta itself is soluble. Transgenic mice and chloroquine myopathy rat are available as animal models for AD. Elucidation of the roles of these missense mutations, and amyloid associated proteins in the cascade of AD, may provide a breakthrough to therapeutics for AD.
Alzheimer Disease↗
[Relationship between SPECT and pathological alterations in Alzheimer's disease--a study of a case with left-hemisphere dominant lesions].
123I-IMP SPECT (SPECT) has been widely used in clinical neuropsychiatry for establishing the clinical diagnosis, and evaluating the course of the disease. However, little is known about the significance of alterations in SPECT. In this paper, we present comparative study between alterations in SPECT and neuropathological findings in the case of Alzheimer's disease (AD). The patient, a 59-year-old female, began to show memory disturbance and the left hemisphere disturbances, non-fluent aphasia, but right hemisphere disturbances, constructional apraxia, visuo-spatial dysfunctions were not notable at the early stage. The neuroimaging also revealed left-side dominant cerebral atrophy in MRI and left-side dominant hypoactive regions in SPECT (especially in parietal lobe). Memory disturbance and non-fluent aphasia gradually progressed after admission. Then, mirror phenomenon and Bálint's syndrome appeared at the age of 63 years. In the advanced stage, hypoactive regions in SPECT were expanded into temporal and frontal areas. The laterality observed at the early stage became unremarkable. The patient died from heart failure at 64 years. Pathological diagnosis was AD. Eleven ROI (region of interests) were determined on each hemisphere in transverse SPECT image. We calculated ROI% (each ROI count/ROI count at central cerebellum). Neuronal cell count (NCC) and amyloid beta protein deposited areas (BDA) were estimated using 3 serial sections stained with Nissl's method and immunostained for amyloid using monoclonal antibody raised against synthetic A beta, mcAb 90/12. Digitized images based on photographs were analyzed with NIH-image 1.45. NCC decreased in number in frontal, temporal, and parietal lobes. Significant asymmetrical reduction of NCC (lt. < rt.) was observed in orbital, superior temporal and angular gyri (p < 0.01). BDA in superior parietal lobule, superior temporal gyrus and superior, middle, inferior frontal gyri were larger than those in precentral gyrus and visual cortex. Asymmetry of BDA (lt. > rt.) was significant in middle temporal gyrus (p < 0.01). ROI% at the early stage was correlated with corresponding NCC (r = 0.49, p < 0.05) and BDA (r = -0.55, p < 0.01), but at the advanced stage was not significantly correlated with corresponding NCC (r = 0.26) and BDA (r = -0.20). It is evident that SPECT shows good correlation with clinical features and pathological alterations during the course of AD. Our observations imply that the changes in SPECT usually precede the appearance of the clinical symptoms. SPECT is very sensitive in detecting the functional decline in certain regions of the CNS. In the case of AD, the hypoactive regions in SPECT at the early stage may indicate functional decline of the neuronal cells, and at the advanced stage, these may indicate the degree of pathological changes, especially neuronal loss and amyloid beta protein deposition.
Alzheimer Disease↗
[A case of amotivational syndrome as a residual symptom after methamphetamine abuse].
We had a case of psychiatric evidence who was homeless and exhibited severe abulia and autism on detention for assault and battery. It was thought that his past history of chronic methamphetamine abuse and his familial history played some part in his showing such symptoms. His mother was alcohol dependent. He was an ACOA (adult child of alcoholics), which might have led to his chronic abuse of methamphetamine. On the other hand, it is well-known fact that the amotivational syndrome induced by marijuana abuse is typified by a diminution of ambition, productivity, and motivation. However, it has been contended that amotivational syndrome is induced not only by marijuana but also by amphetamine and its analogs, cocaine and volatile solvents. Since we positively support this view, we diagnosed the case as amotivational syndrome after long-term methamphetamine abuse. This was also a rare criminal case of amotivational state without hallucinations and delusions after methamphetamine abuse. We suggested that the crime committed in this case was closely related to crime induced by economic problems in residual states of schizophrenic offenders. This could be a case of both ACOA and methamphetamine dependence. There were unresolved alcohol- and drug-related problems in this case. Therefore, careful early intervention in a crisis, cooperation with the authorities and the institutions concerned, and comprehensive rehabilitation should be employed to resolve such alcohol- and drug-related problems.
Adult↗
Alteration of glutamyltranspeptidase binding proteins in postmortem brains of heroin addicts.
Glutamyltranspeptidase binding (G) proteins play an important role in intracellular signal transduction downstream from many receptors, including opioid receptors. Moreover, it was recently reported that the beta-subunits of G proteins, in addition to the alpha-subunits, regulate effector pathways. In this study, membrane G protein immunoreactivity was estimated by Western blotting with polyclonal antibodies (RM/1, AS/7, GC/2, QL, and SW/1) against specific G proteins (G alpha S, G alpha i-1,2, G alpha o, G alpha q, and G beta, respectively) in postmortem temporal cortex obtained from 6 heroin addicts and 6 control subjects without a history of drug abuse. Immunoreactivities of the G beta-subunit increased significantly (p < 0.05) in heroin addicts, compared with controls, and that of G alpha i-1,2 tended to increase in heroin addicts. Present findings suggest that the alterations in G protein-mediated signal transduction may be involved in the mechanism of opiate addiction.
Adult↗