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A microfluidic chip is a microscale chemical laboratory, and a glass substrate is used for the material of the chip. Micromachining is an effective process to produce a 3D micropattern on such a glass plate. In the micromachining process, however, the positioning of the contact point of the tool edge on the surface of the glass workpiece is technically difficult. In this study, a new automated positioning system for the microtool edge is developed using the total internal reflection of a laser beam. The developed system is also applied to detect the change in the cutting mode from ductile to brittle.

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.

To find the residual effects of long term exposure to mercury vapour, neurobehavioural tests were given to ex-mercury miners about 18 years after the end of mercury exposure. Seventy six male ex-mercury miners who had been exposed to high concentrations of mercury vapour (over 1.0 mg/m3) and with a history of mercury intoxication were compared with controls matched for age (within 3 years), sex, and education. Although the extent of the workers' symptoms caused by mercury poisoning, termed erethismus merculialis, decreased considerably after the end of exposure, matched paired comparison showed that performances of motor coordination, simple reaction time, and short term memory had deteriorated significantly in the exposed group. Multiple linear regression analysis of exposure variables with neurological examination measures showed positive correlations between poorer neurological performance and variables related to mercury exposure. Thus the duration of exposure correlated with poorer performance of hand-eye coordination, tapping, and a colour card reading test. Job categories classified by exposure to mercury also had a significant negative correlation with these performances. The period of years after the end of exposure had a significant correlation with better performance of reaction time and digit span. On the other hand, the history of intoxication itself had no significant correlation with any of the current neurobehavioural performances. These results suggest that there are slight but persistent effects on neurobehavioural function, especially on motor coordination, among mercury miners even more than 10 years after the end of exposure.

In order to determine if there are any residual effects of long-term exposure to mercury vapor, neurobehavioral tests were given to ex-mercury miners about 18 years after the cessation of mercury exposure. Seventy-six male ex-mercury miners who had been exposed to relatively high concentrations of mercury vapor (over 1.0 mg/m 3 ) and with a past history of mercury intoxication were compared to age (±3 years)-, sex-, and years of education-matched controls. Although the extent of the workers" symptoms caused by mercury poisoning, termed erethismus merculialis, markedly decreased after the cessation of exposure, the prevalence of neurological symptoms (such as hand tremors, headaches, and slurred speech) and symptoms of senility (such as low-back pain, loss of sexual desire) in the exminers was significantly higher than those in the controls. Matched-pair analysis showed that performances of motor coordination, Simple reaction time, and Short-term memory in the exminers were significantly deteriorated compared to those of controls. There are slight but persistent effects on neurobehavioral function, especially on motor coordination function, among mercury miners more than 10 years after the cessation of exposure.

We carried out a survey on the cases of motor neuron disease (MND) occurring in Hokkaido between 1980 and 1989 in order to establish whether there is a relationship between MND and poliomyelitis. Hokkaido, the northern-most island of Japan, was one of the most affected areas during the poliomyelitis epidemic of the late 1940s to 1950s. We ascertained 389 cases of MND for these 10 years and 2,171 cases of paralytic poliomyelitis for the period 1949–1958, and analysed their geographic distributions. No significant correlation was found between MND and poliomyelitis in their geographic distributions.

The sampling variance of nucleotide diversity or branch length in a phylogenetic tree constructed by any distance method provides a criterion to judge whether a deduction or an inference made from data is statistically significant. However, computation of the sampling variance is usually tedious, particularly when the number of operational taxonomic units (OTUs) or DNA sequences is large, and must rely on computers. Recently, Nei and Jin (1989) have developed a computer algorithm, but it can be applied only to a simple substitution model. In this paper, we derive simple formulas for the minimum and maximum values of the sampling variance, which are independent of underlying substitution models. Application of these formulas demonstrates satisfactorily accurate estimates of the sampling variances and therefore their practical use.

To study rapidly evolving male specific Y (MSY) genes we retrieved and analyzed nine such genes. VCY, HSFY and RBMY were found to have functional X gametologs, but the rest did not. Using chimpanzee orthologs for XKRY, CDY, HSFY, PRY, and TSPY, the average silent substitution is estimated as 0.017 +/- 0.006/site and the substitution rate is 1.42 x 10(-9)/site/year. Except for VCY, all other loci possess two or more pseudogenes on the Y chromosome. Sequence differences from functional genes show that BPY2, DAZ, XKRY, and RBMY each have one pseudogene for each one that is human specific, while others were generated well before the human-chimpanzee split, by means of duplication, retro-transposition or translocation. Some functional MSY gene duplication of VCY, CDY and HSFY, as well as X-linked VCX and HSFX duplication, occurred in the lineage leading to humans; these duplicates have accumulated nucleotide substitutions that permit their identification.

For the purpose of revealing higher brain functions of visual and spatial cognition, the authors investigated the neuronal responses to visual stimulation and eye position as the spatial information, through the use of a 37-channel SQUID magnetometer. The main magnetic field responses were observed at 90-120 (M120), 120-170 (M170) and 180-220 (M220) msec after LED onset. The magnetic field responses of M170 was stable and observed in all subjects, and almost the same in 1 and 2 experiments. The estimated current dipole source of these magnetic field responses of M170 was located at deep PAC, near the intraparietal sulcus.

1. Antidepressants have been used clinically for many years; however, the neurochemical mechanism for their therapeutic effect has not been clarified yet. Recent reports indicate that chronic antidepressant treatment directly affects the postsynaptic membrane to increase the coupling between the stimulatory GTP-binding (G) protein, Gs, and adenylyl cyclase. Tubulin, a cytoskeletal element, is involved in the stimulatory and inhibitory regulation of adenylyl cyclase in rat cerebral cortex via direct transfer of GTP to G proteins. In this study, we investigated whether the functional change of the adenylyl cyclase system caused by chronic antidepressant treatment involves an alteration of tubulin function in the regulation of adenylyl cyclase activity. 2. Male Sprague-Dawley rats were treated once daily with amitriptyline or saline by intraperitoneal injection (10 mg/kg) for 21 days, and their cerebral cortex membranes and GppNHp-liganded tubulin (tubulin-GppNHp) were prepared for what. 3. GppNHp-stimulated adenylyl cyclase activity in cortex membranes from amitriptyline-treated rats was significantly higher than that in control membranes. Furthermore, tubulin-GppNHp prepared from amitriptyline-treated rats was more potent than that from control rats in the stimulation of adenylyl cyclase activity in the cortex membranes of the controls. However, there was no significant difference in manganese-stimulated adenylyl cyclase activity between control and amitriptyline-treated rats. 4. The present results suggest that chronic antidepressant treatment enhances not only the coupling between Gs and the catalytic subunit of adenylyl cyclase but also tubulin interaction with Gs in the cerebral cortex of the rat.

Significant increases were observed in guanylylimidodiphosphate- and fluoride-stimulated adenylyl cyclase activities in synaptic membrane preparations from rat cerebral cortex subsequent to the repeated administration of rolipram and amitriptyline. The potency of GppNHp-dependent inhibition of adenylyl cyclase was decreased by chronic treatment with rolipram but not by amitriptyline treatment. These findings suggest that chronically administered rolipram and amitriptyline share the augmentation of adenylyl cyclase activity by different actions on post-receptor signaling.

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.

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.

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.

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.

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.

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'.

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.

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.

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 (p0.01). 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 (p0.01). ROI% at the early stage was correlated with corresponding NCC (r = 0.49, p0.05) and BDA (r = -0.55, p0.01), 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.

'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.

We studied the differences in alterations of GABAAergic receptor function between pentobarbital (PB)-dependent female Lewis (LEW) and Wistar-Kyoto (WKY) rats. The 36Cl- influx induced by 10 microM GABA in the PB-dependent WKY was significantly lower than that in the control, while there was no significant 36Cl- influx change in both PB-dependent and control LEW. The additions of PB, flunitrazepam (FZ) and ethanol (EtOH) enhanced the GABA-dependent 36Cl- influx in control rats of both strains. However, the enhancements of 36Cl- influx by PB, FZ, EtOH were not recognized in PB-dependent WKY. On the other hand, the enhancement of GABA-dependent 36Cl- influx was observed only with the addition of PB in PB-dependent LEW. The additions of bicuculline (BIC) and picrotoxin (PIC) inhibited GABA-dependent 36Cl- influx in control rats of both strains. However, inhibition of 36Cl- influx by BIC and PIC was not recognized in the PB-dependent WKY. These results suggest that physical dependence on PB in WKY may cause greater functional alterations of the GABA/benzodiazepine receptor complex than those in LEW, and that these changes in this receptor complex may relate to the difference in the development of physical dependence on PB between the two strains.

The case of a chronic alcoholic patient with Wernicke's encephalopathy accompanied by passing blindness is reported and the alcoholic amblyopia is discussed in this study. The patient was a 39 year-old male who had been a heavy drinker for 13 years, and was habitually inebriated for the last one year. Disturbance of consciousness ataxia of gait, nystagmus and blindness were manifested on admission. Decreased level of serum vitamin B1 was also recognized at admission. The symptoms diminished from about a month after admission except for horizontal nystagmus. Since the patient had racket-like scotoma in his central visual field, his blindness was thought to be alcoholic amblyopia. Although alcohol dependence is associated with many physical disabilities, there are few reports about Wernicke's encephalopathy with alcoholic amblyopia. This case demonstrates the importance of careful physical examination for understanding alcohol-related disabilities and alcohol dependence.

In Alzheimer's disease higher brain function disorders such as geographical disorientation, visual agnosia and constructional disability are frequently observed in addition to the progressive memory loss. Visual information processing was studied through newly developed technology, vision analyzer, since visuospatial functions play an important role in the pathophysiology underlying these neuropsychiatric symptoms and dementia itself. We found characteristic findings as to eye movements of focus indicating visual cognitive disorders. Language or language functions, however, are considered to be essentially involved in visuospatial functions. We examined eye movements of patients suffering from Alzheimer's disease (15 cases), MID (5 cases), Parkinson's disease (5 cases) and 10 control subjects during constructional behavior under various conditions in terms of visual information processing. 1. Alzheimer's disease (n = 15): All patients showed constructional disabilities when copying geometrical figures. 1) Three dimensional drawing was possible following verbal instructions in 7 out of 15 patients. 2) Three dimensional drawing was successful when the model figure to be copied was covered in 4 out of these 7 patients. 3) Three dimensional drawing was possible following verbal instruction in a dark room, although they were not so accurate but better than those when copied in 4 out of 7 patients. 4) The analysis of eye movements revealed that typical eye movements were confirmed during copying geometric figures. The distribution of the gazing points of focus, and the average eye movement velocity distribution were also distinctive. But these disorganized eye movements in description of graphic figures following verbal instruction became more similar to those of healthy controls when compared to those in the copying graphic figures. 2. MID (n = 5), Parkinson disease (n = 5), healthy controls (n = 10): 1) No subject showed constructional disability when copying a graphic figure. They were also capable to describe a graphic figure both in the dark and following verbal instruction. 2) No remarkable change was observed in the distribution of the eye movement, or in the average eye movement velocity on these subjects. 3. These results indicate that in an early stage of the patients with Alzheimer's disease, primary or fundamental disorders seem to lay in the verification process of visual information, which results in the difficulties in categorization process of the visual objects. The categorization process is involved with language function, which was preserved in a certain period at an early stage of the disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Publisher Summary The major histocompatibility complex (MHC) is a generic name of a set of clustered loci. MHC genes proper are found in all vertebrates, except jawless fish, but not in invertebrates. Functional MHC molecules bind self and/or foreign peptides and present them to T-cell receptors. Each MHC molecule has two chains, α and β, which form heterodimers with each other. The MHC occupies a chromosomal region 2–4 Mb long. Both the length and the number of genes in the region not only vary from one species to another but also from individual to individual within species. The chapter describes the ways in which the cellular and humoral immune response to MHC alloantigens can be measured.

In this study, we examined the quantity and quality of G proteins in membrane preparations from cortical regions (frontal, parietal, temporal and occipital cortex) in post-mortem brains obtained from subjects with chronic alcoholism and controls matched with respect to age and post-mortem delay (PMDT). Immunoblot analysis showed that the level of GsH alpha (52 kDa) was significantly decreased in temporal cortical membranes from alcoholics compared with controls, while no differences were observed in the amount of any G protein in frontal, parietal and occipital regions. Additionally, ethanol enhanced photoaffinity guanine nucleotide binding to both G alpha and Gi/o alpha in human cortical membranes. The percentage of increase in ethanol-stimulated photoaffinity GTP labeling of Gs alpha and Gi/o alpha was decreased in alcoholic patients in all cortical regions. These observations indicated that subsensitivities to ethanol-induced stimulation in G protein may contribute to impaired trans-signaling in cortical membranes of chronic alcoholics.

This study investigated alterations in the receptor adenylyl cyclase system in the brain and platelets of alcoholics through the study of GTP binding (G) protein, which has a key role in the system, in the membranes of the post-mortem brain and platelets. Quantitative examination of G protein by immunoblotting showed that GsH alpha in the temporal cortex of the post-mortem alcoholic brain was significantly decreased with controls. Moreover, the extent of ethanol enhancement of functional photoaffinity GTP(azidoanilido GTP) labeling to Gs alpha and Gi alpha was decreased in all cortical regions (frontal, temporal, parietal, occipital cortex) from alcoholics. In the platelet membrane, a quantitative reduction in GsH alpha and GsL alpha levels as assessed by immunoblotting was seen in family history positive (FHP) alcoholics. A reduction in ethanol enhancement of AAGTP labeling to Gs alpha and Gi alpha was also observed in the FHP group. These alterations of G protein were not found in the platelets from family history negative (FHN) alcoholics. The dysfunctions of Gs protein occurring in platelet membranes of the FHP group are likely to parallel those that occur in the alcoholic brain. These results suggest that disturbances of G protein-mediated signal transduction may be involved in the pathophysiology of alcoholics and that platelet G protein may be used as a trait marker of alcoholics.

The present study was designed to provide further information regarding the effect of ethanol on the function of inhibitory GTP-binding (Gi) protein. To eliminate the Gs function in the regulation of adenylyl cyclase, cerebral cortex membranes from Wistar or Fischer 344 rats were pretreated at pH 4.5 ("low pH"), whereupon Gpp(NH)p-dependent inhibition of forskolin-stimulated adenylyl cyclase was examined. In the membranes from Wistar rats, ethanol (100 or 250 mM) resulted in left-shifted Gpp(NH)p inhibition curves and reduced IC50 values for Gpp(NH)p in an ethanol dose-dependent manner. In contrast, ethanol exhibited no effect on the Gpp(NH)p-dependent inhibition of the enzyme or on IC50 values for Gpp(NH)p in the membranes from Fischer 344 rats. These results are consistent with the idea that ethanol, in vitro, enhances the Gi function in the cerebral cortex of Wistar rats, and that ethanol's effect on Gi protein in the cerebral cortex is different in Wistar and Fischer 344 rats.

In order to determine if there are any residual effects of long-term exposure to mercury vapor, neurobehavioral tests were given to ex-mercury miners about 18 years after the cessation of mercury exposure. Seventy-six male ex-mercury miners who had been exposed to relatively high concentrations of mercury vapor (over 1.0 mg/m3) and with a past history of mercury intoxication were compared to age (+/- 3 years)-, sex-, and years of education-matched controls. Although the extent of the workers' symptoms caused by mercury poisoning, termed erethismus merculialis, markedly decreased after the cessation of exposure, the prevalence of neurological symptoms (such as hand tremors, headaches, and slurred speech) and symptoms of senility (such as low-back pain, loss of sexual desire) in the ex-miners was significantly higher than those in the controls. Matched-pair analysis showed that performances of motor coordination, Simple reaction time, and Short-term memory in the ex-miners were significantly deteriorated compared to those of controls. There are slight but persistent effects on neurobehavioral function, especially on motor coordination function, among mercury miners more than 10 years after the cessation of exposure.

The effect of ethanol "in vitro" on GTP-binding protein in postmortem human brain cortex membranes was analyzed using by photoaffinity hydrolysis resistant GTP analog (azidoanilido GTP, AAGTP). AAGTP identified stimulatory GTP binding protein [Gs alpha (42 KDa)] and inhibitory GTP binding protein [Gi alpha (40 KDa)] in human brain cortex membranes. Ethanol augmented the amount of AAGTP binding to both Gs alpha and Gi alpha in human temporal and parietal cortex membranes. These results show that ethanol "in vitro" elevates not only Gs functions but also Gi functions in postmortem human brain cortex.

Brain adenylate cyclase (AC) activity in the alcohol-preferring AA (Alko Alcohol) and alcohol-avoiding ANA (Alko, Non-Alcohol) rats was examined. Both basal and Gpp(NH) p-stimulated AC activities were higher in the cerebral cortex of the ANA rats than in the AA rats. Isoproterenol-stimulated AC activity tended to increase in the cerebral cortex of the ANA rats compared to the AA rats. Basal AC activity in the striatum of the AA rats was higher than that in the ANA rats, however, striatal Gpp(NH)p-stimulated AC activity was not different between the two rats lines. In the mesolimbic and cerebellum, there was no difference in AC activity between the rat lines. These results suggest that the noradrenergic function in the cerebral cortex has an important role in the regulation of alcohol intake.

We carried out a survey on the cases of motor neuron disease (MND) occurring in Hokkaido between 1980 and 1989 in order to establish whether there is a relationship between MND and poliomyelitis. Hokkaido, the northern-most island of Japan, was one of the most affected areas during the poliomyelitis epidemic of the late 1940s to 1950s. We ascertained 389 cases of MND for these 10 years and 2,171 cases of paralytic poliomyelitis for the period 1949-1958, and analysed their geographic distributions. No significant correlation was found between MND and poliomyelitis in their geographic distributions.

Platelet adenylate cyclase (AC) activity in the long-term abstinent alcoholics, who maintained abstinence from alcohol for at least one year was examined. Guanine nucleotide [Gpp(NH)p] stimulated AC activity was not changed in platelet membrane from long-term abstinent alcoholics. However, the extent of AC activity induced by 250 mM ethanol in vitro, in the presence of 1 microM Gpp(NH)p, was significantly reduced in platelet membrane from long-term abstinent alcoholics. These results suggest that platelet AC activity may be a biological marker for alcoholics.

The incidence, prevalence and regional distributions of sporadic motor neuron disease (MND) from 1980 through 1989 were evaluated in collaboration with multiple neurological institutes in Hokkaido island. Patients with sporadic MND were collected from three sources: 1) neurologist practicing in Hokkaido island, 2) sending inquiries to 620 major hospitals, 3) notification file of MND provided by Japanese Ministry of Welfare and Health. Three hundred and eighty-nine patients with sporadic MND were ascertained for this study. Of 389 patients, 238 patients were men and 151 patients were women, and the ratio of men to women was 1.6:1. The mean age of onset was 58.2 +/- 10.3 years old, 57.7 +/- 10.4 for men and 58.9 +/- 10.0 for women. Their clinical presentations were 303 patients with ALS, 52 patients were PBP and 34 patients were SPMA. The crude incidence rate for both sexes combined for 1980 through 1989 was estimated as 0.69 per 100,000 person-year. The age- and sex-adjusted incidence for men was 0.86 per 100,000 person-year (95% CI, 0.75 to 0.97) and that is higher than 0.53 per 100,000 person-year (95% CI, 0.45 to 0.61) for women. The average, crude prevalence rate from 1985 through 1989 was estimated as 2.25 per 100,000 person-year. There are no overall trends of changing the pattern in incidence and prevalence of MND in Hokkaido island, however the geographic distributions of the incidence of MND according to towns and cities disclosed the presence of some relative clustering areas.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of ethanol on GTP-binding protein of cortical adenylate cyclase (AC) system in the Wistar and Fischer 344 rats was examined. In both Wistar and Fischer 344 rats, ethanol (100mM) potentiated Gpp (NH) p-stimulated AC activity and decreased EC50 for Gpp (NH)p in the cerebral cortical membrane (CCM). Ethanol treatment also augmented Mn-stimulated AC activity in Wistar CCM, whereas there was no significant change in Fischer 344 CCM. IC50 calculated from the Gpp (NH)p (0.01-0.3 microM) inhibition of forskolin-stimulated AC was decreased by ethanol treatment in Wistar CCM, but this was not the case in Fischer 344 CCM. There was no appreciable change in ADP-ribosylation of Gs and Gi in CCM with pertussis or cholera toxin. These results suggest that ethanol in vitro enhances the Gi function as well as affecting the Gs function in Wistar rat cortical AC system, and the effect of ethanol on Gi protein are different in Wistar and Fischer 344 CCM.

Neurofibrillary tangles (NFT) are one of the most prominent pathological changes seen in the brains of Alzheimer’s disease (Alz) patients. Under the electron microscope these NFT are revealed to be composed of accumulations of paired helical filaments (PHF). These structures are also observed in Parkinsonism-dementia complex of Guam (PD), and some other diseases besides Alz.

I measured with a planimeter X-ray images of Pneumatic cells of temporal bones which were taken by Sonnenkalb's method before the endoaural operation of the middle ear on 20 cases at the Department of Oto-Rhino-Laryngology, Yokohama University School of Medicine from May, 1952 to the end of December, 1956. Then I analysed the relations between the results of the above measurement and the epit-helisation of the middle ear cavity after the operation, and found that so far as my cases are concerned, the endoaural operation of the middle ear can be successfully applied when the area of pneumatic cells is less than 9 cm2.