[Primary aldosteronism due to unilateral adrenal hyperplasia].
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Adrenal Glands↗
Biomedical subjects
Toshikazu Saito
Publications and source records attributed to Toshikazu Saito.
Pisa syndrome-like peculiar posture occurred while running was successfully improved with risperidone.
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Adult↗
Interleukin-12p40 gene (IL-12B) polymorphism and Type 1 diabetes mellitus in Japanese: possible role in subjects without having high-risk HLA haplotypes.
The present study was undertaken to clarify a role of interleukin-12p40 gene (IL-12B) polymorphism, located on chromosome 5q33-34 (IDDM 18), in Japanese subjects with Type 1 diabetes mellitus (T1DM) and autoimmune thyroid diseases (AITD). In 179 subjects with T1DM, 166 with AITD (128 with Graves' disease and 38 with Hashimoto's thyroiditis) and 115 healthy control subjects, the IL-12B 3'UTR A-C polymorphism was determined by PCR-RFLP method. In T1DM subjects, the genotype was also analyzed in relation to human leukocyte antigen (HLA)-DRB1-DQB1 haplotype status. There was a weak difference in the distribution of the genotype frequency between T1DM and control subjects, and the C allele frequency was higher in T1DM subjects (P<0.05). In 68 T1DM subjects without having high-risk HLA haplotypes to T1DM in this population, the genotype distribution and C allele frequency was significantly different from control subjects without high-risk HLA haplotypes (P<0.01), and from T1DM subjects with high-risk HLA haplotypes (n=111) (P<0.05). There was no difference in the genotype and allele frequencies between AITD and control subjects. In conclusion, the IL-12B 3'UTR A-C polymorphism did not seem to play a major role on genetic susceptibility to T1DM and AITD in Japanese, although the polymorphism conferred susceptibility in T1DM subjects without having high-risk HLA haplotypes. The IL-12B 3'UTR A-C polymorphism would be considered as a supplementary risk factor to T1DM in conjunction with HLA haplotypes.
Age of Onset↗
Homocysteic acid induces intraneuronal accumulation of neurotoxic Abeta42: implications for the pathogenesis of Alzheimer's disease.
The causes of neuronal dysfunction and degeneration in Alzheimer's disease (AD) are not fully understood, but increased production of neurotoxic forms of amyloid beta-peptide-42 (Abeta42) seems of major importance. Large extracellular deposits of aggregated Abeta42 (plaques) is a diagnostic feature of AD, but Abeta42 may be particularly cytotoxic when it accumulates inside neurons. The factors that may promote the intracellular accumulation of Abeta42 in AD are unknown, but recent findings suggest that individuals with elevated homocysteine levels are at increased risk for AD. We show that homocysteic acid (HA), an oxidized metabolite of homocysteine, induces intraneuronal accumulation of a Abeta42 that is associated with cytotoxicity. The neurotoxicity of HA can be attenuated by an inhibitor of gamma-secretase, the enzyme activity that generates Abeta42, suggesting a key role for intracellular Abeta42 accumulation in the neurotoxic action of HA. Concentrations of HA in cerebrospinal fluid (CSF) were similar in AD and control subjects. CSF homocysteine levels were elevated significantly in AD patients, however, and homocysteine exacerbated HA-induced neurotoxicity, suggesting a role for HA in the pathogenic action of elevated homocysteine levels in AD. These findings suggest that the intracellular accumulation of Abeta42 plays a role in the neurotoxic action of HA, and suggest a potential therapeutic benefit of agents that modify the production and neurotoxic actions of HA and homocysteine.
Alzheimer Disease↗
Cytotoxicity of acetaldehyde-derived advanced glycation end-products (AA-AGE) in alcoholic-induced neuronal degeneration.
BACKGROUND: The Maillard reaction that leads to the formation of advanced glycation end-products (AGEs) plays an important role in the pathogenesis of angiopathy in diabetic patients, in aging and in neurodegenerative processes. We hypothesize that acetaldehyde (AA), one of the main metabolites of alcohol, may be involved in alcohol-induced neurotoxicity in vivo by formation of AA-derived AGEs (AA-AGE) with brain proteins. METHODS: AA-AGE-bovine serum albumin (BSA) and AA-AGE-rabbit serum albumin (RSA) were prepared as described previously. Antibody specific for AA-AGE was isolated from rabbit antiserum by affinity chromatography. Primary cortical neuronal cell cultures were prepared as described previously. RESULTS: Incubation of cortical neurons with AA-AGE produced a dose-dependent increase in neuronal cell-death, and the neurotoxicity of AA-AGE was neutralized by the addition of an anti-AA-AGE specific antibody, but not by anti-N-ethyllysine (NEL) antibody. The AA-AGE epitope was detected in human brain of alcoholism. CONCLUSIONS: We propose that the structural epitope AA-AGE is an important toxic moiety for neuronal cells in alcoholism.
Acetaldehyde↗
The effect of ethanol on cell fate determination of neural stem cells.
BACKGROUND: Recent studies have described the possible relevance of impaired neural stem cell (NSC) functions to the pathophysiology of psychiatric disorders, including alcoholism. However, relatively little is known about ethanol's effects on the determination of cell fate in NSCs. In this study, we investigated the effect of ethanol on neuronal and glial differentiation of NSCs. METHODS: Under neuron-inductive culture conditions, NSCs were induced to differentiate and exposed to ethanol for 96 hr. Immunocytochemistry with cell-type-specific markers was performed (microtubule-associated protein 2 (MAP2) for neurons, glial fibrillary acidic protein (GFAP) for astrocytes and O4 for oligodendrocytes). The cells positive to MAP2, GFAP or O4 were counted, and the number of MAP2-positive cells was quantified by enzyme-linked immunosorbent assay (ELISA) following immunostaining with anti-MAP2 (MAP2-ELISA). The alteration of MAP2, GFAP or myelin basic protein (MBP, a marker for oligodendrocytes) expression was evaluated by Western blot analysis. RESULTS: Ethanol exposure increased astrocytic and oligodendrocytic differentiation with a statistically significant difference at 100 mM, while 25 to 100 mM ethanol reduced neuronal differentiation without affecting the viability of NSCs. The enhanced expression of glial markers was revealed by Western blot analysis for GFAP or MBP. CONCLUSIONS: Glial cells are known to increase in response to various kinds of insults to the central nervous system. It is possible that the increase of astrocytes and oligodendrocytes after ethanol exposure is a compensatory mechanism to repair the impaired neural network by promoting neurite outgrowth and increasing newly generated neurons.
Animals↗
[Discovery of vasopressin and its significance].
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Animals↗
[Study on mental diseases: neural stem cells].
The neurosciences to understand the pathophysiology of psychiatric disorders such as depression and schizophrenia were started from the analysis of neurotransmitter function change, and proceed to the cellular signaling change in the brains. In the next step, it developed to the studies of neuroplasticity change through expressions various cytokines and transcriptional factor regulations. Recently, the existence of neural stem cells and lineage of stem cells to neurons are identified in the adult mammalian brains. In addition, since the brain structural changes in depression and schizophrenia have well defined by the development of neuroimaging analysis, many researchers have been suggested the relationship between the pathophysiology of these disorders and the dysfunction of neurogenesis which strongly affects the maintenance and repair of brain neuronal network. In this report, we describe the new strategy and approach to the investigation of the treatment of psychiatric illness, and introduce our present study of the way to refine the neural network through promoted actions on stem cell functions such as differentiation to neurons.
Animals↗
Glyceraldehyde-derived advanced glycation end products in Alzheimer's disease.
The Maillard reaction that leads to the formation of advanced glycation end products (AGE) is considered to play an important role in the pathogenesis of Alzheimer's disease (AD). Until now AGE derived from glucose (glucose-AGE) have been mainly investigated, so we established new AGE species derived from alpha-hydroxyaldehydes and dicarbonyl compounds. We have found that AGE derived from glyceraldehyde (glycer-AGE) and glycolaldehyde (glycol-AGE) showed strong neurotoxicity for primary cultured rat cortical neurons in vitro. In this study, we immunohistochemically examined the localization of glycer-AGE and glycol-AGE in the brains of AD patients and elderly controls. Most of the neurons in AD or control brains did not show any immunoreaction with glycol-AGE. In AD brains, glycer-AGE was mainly present in the cytosol of neuron in the hippocampus and para-hippocampal gyrus, but not in senile plaques and astrocytes. The pattern of immunopositivity was uniform and powdery, not dot-like. The distribution of glycer-AGE differed from that of glucose-AGE, which was detected at both intracellular and extracellular sites. This suggests that glycer-AGE has a pathological role different from glucose-AGE in AD. In the central nervous system, glyceraldehyde is generated via the glycolytic pathway from glyceraldehyde-3-phosphate by glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We hypothesize that perikaryal glycer-AGE immunopositivity of neurons reflects an increase of cytoplasmic glycer-AGE along with the decline of GAPDH activity.
Acetaldehyde↗
Decreased expression of NEFH and PCP4/PEP19 in the prefrontal cortex of alcoholics.
Patients with alcoholism exhibit behavioral adaptations to ethanol such as tolerance, dependence, and addiction. Molecular mechanisms that underlie these altered behavioral responses to ethanol are largely unclear. We have performed oligonucleotide microarray analysis in postmortem prefrontal cortices of alcoholics. Among about 12,000 genes represented on microarray, a total of 79 genes showed differential expression changes in alcoholics compared with control subjects, consisting of 54 up- and 25 down-regulated genes. Altered expressions in alcoholics were observed in genes having a wide range of biological functions. The remarkable findings were up-regulation of myelin-related genes and molecular chaperones in alcoholics. Among the genes identified, decreased expressions of NEFH and PCP4/PEP19 were further examined. NEFH encodes a component of neurofilament protein in neurons. PCP4/PEP19 encodes protein involved in calcium signaling and neuronal apoptosis. Observation of their down-regulations in alcoholics in microarray analysis was confirmed by real-time quantitative RT-PCR, and was also confirmed in the independent set of postmortem brains of alcoholics. The present results may provide some insights into understanding the mechanism of ethanol-induced altered behavioral responses at the molecular level.
Adult↗
Ethanol inhibition of neural stem cell differentiation is reduced by neurotrophic factors.
BACKGROUND: Ethanol exposure during development leads to various forms of neuronal damage. Because neural stem cells (NSCs) play a pivotal role in the development and maturation of the central nervous system, it is important to understand the effect of ethanol on NSC differentiation. In this study, we investigated the effect of ethanol on differentiation of cultured NSCs in the presence and absence of neurotrophic factors. METHODS: NSCs were derived from rat embryos on embryonic day 14. Cells were exposed to ethanol with or without neurotrophic factors, insulin-like growth factor-1 (IGF-1), or brain-derived neurotrophic factor (BDNF). The effect of ethanol on differentiation was quantified by measurement of optical density of each sample following to microtubule-associated protein 2 enzyme-linked immunosorbent assay and counting of the number of microtubule-associated protein 2-positive cells microscopically. In addition, cell viability of cultured cortical neurons that were exposed to similar concentrations of ethanol was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. RESULTS: Ethanol (20-100 mM) inhibited NSC differentiation induced by basic fibroblast growth factor removal, whereas those concentrations of ethanol did not affect neuronal survival. Both IGF-1 and BDNF promoted generation of neurons in the absence of ethanol. Moreover, they suppressed the inhibitory effect of ethanol on NSC differentiation. CONCLUSIONS: Ethanol inhibited NSC differentiation at concentrations much lower than what compromised neuronal survival. Ethanol-induced differential inhibition was reduced by both IGF-1 and BDNF. These results suggest that ethanol inhibits stem cell differentiation through alteration of cellular pathways related to neurotrophic factor signaling.
Animals↗
Pulmonary artery obstruction caused by thoracic aortic dissection: a case with unique pathological findings.
Pulmonary artery obstruction is a rare complication of acute thoracic aortic dissection. A 74-year-old woman was admitted to hospital with respiratory distress. Computed tomography scan showed right pulmonary artery occlusion and a thoracic aortic dissection of the Stanford A type. Lung perfusion scan revealed a defect in the entire right lung field. These findings mimicked acute pulmonary thromboembolism accompanying aortic dissection. On the other hand, pulmonary angiography revealed a round smooth defect of the right pulmonary artery, indicating an extrinsic compression. The patient finally died of cardiac tamponade. Autopsy disclosed that the right pulmonary artery was compressed by a hematoma in the adventitial space around the pulmonary artery. Such a mechanism of pulmonary artery obstruction caused by acute aortic dissection is unique, and is distinct from that caused by chronic non-dissecting aortic aneurysms, which themselves compress the pulmonary arteries. This complication inevitably follows aortic rupture; therefore, emergency operation to repair the dissected aorta must be performed to avoid the following catastrophic event.
Aged↗
Beat-to-beat evaluation of systolic time intervals during bicycle exercise using impedance cardiography.
In order to elucidate the beat-to-beat changes of the systolic time intervals (STI) during exercise, we proposed new techniques relating to an adaptive filter and detection algorithms for B- and X-points in the impedance cardiograph (ICG). Six male subjects underwent a ramp bicycle exercise up to maximum intensity during which an ECG, ICG and phonocardiogram (PCG) were continuously measured. Following the application of an adaptive filter, the scaled Fourier linear combiner (SFLC), to the first derivative (dZ/dt) of the base impedance (deltaZ) and PCG waveforms, the B- and X-points were automatically determined. For the B-point detection we used three criteria: the zero-crossing point (B(zero)), the 15% response point (B15%) of the negative peak of the dZ/dt (dZ/dt(min)) and a new algorithm (B(new)). The X-point was separately determined by using the ICG and PCG waveforms. It was found that the shape of the dZ/dt waveform directly affected the determination of the B- and X-points. The B-points determined using B(zero) and B15%, criteria were sometimes unstable caused by the location of a notch preceding the dZ/dt(min) compared to the B(new). The time difference between the X-points measured by the ICG and PCG was mostly within +/- 20 milliseconds but statistically significant. Although a wide variation was seen in R-R intervals, the STI were more stable. The relationships between HR and STI from rest to maximal exercise showed a gentle curvilinear relationship. It is suggested that the STI can be obtained precisely on a beat-to-beat basis by using the adaptive filter and detection algorithms for the inflection points of the ICG even during maximum exercise.
Adult↗
[Possible alterations in brain neural network by ethanol].
Advances in the neurosciences over the past two decades have elucidated that alcoholism is a chronic and easily recurring disorder, which is based on brain damage induced by long-term ethanol consumption. Researchers have identified neural circuits that subsume the actions of ethanol and they have also elaborated many of the intracellular signalling pathways that follow receptor activation by ethanol, suggesting a substantial difference between the addicted brain and non-addicted brain. However, most of the molecular biological changes, which are likely based on the transition from occasional drinking to alcohol dependence, remain to be elucidated. This review summarizes the findings on the biological background of alcoholism concerning the brain rewarding system, its related receptors, and the second messenger-mediated signal transduction system within the cells, especially focusing on the cyclic AMP signaling pathway calcium (Ca2+) system in neurons. In addition, our studies with neural stem cells are introduced to indicate future directions of research on the pathophysiology of alcoholism.
Alcoholism↗
[Diagnosis of and therapy for patients with alcoholism].
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Alcohol Deterrents↗
[Hypertension secondary to primary aldosteronism].
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Adenoma↗
Persistent phenotypic correction of central diabetes insipidus using adeno-associated virus vector expressing arginine-vasopressin in Brattleboro rats.
Adeno-associated virus (AAV) vector is suitable for gene transfer to the central nervous system. However, the efficacy of gene therapy for neuroendocrine disease is still unknown. In this study, we injected AAV vector encoding arginine-vasopressin (AVP) stereotaxically into the bilateral hypothalamus of Brattleboro rats. Brattleboro rats show a central diabetes insipidus (CDI) phenotype and growth retardation due to a complete deficiency of AVP. Following injection, both urine volume and urine osmolality normalized, and these therapeutic effects persisted for more than 50 weeks. In addition to phenotypic correction, secretion of transgene-derived AVP was enhanced after 24 h water deprivation or hypertonic saline injection, and water diuresis was demonstrated after acute water loading. Also, reduced body weight and low plasma insulin-like growth factor I levels of Brattleboro rats were restored after AVP gene transduction, suggesting the importance of AVP in growth. These findings indicate that hypothalamic neurons of Brattleboro rats can produce and release mature AVP following AAV-mediated gene transduction, resulting in long-term phenotypic correction of CDI. Moreover, the fact that transgene-derived AVP was secreted adequately in response to stimuli, even if it was expressed constitutively, suggests advantages of gene therapy for neuroendocrine diseases and offers a basis to investigate AVP function.
Animals↗
Neurotoxicity of acetaldehyde-derived advanced glycation end products for cultured cortical neurons.
The Maillard reaction that leads to the formation of advanced glycation end products (AGEs) plays an important role in the pathogenesis of angiopathy in diabetic patients, in aging, and in neurodegenerative processes. We hypothesize that acetaldehyde (AA), one of the main metabolites of alcohol, may be involved in alcohol-induced neurotoxicity in vivo by formation of AA-derived AGEs (AA-AGEs) with brain proteins. Incubation of cortical neurons with AA-AGE produced a dose-dependent increase in neuronal cell-death, and the neurotoxicity of AA-AGE was neutralized by the addition of an anti-AA-AGE-specific antibody, but not by anti-N-ethyllysine (NEL) antibody. The AA-AGE epitope was detected in human brain of alcoholism. We propose that the structural epitope AA-AGE is an important toxic moiety for neuronal cells in alcoholism.
Acetaldehyde↗