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Biomedical subjects

H Tohgi

Publications and source records attributed to H Tohgi.

At least 37 records · Page 2Linked to original sources
PubMed1999

Alterations of 3-nitrotyrosine concentration in the cerebrospinal fluid during aging and in patients with Alzheimer's disease.

To investigate the significance of nitric oxide (NO)-mediated neuron death in aging and Alzheimer's disease (AD), the 3-nitrotyrosine concentration in the cerebrospinal fluid (CSF) was investigated in neurologically normal controls and patients with AD. The 3-nitrotyrosine concentration and the 3-nitrotyrosine/tyrosine ratio significantly increased with advancing age, whereas the tyrosine concentration was unaltered. In patients with AD, the 3-nitrotyrosine concentration and the 3-nitrotyrosine/tyrosine ratio increased significantly (>six-fold) compared with controls of similar age, and increased significantly with decreasing cognitive functions, whereas the tyrosine concentration did not change. These findings suggest that an activation of tyrosine nitration, increase in nitrated tyrosine-containing proteins, and/or its degradation may be involved in brain aging and play an important role in the pathogenesis of AD.

Aged↗
PubMed1999

An endogenous MPTP-like dopaminergic neurotoxin, N-methyl(R)salsolinol, in the cerebrospinal fluid decreases with progression of Parkinson's disease.

There have been an increasing number of evidences indicating that dopamine-derived N-methyl(R)salsolinol is an endogenous MPTP-like neurotoxin to cause Parkinson's disease. In the cerebrospinal fluid from newly diagnosed untreated patients with Parkinson's disease, the level of this toxin was found to increase significantly, compared to control and a disease control, multiple system atrophy. The effects of the disease duration and the medication on the level of N-methyl(R)salsolinol were studied from the same patients. After about a 2-year period, the level was significantly reduced. The depletion of dopamine neurons by the disease progression may account for the reduction of the neurotoxin level, whereas L-DOPA therapy did not seem to affect the level of this toxin, even though the enhanced dopamine turnover. The results suggest that N-methyl(R)salsolinol level in the cerebrospinal fluid may indicate remaining dopamine neurons in the parkinsonian brain.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Decrease with age in methylcytosines in the promoter region of receptor for advanced glycated end products (RAGE) gene in autopsy human cortex.

Changes with age in the methylation status of cytosines in the promoter region of the receptor for advanced glycated end products (RAGE) in autopsy human cortex were investigated, using the bisulfite method, polymerase chain reaction (PCR), and direct sequencing of PCR products. The total number of methylcytosines significantly decreased with age. While the number of methylated cytosines at CpG dinucleotides was stable throughout adult life, that at sites other than CpG dinucleotides significantly decreased with age in cases >/=70 years old. Of 13 transcription factor binding sites, cytosines in CpG doublets in NF-IL6 and SP-1 binding sites were methylated in all cases, suggesting that these sites are repressed throughout adulthood. In contrast, the number of methylcytosines in AP-2 or SP-1 binding sites located at CpC, CpA, or CTG was significantly lower or at least tended to be lower in cases >/=70 years than <70 years old. These reductions in the number of methylcytosines at transcription factor binding sites may increase expression of RAGE, which may in turn play a role in aging of the brain.

5-Methylcytosine↗
PubMed1999

Increase in oxidized NO products and reduction in oxidized glutathione in cerebrospinal fluid from patients with sporadic form of amyotrophic lateral sclerosis.

To determine the role of free radical mechanisms in the pathogenesis of amyotrophic lateral sclerosis (ALS), cerebrospinal fluid concentrations of oxidized nitric oxide (NO) products (nitrite and nitrate) and reduced and oxidized forms of glutathione (GSH and GSSG, respectively) were compared between patients with the sporadic form of ALS (SALS) and controls. In the SALS patients, the nitrate levels were significantly higher (by 73%) in contrast to remarkably lower GSSG/GSH ratio, approximately 3-fold, compared to controls. These results suggest that NO production or oxidation is activated in SALS patients, leading to a decrease in superoxide radicals to oxidize GSH. The subsequent generation of a highly reactive anion, peroxynitrite, may play a causal role in the pathogenesis of SALS.

Aged↗
PubMed1999

Remarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateral sclerosis.

To investigate the significance of peroxynitrite-mediated oxidative damage in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS), the concentrations of 3-nitrotyrosine and tyrosine in the cerebrospinal fluid (CSF) of patients with SALS were determined. The concentration of 3-nitrotyrosine and the 3-nitrotyrosine/ tyrosine ratio in patients with SALS were approximately seven times those of controls. Thus, the present findings in living patients provide in vivo evidence for a possible role of peroxynitrite, a mediator of oxidative stress, and increased nitration of tyrosine residues in the pathogenesis of SALS.

Adult↗
PubMed1999

Local variation in expression of pro- and antithrombotic factors in vascular endothelium of human autopsy brain.

The expression of tissue factor (TF), tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), endothelial nitric oxide (NO) synthase (eNOS), tissue plasminogen activator (tPA), its inhibitor (PAI-1), and myosin, an indicator of local shear stress, was examined in the endothelium of cerebral vessels according to vessel size and location in human autopsy brains, using immunohistochemistry. Expression of TF, vWF, eNOS, tPA/PAI-1, and myosin was much greater in intracerebral perforating arteries and the microvasculature than the pial and carotid arteries. Expression of all antigens studied was normally faint or negative in the pial and carotid arteries. However, TF, vWF, myosin, tPA, and PAI-1 were strongly expressed in the endothelium of the inner wall of the carotid bifurcation where flowing blood collides, but not in the outer wall. In the endothelium of arteries with fibrillary hyperplasia, vWF, myosin, eNOS, tPA, and PAI-1 were strongly expressed. Within the brain, microvascular expression of TFPI was very faint or negative, whereas that of vWF was intense throughout all brain regions. However, expression of TF and myosin was more intense in the basal gray matter and white matter than in the cortex. eNOS was expressed more strongly in the basal gray matter and cortex than the white matter, whereas tPA and PAI-1 expression was more intense in the white matter than the gray matter. In addition to intrinsic properties of individual vessels, these local variations in expression of pro- and antithrombotic factors in cerebral vessels may in part be due to differences in hemorheological and humoral environments to which they are exposed, and may result in local difference in vulnerability to ischemia. The present findings may in part account for the propensity of thrombus generation in the carotid inner wall, an usual source of artery-to-artery microemboli, frequent development of lacunar (small) infarcts in deep brain regions, and diffuse white matter lesions as seen in Binswanger's leukoencephalopathy.

Adult↗
PubMed1999

Quantitation of nicotinic acetylcholine receptor subunits alpha 4 and beta 2 messenger RNA in postmortem human brain using a non-radioactive RT-PCR and CCD imaging system.

We present a simple and rapid procedure for quantifying mRNA in the brain after RT-PCR, in which the intensity of the ethidium bromide luminescence of PCR products is measured directly from electrophoretic gels by a highly sensitive CCD camera combined with an image analyzing computer system (Gel Doc 1000 system). The CCD camera allows the mRNA in the ethidium bromide-stained PCR-amplified bands to be quantified in a broad exponential range of PCR cycles. The proposed protocol enables standard curves to be constructed to examine the relationship between the number of reaction cycles and amplified log intensity and between the amount of sample RNA for RT-PCR and amplified intensity. The method was applied to nicotinic acetylcholine receptor (nAChR) subunits alpha 4 and beta 2 mRNA in postmortem human putamen in the present study, but is also applicable to mRNAs of other receptors and neurotransmitter precursor peptides.

Actins↗
PubMed1999

[The effect of lymphocytapheresis on multiple sclerosis].

We studied the effect of lymphocytapheresis (LCP) on the expanded disability status scale (EDSS) clinical score, lymphocyte subsets and Interleukin-2 (IL-2) production by peripheral blood mononuclear cell (PBM) in 5 patients with multiple sclerosis (MS). The EDSS clinical score significantly decreased after LCPs (p < 0.05). PBM IL-2 production and CD 4/8 ratio significantly decreased (p < 0.05, p < 0.05), and the number of neutrocytes and CD 11 b+CD 8+ (%) significantly increased immediately after LCP (p < 0.05, p < 0.05). Down-regulation of PBM IL-2 production and CD 4/8 ratio and up-regulation of CD 11 b+CD 8+ may account for therapeutic effect of LCP on MS. However, similar changes were observed in patients with CIDP and MG during immunoadsorbent therapy (IAT). It is possible that down-regulation of PBM IL-2 production and CD 4/8 ratio and up regulation of CD 11 b+CD 8+ and the number of neutrocytes may commonly result from apheresis therapy using extra-corporeal circulation.

Adult↗
PubMed1998

Cerebral blood flow and oxygen metabolism before and after a stroke-like episode in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).

Cerebral blood flow and oxygen metabolism were examined in two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) using positron emission tomography (PET). Regional cerebral blood flow (rCBF), regional cerebral oxygen metabolic rate (rCMRO2) and regional oxygen extraction fraction (rOEF) were determined with the steady-state technique using oxygen-15-labeled tracers (15O2, C15O2 and C15O). Case 1, a 45-year-old woman, presented with abrupt onset of fluent aphasia. T2-weighted magnetic resonance imaging (MRI) showed a high signal intensity lesion in the left temporoparietal region. The first PET study on day 16 showed increased rCBF and decreased rCMRO2 in the temporal region. In the second PET study, on day 35, rCBF in the temporal region had decreased. Case 2 was a 19-year-old male; the second son of Case 1. He complained of transient blurring of vision, and then generalized tonic-clonic convulsion occurred. A PET study six days before this stroke-like episode demonstrated increased rCBF in both frontal lobes and putamen, where MRI showed lesions after the episode. Focal hyperemia of the lesion antedated and lasted for at least sixteen days after the stroke-like episode in these MELAS patients. These stroke-like episodes appear to be the result of metabolic dysfunction in neural tissue, although the role of an ischemic vascular event cannot be ruled out.

Adult↗
PubMed1998

Tissue-specific involvement of multiple mitochondrial DNA deletions in familial mitochondrial myopathy.

It is still uncertain how deleted mitochondrial DNA (mtDNA) is distributed to each tissue during development, although deletions of mtDNA have been extensively observed in various pathologic conditions. This paper presents two Japanese siblings with progressive external ophthalmoplegia exhibiting multiple mtDNA deletions. In one patient, similar multiple mtDNA deletions were found in skeletal muscle specimens as well as in the spinal cord but not in the myocardium, liver or leukocytes. A similar deletion pattern was found in the skeletal muscle but not in the leukocytes of the other patient. The results suggest the complex mechanism to generate, expand and eliminate the deleted mtDNA in humans.

Adult↗
PubMed1998

Alterations with aging and ischemia in nicotinic acetylcholine receptor subunits alpha4 and beta2 messenger RNA expression in postmortem human putamen. Implications for susceptibility to parkinsonism.

Nicotine activates the dopaminergic system and acts to alleviate hypokinetic disorders (parkinsonism). The frequency of parkinsonism increases with age and is sometimes associated with multiple small infarcts (status lacunaris) in the putamen. To investigate changes with aging in control cases free from neurological disease and changes in cases with multiple small infarcts (status lacunaris) in the putamen, the present study determined nicotinic acetylcholine receptor (nAChR) subunit alpha4 and beta2 messenger RNA (mRNA) expression in the postmortem human putamen using the reverse transcription-polymerase chain reaction (RT-PCR). In controls, alpha4 subunit mRNA expression was unaltered, but beta2 subunit mRNA expression decreased significantly with age. In cases with status lacunaris, both beta2 and alpha4 subunit mRNA expressions were significantly lower than in the control cases. The reduction in beta2 mRNA expression alone, or in both alpha4 and beta2 mRNA expressions, suggests a reduction in functional nAChRs in the putamen, which may in part explain the susceptibility to hypokinetic disorders of the elderly and subjects with ischemic damage in the striatum.

Adult↗
PubMed1998

Age-related changes in nicotinic acetylcholine receptor subunits alpha4 and beta2 messenger RNA expression in postmortem human frontal cortex and hippocampus.

Age-related changes in nicotinic acetylcholine receptor (nAChR) subunit alpha4 and beta2 messenger RNA (mRNA) expression in the postmortem human frontal cortex and hippocampus was investigated using the reverse transcription-polymerase chain reaction (RT-PCR). In the frontal cortex, both alpha4 and beta2 subunit mRNA expression decreased with age. In the hippocampus, alpha4 subunit mRNA expression was unaltered, while beta2 subunit mRNA expression significantly decreased with age. These findings suggest that nAChR transcription decreases during aging with differing vulnerability between subunits and brain regions, which could in part contribute to the reduction in cognitive functions seen in the elderly.

Adult↗
PubMed1998

Age-related changes in D1 and D2 receptor mRNA expression in postmortem human putamen with and without multiple small infarcts.

Expression of messenger RNAs (mRNAs) encoding the D1 and D2 dopamine receptors as a function of age was determined in the human putamen using the reverse transcription-polymerase chain reaction (RT-PCR). In cases without multiple small infarcts (status lacunaris) in the putamen, D1 mRNA expression was unaltered, while D2 mRNA expression significantly decreased with age. Both D1 and D2 mRNA expression was lower in cases with status lacunaris. The reduction in D1 receptors primarily located on striatonigral neurons or D2 receptors primarily located on striatopallidal neurons may inhibit thalamocortical neurons. The decreased transcription of D1 and D2 receptor genes may in part account for increased susceptibility to hypokinetic disorders in the elderly.

Actins↗
PubMed1998

Familial amyloid polyneuropathy related to transthyretin mutation Val30 to Leu in a Japanese family.

A rare variant transthyretin that has a leucine-for-valine substitution at position 30 was reported in a sporadic case of type 1 familial amyloid polyneuropathy (FAP). We found the same substitution in members of a Japanese family with FAP. Three individuals in this family had a guanine-to-cytosine mutation at the first base of codon 30 in exon 2. This family shows a direct link between a valine-to-leucine substitution at position 30 and type 1 FAP.

Amino Acid Substitution↗
PubMed1998

Cerebral blood flow and oxygen metabolism in senile dementia of Alzheimer's type and vascular dementia with deep white matter changes.

Regional cerebral blood flow (rCBF), cerebral metabolic rate of oxygen (rCMRO2), oxygen extraction fraction (rOEF), and cerebral blood volume (rCBV) were investigated using positron emission tomography (PET) in 16 patients with senile dementia of Alzheimer's type (SDAT), and compared with those of 6 nondemented and 3 demented patients with deep white matter high signal (DWMH) on T2-weighted MRI and 6 controls. rCBF, rCMRO2 and rCBV were determined using C15O2, 15O2 and C15O, respectively. rCBF and CMRO2 were significantly decreased in the frontal, parietal and temporal cortex (P < 0.05) in patients with SDAT, and showed a significant correlation with the severity of dementia (P < 0.05). In patients with DWMH rCBF was significantly decreased in the parietal cortex and in the frontal white matter in nondemented patients, and in the cerebral cortex and white matter of most regions studied in demented patients (P < 0.05), whereas rCMRO2 was significantly reduced in only the frontal and temporal cortex of demented patients (P < 0.05). rOEF was significantly increased in the parietal cortex of patients with SDAT and in the white matter of patients with SDAT or DWMH (P < 0.05), and the increase in the frontal white matter significantly paralleled the progression of dementia in patients with SDAT (P < 0.05). rCBV was significantly decreased in the parietal and temporal cortex of patients with SDAT (P < 0.05), but not in any areas of those with DWMH. These results suggest that rOEF is increased in both SDAT and patients with DWMH. The increase in rOEF in patients with SDAT may be accounted for by reduction in rCBV resulting from decreased activity in the vasodilatory cholinergic system, impairment of glucose metabolism and white matter changes; the rOEF increase in patients with DWMH suggests relative preservation of oxidative metabolism compared to disturbed perfusion.

Aged↗
PubMed1998

The cerebrospinal fluid oxidized NO metabolites, nitrite and nitrate, in Alzheimer's disease and vascular dementia of Binswanger type and multiple small infarct type.

The concentration of the nitric oxide (NO) metabolites nitrite (NO2-) and nitrate (NO3-) in the cerebrospinal fluid from patients with Alzheimer's disease (AD), vascular dementia of the Binswanger type (VDBT) or multiple small infarct type (MSID), and controls were determined using high performance liquid chromatography. The nitrite concentration was significantly higher in VDBT/MSID patients than in controls (p < 0.005). The nitrate concentration and the combined nitrite and nitrate concentration was significantly higher in both AD (p < 0.05) and VDBT/MSID (p < 0.001) patients than in controls, with these concentrations being significantly greater in VDBT/MSID than AD patients (p < 0.005). The combined nitrite and nitrate concentration significantly decreased as the severity of dementia progressed in AD (rs=0.70, p < 0.01), but remained elevated in all stages of VDBT/MSID. These results suggest that NO production or oxidation in the brain increases in the early stage of AD and then decreases as neuronal cell loss progresses, but increases throughout the course of disease in VDBT/MSID, which may in part contribute to neuronal degeneration in both conditions.

Aged↗
PubMed1998

[A case of chronic, motor, axonal polyneuropathy successfully treated by immunoadsorption].

We reported a 61-year-old male with chronic, motor, axonal polyneuropathy. Neurological examination revealed severe muscle weakness in the proximal parts of the four limbs. Sensory examination was normal. The cerebrospinal fluid protein was elevated to 74 mg/dl, and the cell count was normal. The serum antibodies to GM1, GD1a, GD1b, and GQ1b were all negative. Electrophysiological studies showed reduced compound muscle action potentials (CMAPs) suggesting axonal neuropathy, and the nerve conduction velocity was only mildly reduced. After treatment with plasmapheresis (PP) by the immunoadsorption method, his symptoms significantly improved in three weeks, and the cerebrospinal fluid protein, and CMAPs also improved. Only a few studies have been reported regarding patients with chronic, motor dominant, axonal polyneuropathy that responded to immunosuppressive therapies or PP. It remains to be determined whether chronic, dominantly motor, axonal polyneuropathy as seen in the present case is a subtype of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or a primary axonal immune-mediated neuropathy that is different from CIDP. At present we are not able to answ what kind of clinical or laboratory markers other than an elevated cerebrospinal fluid protein level may help to predict a positive response to immunosuppressive therapy or PP.

Axons↗