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Biomedical subjects

Hiroyuki Arai

Publications and source records attributed to Hiroyuki Arai.

At least 109 records · Page 6Linked to original sources
PubMed2004

Increased plasma 8-isoprostane levels in hypertensive subjects: the Tsurugaya Project.

To examine the relationship between 8-isoprostane and blood pressure, we measured plasma 8-isoprostane concentration and home blood pressure levels in an elderly Japanese population. Our study population comprised 569 subjects aged 70 years and over who were not receiving antihypertensive medication. On the basis of their blood pressure values, the participants were classified into three groups: normotensive (home blood pressure <135/85 mmHg), hypertensive (home blood pressure 135/85-160/90 mmHg), and severely hypertensive (home blood pressure > or =160/90 mmHg). The mean plasma 8-isoprostane level in the severely hypertensive group (21.1+/-5.2 pg/ml) was significantly higher than that in the normotensive (20.2+/-4.9 pg/ml) or hypertensive (19.7+/-5.1 pg/ml) group, and this result was unchanged when we adjusted for possible confounding factors such as age, sex, use of vitamin A, C or E supplements, smoking status, drinking status, body mass index, use of non-steroidal anti-inflammatory drugs, history of diabetes, hypercholesterolemia, home heart rate and serum creatinine level. Thus, the level of plasma 8-isoprostane appears to be elevated in older subjects with severe hypertension.

Aged↗
PubMed2004

A novel imaging probe for in vivo detection of neuritic and diffuse amyloid plaques in the brain.

Extensive deposition of neuritic and diffuse amyloid plaques in the brain is a critical event for the pathogenesis of Alzheimer's disease (AD) and considered to start before the appearance of clinical symptoms. In vivo detection of these brain beta-amyloid (Abeta) deposits using positron emission tomography (PET), therefore, would be a useful marker for presymptomatic detection of AD. To develop a new agent for PET probe of imaging neuritic and diffuse amyloid deposits, novel fluorescent compounds, including styryl-fluorobenzoxazole derivatives, were examined. These compounds showed a high binding affinity for both synthetic Abeta1-40 and Abeta1-42 aggregates. Some of these compounds also displayed distinct staining of neuritic and diffuse amyloid plaques in AD brain sections. A biodistribution study of styryl-fluorobenzoxazole derivatives in normal mice exhibited excellent brain uptakes (4.5-5.5% injected dose/g at 2 min postinjection). Furthermore, iv administration of BF-145, a styryl-fluorobenzoxazole derivative, demonstrated specific in vivo labeling of compact and diffuse amyloid deposits in an APP23 transgenic mouse brain, in contrast to no accumulation in a wild-type mouse brain. These findings suggest that BF-145 is a potential candidate as a probe for imaging early brain pathology in AD patients.

Aged↗
PubMed2004

[Incidence of adverse drug reactions in geriatric wards of university hospitals].

Adverse drug reactions (ADR) in elderly people, which have been shown to increase with age, are often attributed to functional decline and polypharmacy. A multi-institutional retrospective survey was undertaken to investigate the current status of ADR in geriatric wards of university hospitals. The inpatient database from 2000 to 2002 in 5 university hospitals was studied, and a total of 1,289 patients were analyzed. The incidence of ADR, as determined by attending physicians, was 9.2% on the whole but varied from 6.3% to 15.8% among the institutions. The factors significantly related to ADR were number of diagnoses, number of geriatric syndromes, number of prescribed drugs, increase of more than two drugs during admission, longer hospital stay, emergency admission, depression and apathy. These results are mostly consistent with previous reports and will provide important information on pharmacotherapy in elderly people.

Aged↗
PubMed2004

[Current therapies in dementia].

Currently, cholinergic therapies for Alzheimer's disease (AD) have been developed and widely accepted based upon an observation that presynaptic cholinergic neurons in the basal nucleus of Meynert that widely project to the cerebral cortices are consistently damaged in AD brains. Since it is likely that the loss of central cholinergic activity may be associated with cognitive worsening in patients with AD, it is hypothesized that cholinergic augmentation could improve the cognitive ability of patients with AD. Cholinesterase inhibitors represent one way of implementing this strategy by inhibiting the breakdown of acetylcholine and increasing its availability in synapses. Indeed, several recent clinical trials of donepezil, galanthamine and rivastigmine have come to the conclusion that these cholinesterase inhibitors have overall beneficial effects in cognitive as well as global functions. American Academy of Neurology recommended a use of cholinesterase inhibitors as a first choice medicine in the treatment of AD. All 3 major studies of Donepezil from USA, Europe and Japan have reached the same conclusion favoring Donepezil in the treatment of mild to moderate AD. Donepezil can also be used as a safe and efficacious drug in the elderly aged 85 or older. Clinical trial of galantamine is in progress in Japan. Moreover, herbal medicines named kami-untan-to and hachimi-jiou-gan have been shown to be beneficial in some priority studies with a small sample size. It is critically needed to widen therapeutic windows in the treatment of AD.

Aged↗
PubMed2004

[Association between social support and depression in the elderly Japanese population].

To determine the association between social support and depression in elderly Japanese, we conducted a Comprehensive Geriatric Assessment among residents aged 70 years or over. Out of 2,730 eligible subjects, 1,179 participated in the survey and 1,146 (480 men and 666 women) were analyzed. The Geriatric Depression Scale (GDS) was used to estimate depression status. The subjects were divided into two groups: depressive (GDS>11 or taking antidepressant drugs) and non-depressive (GDS<11). Various levels of social support were assessed by the following questions: Do you have someone (1) whom you can consult when you are in trouble ? (2) whom you can consult when your physical condition is not good ? (3) who can help you in daily housework ? (4) who can take you to a hospital when you don't feel well ? (5) who can take care of you when you are ill in bed? In multivariate logistic regression analysis, the calculated odds ratios (95% CIs) for the lack of each type of social support for depression status were: (1) 2.5 (1.5-4.1),(2) 1.9 (1.1-3.2),(3) 2.7 (1.7-4.4),(4) 1.9 (1.1-3.2),(5) 2.8 (1.6-4.9) in men, and (1) 1.2 (0.8-1.8),(2) 1.2 (0.8-1.8),(3) 1.4 (1.0-2.0),(4) 1.6 (1.1-2.3),(5) 2.0 (1.4-2.9) in women. A significant association was found between social support and depression in this elderly population. We also found that this association was stronger in men.

Aged↗
PubMed2004

Evaluation of the response of metastatic brain tumors to stereotactic radiosurgery by proton magnetic resonance spectroscopy, 201TlCl single-photon emission computerized tomography, and gadolinium-enhanced magnetic resonance imaging.

OBJECT: The goal of this study was to investigate the usefulness of proton (1H) magnetic resonance (MR) spectroscopy to evaluate the response of metastatic brain tumors to stereotactic radiosurgery (SRS) in comparison with Gd-enhanced MR imaging and single-photon emission computerized tomography with administration of thallium-201 chloride (201TlCl-SPECT). METHODS: Forty patients with a total of 47 metastatic brain tumors were evaluated. The primary lesion was identified in all cases. Stereotactic radiosurgery was effective in 37 lesions. All patients were examined using Gd-enhanced MR imaging before and after SRS. Thalium-201 chloride was administered to 27 patients with 34 tumors and SPECT images were obtained. Proton MR spectroscopy was performed in 36 patients who harbored 43 tumors. On Gd-enhanced MR images, a decrease in the volume of the Gd-enhanced lesion and a change in the enhanced effect in the lesion after treatment were recognized as showing the effectiveness of SRS between 1 and 3 months or more (mean 8.54 +/- 3.58 weeks). In 201TlCl-SPECT studies, the ratio of lesion to normal brain decreased from 2 weeks to 2 months (mean 5.03 +/- 2.77 weeks) after radiosurgery. On 1H-MR spectroscopy images a high choline (Cho) peak and a lipid-dominant (Lip) peak were observed in 25 lesions and a high Cho peak and a lactate-dominant (Lac) peak were observed in 12 lesions before SRS. A decrease in the Cho peak, a disappearance of the Lac peak, and an increase in the Lip peak were observed between 1 week and 1 month (mean 2.76 +/- 1.62 weeks) after treatment. CONCLUSIONS: Based on histopathological findings obtained at autopsy or at surgery, we assume that a high Cho peak may be observed in viable tumor tissue and a Lip peak in areas of necrosis. The results indicate that 1H-MR spectroscopy is potentially a more sensitive tool in evaluating the response to SRS than 201TlCl-SPECT or Gd-enhanced MR imaging and that it can be used earlier for this purpose than those other imaging methods.

Adult↗
PubMed2004

[Diagnosing the mild cognitive impairment stage of Alzheimer's disease].

Recently, it has become important to diagnose Alzheimer's Disease (AD) at an early stage due to the development of AD therapy. Also, there is increasing recognition of a class of elderly people with complaints of memory loss but who nevertheless do not meet the criteria for dementia. "Mild cognitive impairment" (MCI) is the term used for this disorder, and amnestic MCI is highly converted to AD. In this study we evaluated the accuracy of diagnosis of amnestic MCI by cerebrospinal fluid total-tau protein (CSF/total-tau), cerebrospinal fluid amyloid beta 1-42 protein (CSF/A beta 1-42), and cerebral blood flow in the posterior cingulate cortex using SPECT. CSF/total-tau was the most appropriate to discriminate between normal cognitive individuals and those with amnestic MCI. We also evaluated the CSF/total-tau and MRI images between patients with stable MCI and those with progressive MCI, including those who converted to AD in the following two years. The stable type was characterized by normal CSF/total-tau levels and relatively high grade periventricular white matter lesions (PWML). Conversely, the progressive type was characterized by high CSF-tau levels and relatively low grade PWML. We speculate that stable MCI is due to ischemic change with in the white matter lesion, while progressive MCI may represent a previous stage of AD.

Alzheimer Disease↗
PubMed2004

[Clinical heterogeneity in mild cognitive impairment--beyond clinical diagnosis--towards imaging amyloid].

Alzheimer's disease (AD) generally begins with mild memory problems in an insidious manner and progresses to develop multiple cognitive and functional impairment within a few years. Currently, the diagnosis of AD requires multiple cognitive deficits including memory disturbance and exclusion of other dementing disorders. However, normal elderly people quite commonly complain of increasing forgetfulness with age, and we have not developed an objective tool that can reliably support the diagnosis of AD. Recent advances in our understanding of neurobiology of AD demonstrate that AD starts with accumulation of amyloid beta-protein (A beta) followed by abnormal phosphorylation of tau protein and a massive neuron death in vulnerable brain areas. We have shown that cerebrospinal fluid tau are elevated in subjects with mild cognitive impairment (MCI), the earliest detectable clinical stage of dementia and AD, suggesting that the pathogenic cascade of AD may arrive at the stage that finally leads to an accumulation of abnormally phosphorylated tau in the MCI stage. These results may highlight the need to develop another diagnostic tool that reliably monitors and visualize brain beta-amyloid burden in living subjects who are at increased risk of developing AD. We assume that the detection of asymptomatic stage of AD followed by an early intervention may lead to maximum therapeutic benefits. In an attempt to accomplish this goal, we have generated several novel chemicals that specifically bind to A beta peptide upon entry into rat brain. The "amyloid imaging" seems quite promising if safely and successfully applied in humans because it is a noninvasive technique and applied multiple times in a single subject.

Aged↗
PubMed2003

Characterization of two different 2-oxoglutarate:ferredoxin oxidoreductases from Hydrogenobacter thermophilus TK-6.

A thermophilic, chemolithoautotrophic hydrogen-oxidizing bacterium, Hydrogenobacter thermophilus TK-6, fixes carbon dioxide via the reductive TCA cycle. 2-Oxoglutarate:ferredoxin oxidoreductase (OGOR) is one of the key enzymes of this cycle. Strain TK-6 has two distinct OGOR enzymes termed For and Kor. These enzymes were purified and characterized following heterologous expression in Escherichia coli. The specific activity of For was approximately one-tenth of that of Kor. Additionally, For showed higher thermo-stability than Kor under both aerobic and anaerobic conditions. Western blot analysis showed that both of For and Kor were expressed when strain TK-6 was grown under aerobic conditions. In contrast, only Kor was expressed when the strain was grown under anaerobic conditions using nitrate as a terminal electron acceptor. These results indicate that For supports the optimal growth of strain TK-6 in the presence of oxygen.

Bacteria↗
PubMed2003

Synthesis of migration-resistant hydroxyethoxy analogues of lysophosphatidic acid.

[reaction: see text] The susceptibility of lysophosphatidic acid (LPA) to intramolecular acyl migration impedes the determination of specific receptor activation by the sn-1 and sn-2 LPA regioisomers. An efficient enantioselective synthesis of hydroxyethoxy (HE)-substituted analogues of sn-1-acyl and 2-acyl LPA derivatives that possess palmitoyl and oleoyl chains is described. While the palmitoyl derivatives fail to activate calcium release in cells transfected with LPA(2) or LPA(3) G-protein-coupled receptors, the LPA(3) receptor is activated by both 1-HE and 2-HE oleoyl LPA analogues with a potency 10-fold lower than that of the parent oleoyl LPA.

Acylation↗
PubMed2003

Vascular remodeling induced by naturally occurring unsaturated lysophosphatidic acid in vivo.

BACKGROUND: We previously identified unsaturated (16:1, 18:1, and 18:2) but not saturated (12:0, 14:0, 16:0, and 18:0) lysophosphatidic acids (LPAs) as potent factors for vascular smooth muscle cell (VSMC) dedifferentiation. Unsaturated LPAs strongly induce VSMC dedifferentiation via the coordinated activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK), resulting in the proliferation and migration of dedifferentiated VSMCs. Here, we investigated the effects of 18:1 and 18:0 LPAs (as representative unsaturated and saturated LPAs, respectively) on the vasculature in vivo. METHODS AND RESULTS: Rat common carotid arteries (CCAs) were treated transiently with 18:1 or 18:0 LPA and then examined by histological and biochemical analyses. The 18:1 but not 18:0 LPA potently induced vascular remodeling that was composed primarily of neointima. The incorporation of [3H]18:1 LPA into the CCAs revealed that a sufficient amount of unmetabolized [3H]18:1 LPA to induce VSMC dedifferentiation was present in the vascular wall. The 18:1 LPA-induced neointimal formation in vivo was also dependent on the coordinated activation of ERK and p38MAPK. Unlike balloon-injured CCAs, the 18:1 LPA-treated CCAs showed a histological similarity to human atherosclerotic arteries. CONCLUSIONS: This is the first report demonstrating a role for a naturally occurring unsaturated LPA in inducing vascular remodeling in vivo and provides a novel animal model for neointimal formation.

Animals↗
PubMed2003

Biochemical and molecular characterization of two phosphatidic acid-selective phospholipase A1s, mPA-PLA1alpha and mPA-PLA1beta.

We have identified a novel phospholipase A1, named mPA-PLA1beta, which is specifically expressed in human testis and characterized it biochemically together with previously identified mPA-PLA1alpha. The sequence of mPAPLA1beta encodes a 460-amino acid protein containing a lipase domain with significant homology to the previously identified phosphatidic acid (PA)-selective PLA1, mPA-PLA1alpha. mPA-PLA1beta contains a short lid and deleted beta9 loop, which are characteristics of PLA1 molecules in the lipase family, and is a member of a subfamily in the lipase family that includes mPA-PLA1alpha and phosphatidylserine-specific PLA1. Both mPA-PLA1beta and mPA-PLA1alpha recombinant proteins exhibited PA-specific PLA1 activity and were vanadate-sensitive. When mPAPLA1beta-expressing cells were treated with bacterial phospholipase D, the cells produced lysophosphatidic acid (LPA). In both mPA-PLA1alpha and beta-expressing cells, most of the PA generated by the phospholipase D (PLD) treatment was converted to LPA, whereas in control cells it was converted to diacylglycerol. When expressed in HeLa cells most mPA-PLA1alpha protein was recovered from the cell supernatant. By contrast, mPA-PLA1beta was recovered almost exclusively from cells. Consistent with this observation, we found that mPA-PLA1beta has higher affinity to heparin than mPA-PLA1alpha. We also found that the membrane-associated mPA-PLA1s were insoluble in solubilization by 1% Triton X-100 and were detected in Triton X-100-insoluble buoyant fractions of sucrose gradients. The present study raises the possibility that production of LPA by mPA-PLA1alpha and -beta occurs on detergent-resistant membrane domains of the cells where they compete with lipid phosphate phosphatase for PA.

Amino Acid Sequence↗
PubMed2003

LIS1 missense mutations: variable phenotypes result from unpredictable alterations in biochemical and cellular properties.

Mutations in one allele of the human LIS1 gene cause a severe brain malformation, lissencephaly. Although most LIS1 mutations involve deletions, several point mutations with a single amino acid alteration were described. Patients carrying these mutations reveal variable phenotypic manifestations. We have analyzed the functional importance of these point mutations by examining protein stability, folding, intracellular localization, and protein-protein interactions. Our data suggest that the mutated proteins were affected at different levels, and no single assay could be used to predict the lissencephaly phenotype. Most interesting are those mutant proteins that retain partial folding and interactions. In the case of LIS1 mutated in F31S, the cellular phenotype may be modified by overexpression of specific interacting proteins. Overexpression of the PAF-AH alpha1 subunit dissolved aggregates induced by this mutant protein and increased its half-life. Overexpression of NudE or NudEL localized this mutant protein to spindle poles and kinetochores but had no effect on protein stability. Our results implicate that there are probably different biochemical and cellular mechanisms obstructed in each patient yielding the varied lissencephaly phenotypes.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2003

The hydrolysis of lysophospholipids and nucleotides by autotaxin (NPP2) involves a single catalytic site.

Autotaxin (NPP2) is a tumor cell motility-stimulating factor that displays both a nucleotide pyrophosphatase/phosphodiesterase activity and a recently described lysophospholipase D activity. The hydrolysis of nucleotides is a metal-assisted reaction that occurs via a nucleotidylated threonine in the catalytic site. We show here that the catalytic site threonine and the metal-coordinating residues are also essential for the hydrolysis of lysophospholipids. In comparing the substrate specificity of NPP2 and the closely related NPP1 and NPP3, we found that only NPP2 displayed a lysophospholipase D activity, whereas NPP1 and NPP3 had a much higher nucleotide pyrophosphatase activity.

Animals↗