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Biomedical subjects

Shinji Sato

Publications and source records attributed to Shinji Sato.

At least 19 recordsLinked to original sources
PubMed2007

OTK18, a zinc-finger protein, regulates human immunodeficiency virus type 1 long terminal repeat through two distinct regulatory regions.

It has previously been shown by our laboratory that OTK18, a human immunodeficiency virus (HIV)-inducible zinc-finger protein, reduces progeny-virion production in infected human macrophages. OTK18 antiviral activity is mediated through suppression of Tat-induced HIV-1 long terminal repeat (LTR) promoter activity. Through the use of LTR-scanning mutant vectors, the specific regions responsible for OTK18-mediated LTR suppression have been defined. Two different LTR regions were identified as potential OTK18-binding sites by an enhanced DNA-transcription factor ELISA system; the negative-regulatory element (NRE) at -255/-238 and the Ets-binding site (EBS) at -150/-139 in the LTR. In addition, deletion of the EBS in the LTR blocked OTK18-mediated LTR suppression. These data indicate that OTK18 suppresses LTR activity through two distinct regulatory elements. Spontaneous mutations in these regions might enable HIV-1 to escape from OTK18 antiretroviral activity in human macrophages.

DNA, Viral↗
PubMed2006

Experimental determination of particle range and dose distribution in thick targets through fragmentation reactions of stable heavy ions.

In radiation therapy with highly energetic heavy ions, the conformal irradiation of a tumour can be achieved by using their advantageous features such as the good dose localization and the high relative biological effectiveness around their mean range. For effective utilization of such properties, it is necessary to evaluate the range of incident ions and the deposited dose distribution in a patient's body. Several methods have been proposed to derive such physical quantities; one of them uses positron emitters generated through projectile fragmentation reactions of incident ions with target nuclei. We have proposed the application of the maximum likelihood estimation (MLE) method to a detected annihilation gamma-ray distribution for determination of the range of incident ions in a target and we have demonstrated the effectiveness of the method with computer simulations. In this paper, a water, a polyethylene and a polymethyl methacrylate target were each irradiated with stable (12)C, (14)N, (16)O and (20)Ne beams. Except for a few combinations of incident beams and targets, the MLE method could determine the range of incident ions R(MLE) with a difference between R(MLE) and the experimental range of less than 2.0 mm under the circumstance that the measurement of annihilation gamma rays was started just after the irradiation of 61.4 s and lasted for 500 s. In the process of evaluating the range of incident ions with the MLE method, we must calculate many physical quantities such as the fluence and the energy of both primary ions and fragments as a function of depth in a target. Consequently, by using them we can obtain the dose distribution. Thus, when the mean range of incident ions is determined with the MLE method, the annihilation gamma-ray distribution and the deposited dose distribution can be derived simultaneously. The derived dose distributions in water for the mono-energetic heavy-ion beams of four species were compared with those measured with an ionization chamber. The good agreement between the derived and the measured distributions implies that the deposited dose distribution in a target can be estimated from the detected annihilation gamma-ray distribution with a positron camera.

Algorithms↗
PubMed2006

A preliminary open-label study of 5-HT1A partial agonist tandospirone for behavioural and psychological symptoms associated with dementia.

The aim of this study was to assess the efficacy and safety of tandospirone, a 5-HT1A partial agonist, for treatment of behavioural and psychological symptoms of dementia (BPSD). Thirteen outpatients with DSM-IV diagnosis of Alzheimer's type or vascular dementia were enrolled in this study. Their BPSD and cognitive functions were evaluated with the Neuropsychiatric Inventory (NPI) and Mini-Mental State Examination, respectively, for an 8-wk period of treatment. The maximum benefit of tandospirone was achieved at a mean dose of 19.6 mg/d. There were significant improvements in the NPI subscores for delusion, agitation, depression, anxiety, and irritability at 2 or 4 wk after the start of administration of tandospirone. No patients experienced severe adverse effects. The results suggest that tandospirone was effective at improving BPSD symptoms and well-tolerated in elderly demented patients.

Aged↗
PubMed2006

Tyrosine kinase inhibitors and ATP modulate the conversion of smooth muscle L-type Ca2+ channels toward a second open state.

Properties of smooth and cardiac L-type Ca2+ channels differ prominently in several physiological aspects, including sympathetic modulation. To assess the possible underlying mechanisms, we applied the whole cell patch-clamp technique to guinea pig detrusor smooth muscle cells, in which only L-type Ca2+ channel currents are observed in practice. During depolarization to large positive potentials, the conformation of the majority of L-type Ca2+ channels is converted from the normal (O1) to a second open state (O2), which undergoes little inactivation during depolarization. Extracellular application of genistein, a known tyrosine kinase inhibitor, significantly attenuated the voltage-dependent conversion of Ca2+ channels to O2, accompanied by reduction of availability, whereas genistin, an inactive analog, had little effect. In the absence of ATP in the patch pipette, intracellular application of either genistein or tyrphostin-47 suppressed the conversion to O2. Computer calculation revealed that the acceleration of the O1 to an inactivated state qualitatively reconstructs the unique effects of PTK inhibitors antagonized by ATP. We concluded that under normal conditions smooth muscle L-type Ca2+ channels are already modulated by tyrosine-kinase and ATP-related mechanism(s) and thereby easily achieve the second conversion, which yields voltage-dependent modulation of L-type Ca2+ current analogous to that in cardiac myocytes during beta-adrenoceptor stimulation.

Adenosine Triphosphate↗
PubMed2006

Paradoxical effects of hydrogen peroxide on human airway anion secretion.

The present study concerns intriguing effects of hydrogen peroxide (H2O2) on cAMP-mediated anion secretion in polarized human airway epithelia. Although H2O2 applied to the apical and basolateral membrane increases short-circuit currents (ISC) with analogous properties, it has opposite effects on subsequent cAMP-activated ISC responses. Namely, forskolin (FK)-induced ISC responses were down-regulated by the apical presence of H2O2, whereas they were up-regulated by its basolateral presence. Despite this contrasting effect, oxidative stimuli from either aspect of the monolayer hindered FK-induced increments in cytosolic cAMP levels and apical membrane Cl- conductance. The site-dependent effects of H2O2 were reproduced in the responses to 8-bromo-cAMP. Estimation of the anionic composition of the ISC revealed that the FK up-regulated both bumetanide [an Na+-K+-2Cl- cotransporter (NKCC1) inhibitor]-sensitive and 4,4'-dinitrostilbene-2,2'-disulfonic acid [an HCO3--dependent anion transporter (NBC1/AE2) inhibitor]-sensitive ISC in the control, whereas the up-regulation evidently favored bumetanide-sensitive ISC in the basolateral presence of H2O2. The FK-induced NKCC1 augmentation after exposure to basolateral H2O2 was counteracted by cytochalasin D, an inhibitor of microfilament function, but not by charybdotoxin, a blocker of the intermediate conductance Ca2+-activated K+ channel, whose activation could be related to NKCC1-mediated Cl- secretion. These observations suggest that basolaterally but not apically applied H2O2 potentiates subsequent cAMP-mediated Cl- secretion by an increase in Cl- uptake via basolateral NKCC1, whose sensitivities to cAMP/protein kinase A are up-regulated, overcoming the H2O2-induced inhibition of cAMP-mediated apical anion conductance. The basolateral membrane-specific effects of H2O2 may be relevant to the basolateral cytoskeleton, which is believed to interact with NKCC1.

Anions↗
PubMed2006

Efficacy of perospirone in the management of aggressive behavior associated with dementia.

We assessed the efficacy of the serotonin dopamine antagonist, perospirone (PER) on aggressive and agitated behavior in demented patients. Eighteen outpatients with dementia diagnosed according to the DSM-IV were enrolled in this study, and their behavioral symptoms and cognitive impairments were assessed with the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) and Mini-Mental State Examination (MMSE) instruments for a period of 6 weeks. The maximum benefit of PER was achieved at a mean dose of 7.4 mg/day. Post-hoc analysis showed significant improvement in verbal outbursts after 4 weeks and in agitation scores after 4 and 6 weeks. Only 2 patients dropped out of the study, because of adverse effects, and no serious adverse effect was observed. The data suggest that PER is effective in improving aggressive and agitated behavioral symptoms in demented patients and that it is safe to use in elderly patients.

Aged↗
PubMed2006

c-jun N-terminal kinase hyperphosphorylates R406W tau at the PHF-1 site during mitosis.

Tauopathies such as Alzheimer disease (AD) probably involve a type of phosphorylation imbalance causing the accumulation of abnormally hyperphosphorylated tau in neurons and/or glias. Investigation of R406W tau mutation may provide insight into such abnormal tau hyperphosphorylation, since this mutation causes AD-like dementia and tauopathy in humans and because it has the unique ability to reduce tau phosphorylation in vitro and in cultured cells. Here we show that R406W mutation primarily disrupts tau phosphorylation at Ser404, a priming phosphorylation site of glycogen synthase kinase-3beta (GSK-3beta), thereby reducing subsequent GSK-3beta-mediated phosphorylation at the PHF-1 site (mostly Ser396). In contrast, c-jun N-terminal kinase (JNK) as activated in the mitotic phase directly hyperphosphorylates R406W tau at the PHF-1 site. This was confirmed by PHF-1 hyperphosphorylation of R406W tau in mitotic cells, its association with cytoplasmic JNK activation, and its inhibition by a JNK inhibitor, SP600125. These data unveil the unknown mechanisms of physiological tau phosphorylation at the PHF-1 site and suggest that cytoplasmic JNK activation may play an important role in the abnormal tau hyperphosphorylation associated with R406W tau mutation and in AD.

Animals↗
PubMed2006

Beneficial effects of perospirone on aggressive behavior associated with dementia.

The aim of this study was to assess the efficacy of the serotonin-dopamine antagonist perospirone in treating aggressive and agitated behavior in patients with dementia. Six patients were referred to the outpatient clinic of Ishizaki Hospital and were followed for 6 weeks. Their psychiatric diagnoses were made using the DSM-IV. Their behavioral symptoms and degrees of cognitive impairment were measured using the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) and the Mini-Mental Examination State. The changes in BEHAVE-AD scores were investigated. Maximum benefit was achieved at a mean perospirone dose of 9.0 mg/day. No patient experienced severe adverse effects. Post-hoc analysis showed significant improvement in the total BEHAVE-AD and aggressiveness subscale scores within 2 weeks. This study suggests that perospirone is effective in improving aggressive and agitated behavioral symptoms in demented patients and is safe to use in elderly patients.

Aged↗
PubMed2006

Efficacy of milnacipran on cognitive dysfunction with post-stroke depression: preliminary open-label study.

The aim of this study was to assess the therapeutic efficacy of the serotonin norepinephrine reuptake inhibitor (SNRI), milnacipran, on both cognitive impairment and depression in post-stroke depression (PSD) patients. A total of 18 PSD patients, approximately 3 months after stroke, were divided into two groups, milnacipran and control. A total of 10 patients were assigned to the milnaciprane group and eight were assigned to control group. Their cognitive impairment and mood symptoms were measured using the Mini-Mental State Examination (MMSE) and Hamilton Depression Rating Scale (HAM-D) both at the time of admission and at discharge, an interval of approximately 3 months. This study examined the changes in both MMSE and HAM-D scores during the study period. A significant time-by-group interaction for results of the MMSE was observed, although there was no significant difference between the two groups on the HAM-D. Amelioration of cognitive impairment was greater in the milnacipran group than the control group. For PSD patients, milnacipran is effective in improving cognitive dysfunction.

Adult↗
PubMed2006

Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation.

Neurofibrillary tangles, which are major pathological hallmarks of Alzheimer's disease (AD), are composed of paired helical filaments (PHFs) containing hyperphosphorylated tau. Specific kinases regulate tau phosphorylation and are closely linked to the pathogenesis of AD. We have characterized a human tau-tubulin kinase 1 (TTBK1) gene located on chromosome 6p21.1. TTBK1 is a serine/threonine/tyrosine kinase that is conserved among species and belongs to the casein kinase 1 superfamily. It is specifically expressed in the brain, especially in the cytoplasm of cortical and hippocampal neurons. TTBK1 phosphorylates tau proteins in both a Mg2+- and a Mn2+-dependent manner. Phosphopeptide mapping and immunoblotting analysis confirmed a direct tau phosphorylation by TTBK1 at Ser198, Ser199, Ser202 and Ser422, which are also phosphorylated in PHFs. TTBK1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that TTBK1 is a neuron-specific dual kinase involved in tau phosphorylation at AD-related sites and is also associated with tau aggregation.

Animals↗
PubMed2006

Lactation and risk of endometrial cancer in Japan: a case-control study.

The incidence of endometrial cancer is rapidly increasing in Japan. Although the risk factors in European populations have been well described, there are few epidemiologic studies regarding risk factors for endometrial cancer in Japanese women. This hospital-based case-control study among Japanese women was carried out from 1998 to 2000. The cases were selected from women with endometrial cancer (n =155), and the controls selected from women attending the university gynecological outpatient clinic for cervical cancer screening (n = 96). Subjects were interviewed to ascertain breast feeding practices, contraceptive usage, as well as potential risk factors for endometrial cancer. We observed a lower risk of endometrial cancer associated with oral contraceptive (OC) and a higher risk associated with higher body mass index (BMI), and older ages at first and last delivery. Gravidity reduced odds ratio (OR) for endometrial cancer to 0.34 (95% confidence interval [CI] 0.13-0.92). Compared with parous women who had never breastfed, the multivariate OR for women with a history of breastfeeding was 0.37 (95% CI, 0.17-0.82). Additionally, a greater lapse of time since breastfeeding increased OR for endometrial cancer by over three times. In conclusion, the present study has indicated that breastfeeding reduces the risk of endometrial cancer in Japanese women.

Adult↗
PubMed2006

[Autoantibodies specifically detected in patients with polymyositis/dermatomyositis].

Polymyositis/Dermatomyositis (PM/DM) is a chronic inflammatory disorder that culminates in injury to the skin and muscle and, sometimes, is accompanied by interstitial lung disease (ILD). A number of autoantibodies are associated with myositis, including those specific for aminoacyl-tRNA synthetase (anti-ARS), signal recognition particle (anti-SRP), and Mi-2. These autoantibodies have proven to be useful in the diagnosis and classification of the diseases and are predictive of prognosis. It has been known that certain patients may have typical DM skin manifestations without clinical evidence of myositis for at least 2 years (Clinically Amyopathic DM; C-ADM). Although classical myositis-related antibodies are well known, specificities related to C-ADM have not been examined in detail. Therefore, we have examined sera from 15 Japanese patients with C-ADM to identify additional autoantibodies associated with this disease. Eight sera of C-ADM patient recognized a polypeptide of approximately 140 kDa and we named this new antibody specificity anti-CADM-140. Anti-CADM-140 antibodies were detected in 8 of 42 patients with DM, but not in patients with other connective tissue diseases or idiopathic pulmonary fibrosis. It is noteworthy that DM patients with anti-CADM-140 had significantly more rapidly progressive ILD when compared to patients without anti-CADM-140 (50% vs 6%, P=0.008). Further studies of the pathogenicity of these autoantibodies specificity may provide insight into the pathogenic mechanisms of PM/DM accompanied by rapidly progressive ILD.

Adult↗
PubMed2006

[Case of polymer fume fever with interstitial pneumonia caused by inhalation of polytetrafluoroethylene (Teflon)].

A 30-year old man was admitted to our hospital with cough, slight fever, and dyspnea that he had developed several hours after inhaling the fumes produced from a Teflon-coated pan, after evaporation of the water in the pan. Chest radiography revealed diffuse infiltrations, and a computed tomography (CT) scan revealed patchy interstitial shadows in both lungs. In pulmonary function tests, the diffusing capacity of the lungs showed a moderate decrease. Leukocytosis and slight hypoxemia were observed. The patient recovered clinically in a few days without any specific treatment. We speculated that the pulmonary problems in this patient may have been induced by the products of thermal degradation of Teflon that were present in the fumes. When Teflon is heated, the fumes generated cause an influenza like syndrome (polymer fume fever) or cause severe toxic effects such as pulmonary edema, pneumonitis, and death in the exposed individual.

Acute Disease↗
PubMed2006

[A clinical psychiatric study about post-stroke depression].

We examined the clinical characteristics of post stroke depression (PSD) patients in a rehabilitation hospital. The subjects were inpatients at the Ibaraki Prefectural University of Health Sciences Hospital who had been diagnosed with stroke and admitted between May 2002 and January 2004. Of 123 patients enrolled, 18 were diagnosed with PSD. We investigated the clinical differences between PSD patients and non-depressed (ND) patients. There were no significant differences between PSD and ND groups in terms of sex, age, past psychiatric history, family psychiatric history, stroke diagnosis, or neurological symptoms. The scores of PSD patients on Zung's self-rating depression scale and the Hamilton depression rating scale were significantly higher than those of ND patients. Furthermore, the Activities of Daily Living measured by the Functional Independence Measure and cognitive function evaluated by the Mini-Mental State Examination of ND patients were significantly better than those of PSD subjects. These results suggest that the detection of PSD in stroke patients is important for promoting their rehabilitation and improving their Activities of Daily Living and cognitive function.

Depression↗
PubMed2005

Enhanced efficiency in cell killing at the penetration depths around the Bragg peak of a radioactive 9C-ion beam.

PURPOSE: To evaluate the potential importance of radioactive 9C-ion beam in cancer radiotherapy. METHODS AND MATERIALS: Human salivary gland (HSG) cells were exposed to a double-radiation-source 9C beam at different depths around the Bragg peak. Cell survival fraction was determined by standard clonogenic assay. For comparison, the same experiment was conducted for a therapeutic 12C beam. To determine relative biologic effectiveness (RBE) values, HSG cells were also irradiated with 60Co gamma-rays of fractionation scheme as the reference. RESULTS: The 9C beam was more efficient in cell killing at the depths around its Bragg peak than was the 12C beam, which corresponded to the 9C-ion stopping region and where delayed low-energy particles were emitted. The RBE value at 50% survival level for the 9C beam varied from 1.38 to 4.23. Compared with the 12C beam, the RBE values for the 9C beam were always higher; an increase in RBE by a factor of up to 1.87 has been observed at the depths distal to the Bragg peak. CONCLUSION: The potential advantage of radioactive 9C-ion beam in cancer therapy has been revealed at low dose rate in comparison with a therapeutic 12C beam. This observation, however, remains to be investigated at therapeutic dose rates in the future.

Carbon↗
PubMed2005

Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis.

OBJECTIVE: To identify novel autoantibodies specific for dermatomyositis (DM), especially those specific for clinically amyopathic DM (C-ADM). METHODS: Autoantibodies were analyzed by immunoprecipitation in 298 serum samples from patients with various connective tissue diseases (CTDs) or idiopathic pulmonary fibrosis (IPF). Antigen specificity of the sera was further examined by immunoblotting and indirect immunofluorescence (IF). The disease specificity and clinical features associated with the antibody of interest were determined. RESULTS: Eight sera recognized a polypeptide of approximately 140 kd (CADM-140 autoantigen) by immunoprecipitation and immunoblotting. Immunoreactivity was detected in the cytoplasm, and indirect IF revealed a granular or reticular pattern. Anti-CADM-140 antibodies were detected in 8 of 42 patients with DM, but not in patients with other CTDs or IPF. Interestingly, all 8 patients with anti-CADM-140 antibodies had C-ADM. Among 42 patients with DM, those with anti-CADM-140 autoantibodies had significantly more rapidly progressive interstitial lung disease (ILD) when compared with patients without anti-CADM-140 autoantibodies (50% versus 6%; P = 0.008). CONCLUSION: These results indicate that the presence of anti-CADM-140 autoantibodies may be a novel marker for C-ADM. Further attention should be directed to the detection of rapidly progressive ILD in those patients with anti-CADM-140 autoantibodies.

Adult↗
PubMed2005

Sensorimotor polyneuropathy as an initial clinical manifestation of sarcoidosis.

A 45 year-old Japanese woman developed numbness and tingling of both hands and feet. Electrophysiological examination revealed sensorimotor polyneuropathy. She was diagnosed as suffering from sarcoidosis on the basis of the pathological findings from dermal biopsy. Steroid therapy effectively improved the clinical symptoms. Although sarcoid neuropathy is rare, this case suggests sensorimotor polyneuropathy is an important symptom of sarcoidosis and can represent the initial clinical manifestation of the disease.

Journal Article↗