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Biomedical subjects

M Iwata

Publications and source records attributed to M Iwata.

At least 37 records · Page 2Linked to original sources
PubMed2001

Immunohistochemical and ultrastructural study of basophilic inclusions in adult-onset motor neuron disease.

We immunohistochemically and ultrastructurally studied basophilic inclusions (BI) in a patient with adult-onset sporadic motor neuron disease (MND). BI were frequently observed not only in degenerated anterior horn cells, such as central chromatolytic neurons, but also in normal-appearing large anterior horn neurons. They had various shapes, round, elliptical or irregular, and occasionally they had distinct basophilic rims. They also varied in size. There were no halos around them nor core in their centers. Immunohistochemically, some BI were immunostained for ubiquitin or SOD1, but BI were not immunoreactive with anti-phosphorylated neurofilament (SMI 31), phosphorylated tau, cystatin C or Golgi (MG-160) antibodies. Ubiquitin-positive skein-like inclusions (SI) were occasionally observed in the somata of anterior horn neurons. Ultrastructurally, BI consisted of filamentous structures associated with granules, which were attached to thick filaments. The thick filaments were straight without constriction or side arms and their diameter was twice that of the neurofilaments. BI occasionally contained tubular structures among the granule-associated filaments. The granulo-filamentous profiles varied from being compactly arranged to being more loosely packed. The structure of BI resembles that of the Lewy body-like hyaline inclusions (LBHI) observed in sporadic MND patients. Bundles of filaments resembling SI, which were composed of compactly packed filaments without fine granules running parallel to the longitudinal axis, were frequently observed inside or at the periphery of BI, and occasionally clustered in the perikarya. Each filament measured approximately 15-25 nm in diameter, and a bundle of these grouped filaments was sometimes surrounded by a unit membrane. We also occasionally observed in-between structures of BI and bundles of filaments resembling SI. These findings suggest a certain relationship between BI, SI and LBHI in the pathomechanism of BI development. Further studies are needed to elucidate whether sporadic adult-onset MND characterized by BI forms a different subtype of MND.

Anterior Horn Cells↗
PubMed2001

Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy.

OBJECTIVES: We sought to define the clinical and long-term prognostic implications of autoantibodies that act against the second extracellular loop of beta1-adrenergic receptors (ARs) in patients with idiopathic dilated cardiomyopathy (IDC). BACKGROUND: Although autoantibodies directed against various domains of beta-ARs are found in patients with IDC, only a subgroup against the second extracellular domain of beta1-ARs exerts intrinsic sympathomimetic-like actions on human beta-ARs. It is suggested that the autoantibodies take part in the pathophysiology of IDC and may affect long-term prognosis of patients with this disorder. METHODS: Sera from 104 patients with IDC were screened for autoantibodies that act against the second extracellular loop of beta1-ARs by enzyme-linked immunosorbent assay, using a synthetic peptide corresponding to the domain. Relations of the autoantibodies to clinical variables and long-term prognosis were assessed by multivariate analysis. RESULTS: Autoantibodies were detected in 40 patients (38%). Multifocal ventricular premature contractions (p < 0.01) and ventricular tachycardia (VT; p < 0.01) were more common in autoantibody-positive than in autoantibody-negative patients, although no differences in cardiac function or neurohormonal levels were demonstrated. The presence of autoantibodies (p = 0.001) and a low left ventricular ejection fraction (LVEF <30%; p = 0.02) were independent predictors of VT. Sudden death was independently predicted by the presence of autoantibodies (p = 0.03), as well as by LVEF <30% (p = 0.01), whereas total mortality was predicted only by LVEF <30% (p = 0.001). CONCLUSIONS: Autoantibodies directed against the second extracellular loop of beta1-ARs were closely related to serious ventricular arrhythmias in patients with IDC, and the presence of autoantibodies independently predicted sudden death. These autoantibodies may contribute to electrical instability in patients with IDC.

Adult↗
PubMed2001

Cortical activity associated with vocalization and reading proper.

To determine whether motor and premotor areas are involved in silent reading, we report a positron emission tomography study on reading aloud and covert reading. The anterior insula, primary sensorimotor cortex and supplementary motor area were activated separately in reading aloud compared with covert reading, but they were not activated in covert reading compared with fixation control, nor in a conjunction involving reading aloud and covert reading, suggesting the role of articulation or vocalization.

Brain Mapping↗
PubMed2001

Cortical activation in reading assessed by region of interest-based analysis and statistical parametric mapping.

Reanalysis of our positron emission tomography study on the reading of Japanese Kanji (morphograms) and Kana (phonograms) with Statistical Parametric Mapping (SPM) Version 96 (Cogn. Brain Res. 9 (2000) 111) were described in comparison with our previous region of interest (ROI)-based analysis. Some areas were activated in one analysis but not in the other, which was due to the methodological differences. Furthermore, we conducted cognitive subtraction analysis between Kanji and Kana and between Kana words and nonwords and confirmed that Kana words activated the lateral occipital gyri more extensively than Kanji words.

Adolescent↗
PubMed2001

Importance of achieving complete necrosis during the first treatment for hepatocellular carcinoma to prevent bone metastasis: a prospective study.

BACKGROUND AND AIMS: Recent advances in the treatment of hepatocellular carcinoma (HCC) have changed the importance of bone metastasis during the follow up of such patients. In the present study, we investigated risk factors for bone metastasis after treatment for HCC. METHODS: Two hundred and two patients with HCC were diagnosed as free of bone metastasis by technecium 99m-methylene diphosphonate bone scintigraphy and were followed prospectively after treatment of the primary lesions (follow-up period 2-146 months; median 20 months). We statistically analyzed the risk factors for bone metastasis using the clinical characteristics at the time of first treatment. RESULTS: Multiple tumors (P < 0.005), main tumor size > 5 cm in diameter (P < 0.005), the presence of distant metastasis (P < 0.005), elevation of serum alpha-fetoprotein (> 100 ng/mL; P < 0.05), chemotherapy (P < 0.05) and insufficient therapeutic response (P < 0.0005) were identified as risk factors for bone metastasis by univariate analyses. Insufficient therapeutic response and main tumor size > 5 cm in diameter (both P < 0.05) were identified as independent predisposing factors for bone metastasis. CONCLUSIONS: Complete necrosis of primary HCC during the first treatment is important to prevent subsequent bone metastasis.

Aged↗
PubMed2001

Ultrastructural study of Betz cells in the primary motor cortex of the human brain.

The ultrastructure of Betz cells in the 5th layer of the primary motor cortex of 17 neurologically and psychiatrically normal control individuals was studied. Normal-appearing Betz cells showed a wide range of features including novel electron-dense inclusion bodies (Bunina-like bodies) resembling Bunina bodies characteristic of amyotrophic lateral sclerosis (ALS), accumulations of neurofilaments (10 nm in diameter), bundles of filaments (20-25 nm in diameter) thicker than neurofilaments, lamellar structures, lamellar bodies and structures similar to Hirano bodies. Among these 'abnormal' features, the presence of Bunina-like bodies may be an age-related nonspecific degenerative change, since they appeared more frequently in elderly individuals. The presence of these abnormal features--particularly the Bunina-like bodies--in the Betz cells of normal human brains must be considered in the assessment of the pathognomonic significance of such structures in ALS and other neurological diseases that affect the motor cortex.

Adult↗
PubMed2001

Protocol to prevent shoulder-hand syndrome after stroke.

OBJECTIVE: To determine the effectiveness of a protocol designed to restrict passive movement of affected upper extremity on the incidence of shoulder-hand syndrome (SHS) after stroke. DESIGN: Before-and-after trial: follow-up duration of subject group and historical control group 231.6 and 257.2 days, respectively. SETTING: Rehabilitation medicine department in a hospital in Japan. PARTICIPANTS SUBJECTS: 81 stroke patients treated with the protocol from 1994 to 1996 who were followed for at least 4 months from the onset of stroke; controls: 71 stroke patients treated without the protocol from 1991 to 1994 who were followed for same length of time. INTERVENTION: Use of a set protocol for controlled passive movement by trained therapists and restriction of passive movement by the patients for 4 months after stroke. The SHS criterion used to detect early signs of SHS has not yet been validated. Corticosteroids were given to all subjects diagnosed with SHS. MAIN OUTCOME MEASURES: Swelling index, SHS diagnostic criteria applied in physical exam, Brunnstrom stage, and sensory disturbance evaluations. RESULT: The incidence of SHS in the subject group was 18.5% (n = 15), whereas the incidence of SHS in the control group was 32.4% (n = 23). The difference between the 2 groups was statistically significant (chi(2) = 3.885, p < .05). CONCLUSION: The protocol helped to prevent development of SHS.

Chi-Square Distribution↗
PubMed2001

Potential role of Gab1 and phospholipase C-gamma in osmotic shock-induced glucose uptake in 3T3-L1 adipocytes.

Osmotic shock induces GLUT4 translocation and glucose uptake through a mechanism independent of PI 3-kinase, but dependent on tyrosine phosphorylation of cellular proteins. To identify the tyrosine phosphorylated proteins required for osmotic shock-stimulated glucose uptake, we examined tyrosine phosphorylation of candidate proteins, and found that the 60-80kDa species including paxillin and the 120-130kDa species including p130Cas, PYK2, FAK and Gab1 were tyrosine-phosphorylated in response to osmotic shock. Inhibition of actin polymerization by cytochalasin D significantly decreased the tyrosine phosphorylation of paxillin, p130Cas, PYK2 and FAK but not Gab1, but had no effect on 2-deoxyglucose (DOG) uptake, suggesting a role for Gab1 in osmotic shock-induced glucose transport. Also, we found that osmotic shock increases the association of phospholipase C-gamma (PLC-gamma) with Gab1 and stimulates tyrosine phosphorylation of PLC-gamma itself. The PLC inhibitor, U73122, inhibited osmotic shock-induced 2-DOG uptake. These results suggest that tyrosine phosphorylation of Gab1 and subsequent recruitment and activation of PLC-gamma may play a role in osmotic shock-induced glucose transport.

3T3 Cells↗
PubMed2001

Intrahepatic cholangitis and arteritis after transcatheter arterial embolization in a patient with tumor-like lesion-associated autoimmune hepatitis.

Autoimmune hepatitis is a chronic liver disease characterized by immune-mediated, progressive hepatocellular damage, although the target autoantigen remains speculative. Intrahepatic biliary lesions are not a feature of this disease. We describe herein a female patient, 57 years, with autoimmune hepatitis who developed hepatic regenerative mass after acute exacerbation of hepatitis. This hepatic regenerative mass was clinically diagnosed as hepatocellular carcinoma and was surgically resected after transcatheter arterial embolization therapy. Widespread nonsuppurative destructive granulomatous cholangitis as well as necrotizing, granulomatous arteritis of the intrahepatic small arteries were found in the surgically resected hepatic regenerative mass. The bile duct lesions were histologically and immunohistochemically very similar to the granulomatous cholangitis of primary biliary cirrhosis. We would like to propose that these unusual lesions in the intrahepatic bile ducts and intrahepatic arteries represent a reaction of this patient to an anti-cancer drug included in chemoembolization. No such cases have been reported so far.

Arteritis↗
PubMed2001

Release property of progesterone from a mixed-base suppository consisting of Witepsol W35 and Witepsol E85.

The mechanism of drug release from progesterone suppositories that consist of two types of hard fat (Witepsol W35 and Witepsol E85) was investigated. The strength, the thermodynamic characteristics, the surface structures, the drug release property, methylene blue penetration into suppositories, and change of surface structure after the dissolution test were employed for detecting characteristics of progesterone suppositories. The formulation with a mixing ratio of Witepsol W35 and Witepsol E85 at a 1:1 ratio showed the maximum strength value. The peak temperature of the suppositories showed a tendency to increase with increases in the ratio of Witepsol E85. The maximum height of the profiles measured with laser microscopy, from 20.8 microm to 29.2 microm, reached a maximum after 3 h of the dissolution test. When the suppositories were immersed in pH 7.4 phosphate buffer containing 0.5% methylene blue at 37 degrees C, the penetrating area increased with time. The weight of the suppositories also increased with time. According to these findings, it was suggested that the release of drug from a mixed type of suppository containing progesterone was via the matrix and pores.

Adjuvants, Pharmaceutic↗
PubMed2001

Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in sputum from patients with bronchial asthma.

To examine a possibility that matrix metalloproteinases (MMPs) participate in the pathogenesis of asthma and/or the development of asthma attack, we measured the concentrations of MMP-2, MMP-9, and their respective tissue inhibitors of metalloproteinases (TIMP)-2 and TIMP-1, in induced sputa collected from 28 patients with moderate to severe bronchial asthma. Specimens were collected during both the attack and the remission from 15 age- and sex-matched healthy control subjects. The concentration of MMP-9 was significantly (p < 0.05) higher in the patients, even during the remission, as compared to that in healthy controls. The concentrations of MMP-9 (p < 0.05) and its specific inhibitor TIMP-1 (p < 0.01), and MMP-2 (p < 0.01) in these patients during the attack were significantly higher than those in healthy controls. In these patients, the MMP-9 concentration was significantly higher (p < 0.05) during the attack than during the remission. These results suggest that MMPs and TIMPs may be involved in the pathogenesis of bronchial asthma, and that the increased MMP-9 might be involved in the development of attack in patients with chronic asthma.

Adolescent↗
PubMed2001

Inducible nitric oxide synthase (iNOS) and nitrotyrosine immunoreactivity in the spinal cords of transgenic mice with a G93A mutant SOD1 gene.

We performed a prospective, longitudinal immunohistochemical study of the spinal cords of transgenic mice with a G93A mutant SOD1 gene at 4 fixed points in time, using antibodies to inducible nitric oxide synthase (iNOS) and nitrotyrosine. The purpose of this study was to characterize the temporal and topographic distribution of iNOS and nitrotyrosine immunoreactivity in the spinal cord over a certain period, thus illuminating the possible role of increased oxidative damage to the motor system in the neurodegenerative process in this animal model. Specimens from age-matched non-transgenic wild-type mice served as controls. The control mice showed no positive iNOS or nitrotyrosine immuunoreactivity in the somata of anterior horn neurons or their neuronal processes at any age. On the other hand, the transgenic mice demonstrated a common immunostaining pattern of iNOS and nitrotyrosine in the anterior horn neurons. When the mice reached the age of 24 wk (early presymptomatic stage), the anterior horn neurons and their neuronal processes were occasionally immunostained for iNOS and nitrotyrosine; at 28 wk (late presymptomatic stage), the anterior horn neurons were not uncommonly immunostained; at 32 wk (early symptomatic stage) and 35 wk (end-stage), positive iNOS and nitrotyrosine immunoreactivity was frequently observed in proliferated reactive astrocytes as well as in the somata of the anterior horn cells. The selective localization of positive iNOS and nitrotyrosine immunoreactivity in the anterior horn neurons suggests that oxidative stress may be involved in the pathomechanism of degeneration of motor neurons in this transgenic animal model.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Lower cervical origin of the P13-like potential in median SSEPS.

The authors studied the origin of the scalp P13-like potential in median somatosensory evoked potentials, which have been reported to be preserved in patients with cervicomedullary lesions or in brain death. There were five patients with high to middle cervical lesions (C2/3 or C3/4 level). Small P13-like potentials after P11 were identified for all patients with a noncephalic reference but not with an ear reference. Their onset latencies were slightly earlier than the expected latency of the true P13/14 onset. In two patients, delayed true P13/14s followed by N18s were identified with both noncephalic and ear references. The authors argue that the P13-like potential observed in these patients is a different entity from scalp P13 in normal subjects. Because the C3/4 vertebral level corresponds to the C5 cord level, the origin of the P13-like potential must be below C5, contradicting the previous opinion that it is generated at the cervicomedullary junction or at the high cervical dorsal column. The authors named this potential lower cervical P13 (or lcP13), and present an opinion that it is generated by the beginning of the second spinal ascending volley, which has been described by direct-recording studies in humans.

Adult↗
PubMed2001

Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin.

A pathway sensitive to rapamycin, a selective inhibitor of mammalian target of rapamycin (mTOR), down-regulates effects of insulin such as activation of Akt (protein kinase B) via proteasomal degradation of insulin receptor substrate 1 (IRS-1). We report here that the pathway also plays an important role in insulin-induced subcellular redistribution of IRS-1 from the low-density microsomes (LDM) to the cytosol. After prolonged insulin stimulation, inhibition of the redistribution of IRS-1 by rapamycin resulted in increased levels of IRS-1 and the associated phosphatidylinositol (PI) 3-kinase in both the LDM and cytosol, whereas the proteasome inhibitor lactacystin increased the levels only in the cytosol. Since rapamycin but not lactacystin enhances insulin-stimulated 2-deoxyglucose (2-DOG) uptake, IRS-1-associated PI 3-kinase localized at the LDM was suggested to be important in the regulation of glucose transport. The amino acid deprivation attenuated and the amino acid excess enhanced insulin-induced Ser/Thr phosphorylation and subcellular redistribution and degradation of IRS-1 in parallel with the effects on phosphorylation of p70 S6 kinase and 4E-BP1. Accordingly, the amino acid deprivation increased and the amino acid excess decreased insulin-stimulated activation of Akt and 2-DOG uptake. Furthermore, 2-DOG uptake was affected by amino acid availability even when the degradation of IRS-1 was inhibited by lactacystin. We propose that subcellular redistribution of IRS-1, regulated by the mTOR-dependent pathway, facilitates proteasomal degradation of IRS-1, thereby down-regulating Akt, and that the pathway also negatively regulates insulin-stimulated glucose transport, probably through the redistribution of IRS-1. This work identifies a novel function of mTOR that integrates nutritional signals and metabolic signals of insulin.

Acetylcysteine↗
PubMed2001

[Enhancing effect of switching iontophoresis on transdermal absorption of glibenclamide].

Glibenclamide(GLI) is widely used as an oral hypoglycemic drug in the treatment of non-insulin dependent diabetes mellitus (NIDDM). We investigated The enhancing effect of switching iontophoresis on the transdermal absorption and reduction of skin irritation to develop a transdermal dosage form of GLI. The 0.1% of Gli suspensions in 0.2 M tris-HCl buffer of pH 7.4, 8.0 and 8.5 were prepared as donor solutions. We examined drug permeation through the excised rat abdominal skin, drug absorption in rats and reduction of skin irritation after application of switching iontophoresis for 1 h using DC 10 V. The solubility of GLI in 0.2 M tris-HCl buffer increased with a rise in pH. In the permeation study, GLI was permeated continuously and the cumulative amount of permeated GLI increased using an alkaline donor solution. In the drug absorption study, the application group of pH 8.5 gave higher plasma concentration levels than those of pH 7.4 and 8.0 groups. The skin irritation evoked by the application of iontophoresis was pathologically studied. A total irritation score (TIS) was estimated as a judging standard for the skin damage. The TIS value increased dependently with a rise in pH. However, it was considered that the skin irritations were not serious and small matters. The results demonstrate the possibility of iontophoretic transdermal administration of GLI and the effect of drug solubility in the donor solution on the absorption of GLI.

Animals↗
PubMed2001

Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator--activated receptor-gamma.

Tumor necrosis factor (TNF)-alpha is one of the candidate mediators of insulin resistance associated with obesity, a major risk factor for the development of type 2 diabetes. The insulin resistance induced by TNF-alpha is antagonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. The aim of the current study was to dissect the mechanism whereby pioglitazone, one of the TZDs, ameliorates TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes. Pioglitazone restored insulin-stimulated 2-deoxyglucose (DOG) uptake, which was reduced by TNF-alpha, with concomitant restorations in tyrosine phosphorylation and protein levels of insulin receptor (IR) and insulin receptor substrate (IRS)-1, as well as association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity. Adenovirus-mediated gene transfer of either wild-type human peroxisome proliferator-activated receptor (PPAR)-gamma2 or a mutant carrying a replacement at the consensus mitogen-activated protein kinase phosphorylation site (hPPAR-gamma2-S112A) promoted adipogenesis of 3T3-L1 fibroblasts and restored TNF-alpha-induced decrease of triglyceride in adipocytes as effectively as pioglitazone. Overexpression of the PPAR-gamma proteins in TNF-alpha-treated adipocytes restored protein levels of IR/IRS-1, but did not improve insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated 2-DOG uptake. These results indicate that the ability of pioglitazone to restore insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for amelioration of TNF-alpha-induced insulin resistance, may be independent of the adipogenic activity of PPAR-gamma that regulates protein levels of IR/IRS-1.

3T3 Cells↗
PubMed2001

Growth hormone induces cellular insulin resistance by uncoupling phosphatidylinositol 3-kinase and its downstream signals in 3T3-L1 adipocytes.

Growth hormone (GH) is well known to induce in vivo insulin resistance. However, the molecular mechanism of GH-induced cellular insulin resistance is largely unknown. In this study, we demonstrated that chronic GH treatment of differentiated 3T3-L1 adipocytes reduces insulin-stimulated 2-deoxyglucose (DOG) uptake and activation of Akt (also known as protein kinase B), both of which are downstream effects of phosphatidylinositol (PI) 3-kinase, despite enhanced tyrosine phosphorylation of insulin receptor substrate (IRS)-1, association of IRS-1 with the p85 subunit of PI 3-kinase, and IRS-1-associated PI 3-kinase activity. In contrast, chronic GH treatment did not affect 2-DOG uptake and Akt activation induced by overexpression of a membrane-targeted form of the p110 subunit of PI 3-kinase (p110(CAAX)) or Akt activation stimulated by platelet-derived growth factor. Fractionation studies indicated that chronic GH treatment reduces insulin-stimulated translocation of Akt from the cytosol to the plasma membrane. Interestingly, chronic GH treatment increased insulin-stimulated association of IRS-1 with p85 and IRS-1-associated PI 3-kinase activity preferentially in the cytosol. These results indicate that cellular insulin resistance induced by chronic GH treatment in 3T3-L1 adipocytes is caused by uncoupling between activation of PI 3-kinase and its downstream signals, which is specific to the insulin-stimulated PI 3-kinase pathway. This effect of GH might result from the altered subcellular distribution of IRS-1-associated PI 3-kinase.

3T3 Cells↗