[Significance of PPAR gamma(peroxisome proliferator-activated receptor gamma) in hypertension and its vascular complications].
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Animals↗
Biomedical subjects
H Itoh
Publications and source records attributed to H Itoh.
[Prognostic assessment of the new UICC TNM classification for resected lung cancer].
To evaluated the new UICC TNM classification, we investigated the prognosis of patients who had resection of non-small cell lung cancer. A total of 670 patients with non-small cell lung cancer underwent complete resection and pathologic staging of the disease from 1987 to 1994. The survivals were calculated with Kaplan-Meier methods on the basis of overall deaths, and the survival curves were compared by Logrank test. The 5-year survival rates were 84.6% in stage I A (n = 187), 65.2% in stage I B (n = 177), 41.5% in stage IIA (n = 24), 46.7% in stage IIB (n = 100), 25.6% in stage IIIA (n = 139), 25.8% in stage IIIB and 0 in stage IV. There were significant differences in survival between stage I A and stage I B as well as between stage IIB and stage IIIA. However, there were no significant differences in survival between stage IIA and stage IIB, between stage IIIA and stage IIIB. No significant difference in survival was observed among patients with T1N1M0, T2N1M0 and T3N0M0 (43.9%). In stage IIIB, the patients with pm1 N2 disease (8.9%) had more poorly prognosis than the patients with pm1N0 disease (70.1%) and pm1N1 (38.9%) disease. We concluded that the dividing stage I into A and B categories and placing T3N0M0 in stage II and placing pm2 in stage IV were adequate. In the patients with satellite tumors within the primary lobe of the lung, we think that a new category depended on the N-category is necessary.
Adult↗
[Neurosarcoidosis with girdle sensation and polyradiculoneuropathy masquerading as Guillain-Barré syndrome].
We herein report two patients with neurosarcoidosis presenting girdle sensation in the trunk and polyradiculoneuritis. The first patient, a 53-year-old woman, manifested subacute progressive paresthesia in all four limbs and below the Th 3 level with girdle sensation from the thorax to lower abdomen and mild weakness in the left upper limb and the bilateral lower limbs. The patient was diagnosed to have sarcoidosis based on a biopsy of the scalenus anticus lymph nodes. The second patient, a 63-year-old woman, showed an acute onset of weakness and paresthesia in all four limbs and girdle sensation from the Th 5 to Th 8 level. On examination, she demonstrated diminished tendon reflexes in all four limbs, mild to severe weakness in all four limbs, paresthesia in all four limbs and below the Th 5 level. Although Guillain-Barré syndrome was initially suspected in this patient, the presence of girdle sensation led us to examine the possibility of neurosarcoidosis. Her examination demonstrated an abnormal accumulation of gallium in the bilateral hilar lymph nodes and mediastinum on scintigraphy, an elevated CD 4/CD 8 ratio in the bronchoalveolar lavage fluid, a negative tuberculin reaction, and elevated serum lysozyme level. These findings thus fulfilled the clinical criteria for sarcoidosis. None of the two patients showed any abnormalities in the thoracic cord MRI. In the first patient F wave was not evoked in either upper or lower limbs, while in the second patient temporal dispersion on M wave was observed in the right median and both ulnar nerves. We therefore consider the girdle sensation to have not been caused by myelopathy but instead by polyradiculopathy. When sarcoid peripheral neuropathy masquerades as Guillain-Barré syndrome, then the presence of girdle sensation may help diagnosis of neurosarcoidosis.
Diagnosis, Differential↗
[Effect of angiotensin converting enzyme inhibitor lisinopril on sympathetic heart rate response during exercise in the early phase of acute myocardial infarction].
OBJECTIVES: Sympathetic heart rate response decreases in patients with left ventricular dysfunction. Angiotensin converting enzyme (ACE) inhibitors effectively prevent heart failure after myocardial infarction. However, the effect of ACE inhibitors on heart rate response is not well known. The present study investigated the effect of ACE inhibitors on sympathetic heart rate response in the early phase of acute myocardial infarction. METHODS: Sixty-five patients with acute myocardial infarction receiving no beta-blocking agents participated in the study. The subjects consisted of 25 patients (mean age 60.2 +/- 10.7 years) treated with ACE inhibitor lisinopril from the initial stage and 40 control subjects (mean age 57.7 +/- 7.6 years). Cardiopulmonary exercise testing with a treadmill was performed using the ramp protocol in the first month and the third month after the onset of the disease. Heart rate (HR) was measured in the resting state (rest) and immediately after peak exercise (peak). At the same time, blood samples were obtained to investigate the changes in the plasma level of norepinephrine (NE). The degree of sympathetic heart rate response was evaluated as follows: (peak HR - rest HR)/¿(peak NE - rest NE)/rest NE¿ x 100. RESULTS: There were no significant differences between the 2 groups in the first month in anaerobic threshold, peak oxygen uptake and plasma brain natriuretic peptide concentration. Though the change of heart rate was not significant, the change in the plasma level of norepinephrine was significantly lower in the lisinopril group (9.3 +/- 4.4 vs 5.7 +/- 2.8, p < 0.01). In the first month, the heart rate response in the control group was markedly lower than that in the lisinopril group (8.7 +/- 3.5 vs 15.2 +/- 8.5 beats/min/%, p < 0.01). In the third month, the significant difference between the 2 groups disappeared (10.7 +/- 7.9 vs 14.0 +/- 9.7 beats/min/%, NS) due to the increase of the value in the control subjects. CONCLUSIONS: From these results, we conclude that ACE inhibitors are effective to improve sympathetic heart rate response during exercise in the early phase of myocardial infarction.
Anaerobic Threshold↗
Immunohistochemical and statistical studies on the islets of Langerhans pancreas in autopsied patients after gastrectomy.
We describe in detail the pathologic features of the islets of Langerhans in specimens of the pancreas from 75 autopsy specimens of patients who underwent gastrectomy and compare them with specimens from 22 patients not having gastrectomy with respect to the duration of the postoperative period and the operative procedure. In comparison with the control group, the islets of Langerhans from the gastrectomy patients showed hyperplasia and increased numbers of endocrine cells within 5 years of gastrectomy but atrophy and decreased numbers of endocrine cells thereafter. These changes are compatible with anti-insulin immunoreactivity (B-cells) in the islets of Langerhans, where B-cell counts correlated with the area of the islets. The proliferating cell nuclear antigen (PCNA)-positive cell ratio in the islets was higher during the early phase after gastrectomy, whereas the apoptotic cell ratio was not affected by the time after gastrectomy. Hyalinization of the islets of Langerhans was first recognized after 5 years postoperatively, and the percentage of hyalinization gradually increased. Amylin deposits, detected by immunostaining, increased progressively in the islets in relation to the duration of postoperative period, correlating inversely with B-cell count and PCNA positivity. These histologic changes suggest that B cells proliferated secondary to oxyhyperglycemia in the early phase after gastrectomy followed by the state of waste, finally resulting in atrophy and amylin deposits, which led to hypofunction of the islets of Langerhans with resultant glucose intolerance. HUM PATHOL 31:1368-1376.
Amyloid↗
Biomechanics of cervical tooth structure lesions and their restoration.
OBJECTIVE: The purpose of this study was to evaluate photoelastically the effects of a cervical tooth structure lesion and its restoration on stress distribution within a tooth. METHOD AND MATERIALS: Three-dimensional composite models of a maxillary first premolar with a buccal cervical lesion were fabricated. Two types of cervical lesion were tested: one was wedge shaped and had a sharp line angle at the apex of the lesion, and the other was more rounded and saucer shaped. Vertical loads of 10 lb were applied to the unrestored and restored models at the tip of the buccal cusp, the tip of the lingual cusp, and the center of the occlusal surface. The resulting stresses within the tooth model were monitored and recorded photographically in the field of a circular polariscope arrangement. RESULTS: In the unrestored situation, stress concentrated at the apex of the lesion, regardless of the lesion configuration. However, the sharper, wedge-shaped lesion demonstrated a more severe stress concentration. In the restored situation, stress around the lesion apex and the lingual cervical lesion decreased, while stresses at the gingival and occlusal margins of the lesion increased, compared with the unrestored situation. These tendencies were most obvious when the buccal cusp was loaded. CONCLUSION: The presence of a cervical lesion changed occlusal load-induced stress distribution and concentrated stress at the apex of the lesion. The shape and dimension of the lesion governed the severity of stress concentration. Restoration of the cervical lesion relieved concentrated stress at the apex of the lesion.
Bicuspid↗
[Repeated deterioration of tuberculous meningitis due to a reduction in the corticosteroid dosage during chemotherapy].
A 17-year-old man with a high fever, confusion and neck stiffness was diagnosed to have tuberculous meningitis, and was immediately placed on prednisolone (40 mg/day) as well as standard antituberculosis drugs (isoniazid, rifampicin and pyrazinamide). The clinical symptoms improved rapidly and the number of cerebrospinal fluid(CSF) cells decreased from 1837/mm3 on admission to 76/mm3 on the 7th day. Thereafter the dosage of prednisolone was gradually reduced. As a result, however increased nuchal rigidity, papilloedema and an increase in the number of CSF cells of 934/mm3 were all observed on the 35th day. Prednisolone thus again administered at the original dosage and the patient quickly showed a clinical improvement. CSF cells decreased to 271/mm3 on the 70th day. When prednisolone was again tapered down, increased nuchal rigidity, abducent nerve palsy and papilloedema appeared again with a marked increase in the number of CSF cells of 1309/mm3 on the 91th day. Therefore, we continued to treat the patient with prednisolone, in addition to the standard antituberculosis treatment, at a dose of 80 mg/day and tapered off very slowly over six months. This treatment resulted in a marked recovery with no recurrence. In this case, prednisolone was indispensable for treating tuberculous meningitis in combination with appropriate antituberculosis drugs, though the role of corticosteroids has remained controversial over the years. This case might be an example of paradoxical progression in tuberculous meningitis.
Adolescent↗
Effect of prostaglandin E2 on nitric oxide synthesis in articular chondrocytes.
Both nitric oxide (NO) and prostaglandin E2 (PGE2) are known to play an important role in cartilage metabolism. The present study investigated the novel intercellular mechanism of inducible NO synthase (iNOS) induction mediated by PGE2 in articular chondrocytes. Bovine articular chondrocytes were stimulated by cyclic adenosine monophosphate (cAMP) elevating agents like PGE2 in the presence of interleukin-1 alpha (IL-1 alpha). NO generation was measured by using the Griess reaction. Inducible NOS mRNA was semi-quantitated by reverse transcription-polymerase chain reaction (RT-PCR). While little NO was released from articular chondrocytes in the presence of PGE2 or direct adenylate cyclase activator such as forskolin, synergistic augmentation of NO generation was observed when chondrocytes were stimulated by PGE2 or forskolin in combination with IL-1 alpha. Further expression of iNOS mRNA by stimulation of PGE2 in the presence of IL-1 alpha simultaneously was also detected by RT-PCR in comparison with the mRNA induction by IL-1 alpha stimulation alone. These results indicated that PGE2 might modulate the articular cartilage metabolism by augmentation of chondrocyte NO synthesis in inflammatory process through cAMP-protein kinase A system.
Adenylyl Cyclases↗
Importance of the G protein gamma subunit in activating G protein-coupled inward rectifier K(+) channels.
The G protein-coupled inward rectifier K(+) channel (GIRK) is activated by direct interaction with the heterotrimeric GTP-binding protein betagamma subunits (Gbetagamma). However, the precise role of Gbeta and Ggamma in GIRK activation remains to be elucidated. Using transient expression of GIRK1, GIRK2, Gbeta1, and Ggamma2 in human embryonic kidney 293 cells, we show that C-terminal mutants of Gbeta1, which do not bind to Ggamma2, are still able to associate with GIRK, but these mutants are unable to induce activation of GIRK channels. In contrast, other C-terminal mutants of Gbeta1 that bind to Ggamma2, are capable of activating the GIRK channel. These results suggest that Ggamma plays a more important role than that of an anchoring device for the Gbetagamma-induced GIRK activation.
Cell Line↗
Structural basis for the regulation of UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-3 gene expression in adenocarcinoma cells.
The UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-3 (Gal NAc-T3) gene, a member of the Gal NAc transferase gene family, is expressed in a tissue-specific manner. To elucidate the function of this gene, we have focused on the molecular mechanism underlying regulation of gene expression. We have cloned Gal NAc-T3 cDNA and used it to show that Gal NAc-T3 mRNA is expressed in tumor cell lines derived from secretory epithelial tissue adenocarcinomas but not in cell lines derived from bladder and epidermoid carcinomas. Using a polyclonal antibody to Gal NAc-T3, we observed protein expression in adenocarcinoma but not non-adenocarcinoma cell lines, and in breast carcinoma cells but not in normal breast tissue. We used Gal NAc-T3 cDNA to isolate three overlapping genomic clones containing the 5'-portion of the human Gal NAc-T3 gene, and we sequenced 1.6 kb around the first exon. A transient expression assay using the luciferase gene showed that promoter activity was much higher in MCF-7 cells than in KB cells. In vivo footprint experiments showed significant protection of a distal GC box, an NRF-1 site, and an AP-2 site in MCF-7 cells. A novel stem and loop structure extending from nucleotide -103 to nucleotide -165 and contiguous to these transcription factor binding sites seemed to be functional in regulating Gal NAc-T3 gene transcription, and a KMnO4 footprint experiment showed that this stem and loop structure could be formed in vivo. We also observed dimethyl sulfate hypersensitive sites in the untranslated region around nucleotide +50 in MCF-7 but not in KB cells. These findings indicate that Gal NAc-T3 gene expression is regulated by multiple systems, including transcription factor binding sites and a stem-and-loop structure, and that this regulation is restricted to cell lines derived from epithelial gland adenocarcinomas but not cells derived from nonsecretory epithelial tissue carcinomas. In addition, our immunohistochemical results suggest that our anti-Gal NAc-T3 antibody may be useful for diagnostic purposes in the early stages of breast cancer.
Adenocarcinoma↗
Enhanced coexpression of YB-1 and DNA topoisomerase II alpha genes in human colorectal carcinomas.
The transcription factor YB-1 is expressed in a wide range of cell types and has been implicated in the regulation of various genes involved in cell proliferation. Nuclear expression of YB-1 is correlated with MDR-1 gene expression in breast cancer and osteosarcoma. In this study, we asked whether YB-1 expression is enhanced in human colorectral carcinoma and if it is associated with the expression of target genes such as MDR-1, DNA topoisomerase II alpha and PCNA. YB-1, DNA topoisomerase II alpha, PCNA and MDR-1 expression were assessed by Western blotting, Northern blotting and immunohistochemistry in 26 human colorectal carcinomas. The involvement of YB-1 in DNA topoisomerase II alpha gene expression was examined by transient DNA transfection assays. YB-1 was overexpressed in almost all cancerous lesions in comparison with normal mucosa in surgically resected colorectal carcinomas of 26 patients. YB-1 expression correlated well with both DNA topoisomerase II alpha and PCNA expression. In contrast, no correlation was observed between YB-1 and MDR-1 expression. We also found that a transient co-transfection with a DNA topoisomerase II alpha promoter-luciferase plasmid and an antisense YB-1 expression construct resulted in a significant reduction of the promoter activity in KM12C human colon cancer cells. YB-1 may be an excellent proliferation-associated marker and may be a transcription factor regulating DNA topoisomerase II alpha gene expression in human colorectal carcinoma.
Aged↗
Mammalian HSP60 is a major target for an immunosuppressant mizoribine.
It has been reported that immunosuppressant cyclosporin A or FK506 binds to immunophilins in the cell and that these immunophilins make a complex with molecular chaperones HSP70 or HSP90. Although mizoribine has been used clinically as an immunosuppressant, immunophilins of the agent have not yet been fully understood. We investigated their specific binding proteins using mizoribine affinity column chromatography and porcine kidney cytosols. By increasing mizoribine in the eluant from the column, two major proteins (with molecular masses of 60 and 43 kDa) were detected by SDS-polyacrylamide gel electrophoresis. Based on the amino acid sequence analysis of these proteins, 60- and 43-kDa mizoribine-binding proteins were identified with HSP60 and cytosolic actin, respectively. A considerable amount of actin was also eluted from the affinity column by nucleotides, but a very low quantity of HSP60 was eluted under the same conditions. On the other hand, HSP60 was eluted as a major protein in the eluant that was eluted preferentially, with nucleotide followed by mizoribine. Actin was also detected in the eluant, but the quantity of the protein was very low. These results indicated that HSP60 has high affinity to mizoribine, and the interaction was also observed on surface plasmon resonance analysis. Although HSP60 or GroE facilitated refolding of citrate synthase in vitro, mizoribine interfered with the chaperone activity of HSP60. On different types of mizoribine affinity columns, HSP60 or actin recognized the NH(2) group of mizoribine, and this group may be a functional group of the agent.
Amino Acid Sequence↗
A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90.
The 90-kDa heat shock protein (HSP90) acts as a specific molecular chaperone in the folding and regulates a wide range of associated proteins such as steroid hormone receptors. It is known that HSP90 possesses two different chaperone sites, both in the N- and C-domains, and that the chaperone activity of HSP90 is blocked by binding of geldanamycin (GA) to the N-domain, the same as the ATP-binding site. Here we show that Cisplatin [cis-diamminedichloroplatinum (II), CDDP], an antineoplastic agent, associates with HSP90 and reduces its chaperone activity. In order to analyse the binding proteins, bovine brain cytosols were applied to a CDDP-affinity column and binding proteins were eluted by CDDP. In the elutants, only 90-kDa protein bands were detected on SDS/PAGE, and the protein was cross-reacted with the anti-HSP90 antibody on immunoblotting. No protein bands were detected in the elutants from the control column on SDS/PAGE. These results indicated that CDDP has a high affinity for HSP90. On CD spectrum analysis, the binding of CDDP to HSP90 resulted in a conformational change in the protein. Although HSP90 inhibited the aggregation of citrate synthase as a molecular chaperone in vitro, the activity was suppressed almost completely in the presence of CDDP. Mg/ATP has an influence on the chaperone activity to some extent. The CDDP binding region of HSP90 is near the C-terminal which is quite different from the GA-binding site. Our results suggest that the chaperone activity of HSP90 may be inhibited by the binding of CDDP or GA by different mechanisms.
Adenosine Triphosphate↗
Expression of NADH/NADPH oxidase p22phox in human coronary arteries.
BACKGROUND: NADH/NADPH oxidase is an important source of superoxide in the vasculature. Recently, we found that polymorphism of the gene p22phox, a critical component of this oxidase, is associated with a risk of coronary artery disease. The aim of this study was to investigate the localization of p22phox in human coronary arteries and to examine its difference in expression between nonatherosclerotic and atherosclerotic coronary arteries. METHODS AND RESULTS: Using coronary artery sections from autopsied cases (n=11), the expression of p22phox was examined by immunohistochemistry and Western blotting. In nonatherosclerotic coronary arteries, p22phox was weakly expressed, mainly in the adventitia. In atherosclerotic coronary arteries, intensive immunoreactivity was detected in neointimal and medial smooth muscle cells and infiltrating macrophages in hypercellular regions and at the shoulder region. Semiquantitative analysis and Western blotting showed that the expression of p22phox in atherosclerotic coronary arteries was more pronounced than that in nonatherosclerotic arteries. Double staining revealed p22phox expression in adventitial fibroblasts, smooth muscle cells, macrophages in the neointima and media, and endothelial cells. CONCLUSIONS: As atherosclerosis progressed, the expression of p22phox increased through the vessel wall. p22phox might participate in the pathogenesis and pathophysiology of atherosclerotic coronary disease.
Adult↗
Glycation of apolipoprotein E impairs its binding to heparin: identification of the major glycation site.
The increased glycation of plasma apolipoproteins represents a possible major factor for lipid disturbances and accelerated atherogenesis in diabetic patients. The glycation of apolipoprotein E (apoE), a key lipid-transport protein in plasma, was studied both in vivo and in vitro. ApoE was shown to be glycated in plasma very low density lipoproteins of both normal subjects and hyperglycemic, diabetic patients. However, diabetic patients with hyperglycemia showed a 2-3-fold increased level of apoE glycation. ApoE from diabetic plasma showed decreased binding to heparin compared to normal plasma apoE. The rate of Amadori product formation in apoE in vitro was similar to that for albumin and apolipoproteins A-I and A-II. The glycation of apoE in vitro significantly decreased its ability to bind to heparin, a critical process in the sequestration and uptake of apoE-containing lipoproteins by cells. Diethylenetriaminepentaacetic acid, a transition metal chelator, had no effect on the loss of apoE heparin-binding activity, suggesting that glycation rather than glycoxidation is responsible for this effect. In contrast, glycation had no effect on the interaction of apoE with amyloid beta-peptide. ApoE glycation was demonstrated to be isoform-specific. ApoE(2) showed a higher glycation rate and the following order was observed: apoE(2)>apoE(4)>apoE(3). The major glycated site of apoE was found to be Lys-75. These findings suggest that apoE is glycated in an isoform-specific manner and that the glycation, in turn, significantly decreases apoE heparin-binding activity. We propose that apoE glycation impairs lipoprotein-cell interactions, which are mediated via heparan sulfate proteoglycans and may result in the enhancement of lipid abnormalities in hyperglycemic, diabetic patients.
Aged↗
Predominant germ-line mutation of the hMSH2 gene in Japanese hereditary non-polyposis colorectal cancer kindreds.
By means of PCR-SSCP and direct sequencing, we detected 12 germ-line mutations of hMSH2 or hMLH1 in 37 Japanese hereditary non-polyposis colorectal cancer (HNPCC) kindreds, of whom 15 satisfied the Amsterdam and 22 the Japanese criteria. The germ-line mutation detection rate of hMSH2 was much higher than that of hMLH1 (11/37 vs. 1/37). The total mutation detection rate of hMSH2 and hMLH1 in the Amsterdam criteria group was significantly higher than that in the Japanese criteria group (9/15 vs. 3/22). Furthermore, the mean age of the HNPCC patients in the mutation-positive group was lower than that in the mutation-negative one; the rates of both vertical transmission and multiplicity of tumors in the mutation-positive group were higher than those in the mutation-negative one. In addition, the number of patients with microsatellite instability-positive cancers in the mutation-positive group was higher than that in the mutation-negative one. Our results suggest firstly that the hMSH2 gene plays a much more important role than hMLH1 in the carcinogenesis of Japanese HNPCC patients, secondly that the rate of hMSH2 and hMLH1 mutations is high in the kindreds satisfying the Amsterdam criteria and thirdly that both the clinical phenotypes (early onset, vertical transmission and multiplicity of tumors) and the microsatellite instability status are important for the genetic screening of HNPCC.
Colorectal Neoplasms, Hereditary Nonpolyposis↗
The Src family tyrosine kinase is involved in Rho-dependent activation of c-Jun N-terminal kinase by Galpha12.
Gt12, a member of alpha subunit of heterotrimeric G protein G12 subfamily, has been shown to stimulate c-Jun N-terminal kinase (JNK) activity through the low molecular weight GTP-binding proteins Ras, Rac, and Cdc42. In this study using the transient expression of a constitutively activated mutant of Galpha12 (Galpha12Q229L) in human embryonic kidney (HEK) 293 cells, we found that Rho and Src family kinase are also involved in the Galpha12-induced activation of JNK. The activation of JNK by Galpha12Q229L was inhibited by dominant-negative RhoA(T19N), and botulinum C3 exoenzyme which specifically inactivates Rho. In addition, the expression of activated RhoA(G14V) elevated JNK activity in HEK 293 cells. The Galpha12Q229L-stimulated activation of JNK was blocked by a specific inhibitor of protein tyrosine kinases (PP2), and C-terminal Src kinase (Csk). Moreover, we observed that Galpha12Q229L stimulated Src family kinase activity and v-Src induced JNK activation. Interestingly, the v-Src-induced activation of JNK was inhibited by dominant-negative RhoA(T19N). In contrast, Csk did not inhibit the JNK activation by activated RhoA(G14V). These results suggest that Rho and Src family kinase are required for the Galpha12-induced JNK activation, and that Src family kinase acts upstream of Rho activation in the JNK pathway.
3T3 Cells↗