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Biomedical subjects

K Iwai

Publications and source records attributed to K Iwai.

At least 55 records · Page 3Linked to original sources
PubMed2000

Early oxidative DNA damages and late development of lung cancer in diesel exhaust-exposed rats.

To demonstrate DNA damages in the early stage of diesel exhaust exposure, an inhalation study of 1 through 12 months was conducted. The lung burden of diesel soot increased with increase in exposure duration. Histologically, hyperplastic foci of alveolar epithelia were found at 6-month exposure and became prominent at the 12th month, with slight nuclear atypia and positive p53 staining. The level of 8-OH-hydroxyguanosine (8-OH-dG) in the exposed rat lungs showed an increase from 1 month of exposure, followed by a gradual increase, reaching almost a plateau level at the 9th month. An in vitro experiment demonstrated significant 8-OH-dG formation when diesel particles and H(2)O(2) were added to the DNA solution. The level of bulky aromatic DNA adducts peaked at the 1st month of exposure, followed by a decrease. By the end of the observation period of 30 months, lung tumors developed even in the 6-month exposure group, and the earliest lung tumors were found only in rats that survived longer than 18 months. In conclusion, persisting oxidative stress on DNA induced in the early phase of diesel exhaust exposure, together with inflammation, seems to play an important role in carcinogenesis at advance ages after a long latent period.

Animals↗
PubMed2000

Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase.

Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.

Humans↗
PubMed2000

Fulminant hepatitis B following bone marrow transplantation in an HBsAg-negative, HBsAb-positive recipient; reactivation of dormant virus during the immunosuppressive period.

It is widely accepted that seroconversion of HBsAg to HBsAb indicates clearance of hepatitis B virus. We describe a 50-year-old man with chronic myelocytic leukemia who developed lethal hepatitis B 22 months after allo-BMT. He had been negative for HBsAg and positive for HBsAb before BMT. Hepatitis B virus latently existing in the liver cells before BMT proliferated during the immunosuppressed period causing fatal hepatitis. Recipients with positive HBsAb should be considered to have the potential for active hepatitis B to emerge after BMT. Bone Marrow Transplantation (2000) 25, 105-108.

Bone Marrow Transplantation↗
PubMed2000

Diagnostic efficacy of three-dimensional images by helical CT for lesions in the maxillofacial region.

The purpose of this study was to evaluate the efficacy of three-dimensional (3-D) images produced with a helical CT for the diagnosis of lesions occurring in the maxillofacial region. Thirty-four patients, who had lesions in the maxillofacial region, were examined by plain radiography (intra and extraoral) and the helical CT. Further, 3-D images were reconstructed from the data provided by the helical CT using the volume rendering method. These images were compared with plain radiographic images and conventional two-dimensional (2-D) CT images in terms of the information they provided for diagnosis. Using the 3-D images for tumors, bone destruction, inner components, extent of the lesion,the relationship between the lesion and surrounding anatomical landmarks, and the roots of the adjacent teeth were observed in overall views. We conclude that 3-D images produced by helical CT may provide useful information for the diagnosis of lesions.

Adult↗
PubMed2000

[A study of recovery factor about drug addiction recovery center "DARC"].

This study examines the effectiveness of the 'DARC' (Drug Addiction Rehabilitation Center) and its program in treating patients with drug dependence. DARC is the only rehabilitation facility group managed by recovered drug users in Japan. It uses the 'Twelve Step Program' as part of its recovery regime. Through structured questionnaires, the changes of participants' and ex-participants' everyday behavior, their acceptance of spirituality, attitude toward drugs, self-esteem, their coping skills and loneliness were examined. The results revealed: a.. Negative partial correlation between loneliness and everyday behavior. b.. Negative partial correlation between loneliness and positive/effective coping skills. c.. Positive partial correlation between acceptance of 'spirituality' and attitude toward drugs. d.. Positive partial correlation between acceptance of 'spirituality' and positive/effective coping skills. These results suggest that the acceptance of 'spirituality' and decreasing loneliness are important factors in the recovery from drug dependence.

Adaptation, Psychological↗
PubMed2000

[Three cases of measles-associated interstitial pneumonia].

It has been reported that measles-associated pneumonia is easily complicated with fatal respiratory failure. During the 6 months from January to June 1998, we treated three young patients with measles-associated pneumonia who had previously been healthy. Their chest X-ray and CT examinations revealed mainly interstitial and partially alveolar pneumonia surrounding extensive areas of bronchiolitis. In one patient, respiratory failure was present, and arterial blood gas analysis showed severe hypoxemia. Therefore, this patient was treated with a mechanical ventilator, which dramatically improved the condition. The other two patients received steroid-pulse therapy and improved rapidly. We believed that in measles-associated pneumonia, steroid pulse therapy is to be recommended for the severely ill patient. According to a report by the Japanese Ministry of Health and Welfare, measles-like disease was widespread in Japan in 1991 and occasionally encountered in 1996. But in Yamanashi Prefecture, the disease was prevalent in 1991, 1994 and 1998. The number of patients in our hospital had reflected the prevalence in the prefecture. It is suggested that the measles is a disease of regional prevalence.

Adult↗
PubMed1999

A single-chain antibody fragment specific for the Plasmodium berghei ookinete protein Pbs21 confers transmission blockade in the mosquito midgut.

Mouse monoclonal antibody 13.1 (mAb 13.1) directed against Pbs21, a 21-kDa sexual-stage surface protein of Plasmodium berghei, is known to inhibit oocyst development from gametocytes and ookinetes in the mosquito midgut. To examine the properties and potential uses of a single-chain antibody fragment (scFv) for blocking transmission of malaria parasites to mosquitoes, we have cloned and sequenced the genes encoding variable regions of the immunoglobulin heavy and light chains (V(H) and V(L)) of mAb 13.1. The V(H) and V(L) genes were assembled as an scFv gene, and expressed in a baculovirus expression system. Following purification of 13.1 scFv, Western blotting and inhibition ELISA assays confirmed that 13.1 scFv retained the binding specificity of the parent mAb 13.1 for Pbs21. Furthermore, 13.1 scFv bound to the surface of P. berghei ookinetes, and blocked oocyst development in the mosquito midgut by at least 93%, as assessed by oocyst counts in mosquitoes. We suggest that the 13.1 scFv gene could be useful not only in studying the mechanism of transmission blockade, but also in generating, by mosquito germline transformation, a model system to evaluate the production of mosquitoes refractory to malaria.

Amino Acid Sequence↗
PubMed1999

Stabilization of iron regulatory protein 2, IRP2, by aluminum.

Iron regulatory protein 2 (IRP2) is one of the central regulators of iron homeostasis. IRP2 regulates expression of molecules involved in iron metabolism by binding to iron responsive elements (IREs) in the transcripts of those molecules in iron depletion. IRP2 is regulated by the accelerated degradation initiated by the iron-catalyzed oxidation. Here we report that aluminum antagonizes the iron-induced decrease in IRE binding activity of IRP2. Aluminum also inhibits iron-induced oxidation of IRP2 in vitro. These results suggest that aluminum stabilizes IRP2 by interfering with the iron-catalyzed oxidation, which results in perturbation of iron metabolism.

Aluminum↗
PubMed1999

Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex.

Mutations of von Hippel-Lindau disease (VHL) tumor-suppressor gene product (pVHL) are found in patients with dominant inherited VHL syndrome and in the vast majority of sporadic clear cell renal carcinomas. The function of the pVHL protein has not been clarified. pVHL has been shown to form a complex with elongin B and elongin C (VBC) and with cullin (CUL)-2. In light of the structural analogy of VBC-CUL-2 to SKP1-CUL-1-F-box ubiquitin ligases, the ubiquitin ligase activity of VBC-CUL-2 was examined in this study. We show that VBC-CUL-2 exhibits ubiquitin ligase activity, and we identified UbcH5a, b, and c, but not CDC34, as the ubiquitin-conjugating enzymes of the VBC-CUL-2 ubiquitin ligase. The protein Rbx1/ROC1 enhances ligase activity of VBC-CUL-2 as it does in the SKP1-CUL-1-F-box protein ligase complex. We also found that pVHL associates with two proteins, p100 and p220, which migrate at a similar molecular weight as two major bands in the ubiquitination assay. Furthermore, naturally occurring pVHL missense mutations, including mutants capable of forming a complex with elongin B-elongin C-CUL-2, fail to associate with p100 and p220 and cannot exhibit the E3 ligase activity. These results suggest that pVHL might be the substrate recognition subunit of the VBC-CUL-2 E3 ligase. This is also, to our knowledge, the first example of a human tumor-suppressor protein being directly involved in the ubiquitin conjugation system which leads to the targeted degradation of substrate proteins.

Carrier Proteins↗
PubMed1999

Identification of the ubiquitin carrier proteins, E2s, involved in signal-induced conjugation and subsequent degradation of IkappaBalpha.

The last step in the activation of the transcription factor NF-kappaB is signal-induced, ubiquitin- and proteasome-mediated degradation of the inhibitor IkappaBalpha. Although most of the components involved in the activation and degradation pathways have been identified, the ubiquitin carrier proteins (E2) have remained elusive. Here we show that the two highly homologous members of the UBCH5 family, UBCH5b and UBCH5c, and CDC34/UBC3, the mammalian homolog of yeast Cdc34/Ubc3, are the E2 enzymes involved in the process. The conjugation reaction they catalyze in vitro is specific, as they do not recognize the S32A,S36A mutant species of IkappaBalpha that cannot be phosphorylated and conjugated following an extracellular signal. Furthermore, the reaction is specifically inhibited by a doubly phosphorylated peptide that spans the ubiquitin ligase recognition domain of the inhibitor. Cys-to-Ala mutant species of the enzymes that cannot bind ubiquitin inhibit tumor necrosis factor alpha-induced degradation of the inhibitor in vivo. Not surprisingly, they have a similar effect in a cell-free system as well. Although it is clear that the E2 enzymes are not entirely specific to IkappaBalpha, they are also not involved in the conjugation and degradation of the bulk of cellular proteins, thus exhibiting some degree of specificity that is mediated probably via their association with a defined subset of ubiquitin-protein ligases. The mechanisms that underlie the involvement of two different E2 species in IkappaBalpha conjugation are not clear at present. It is possible that different conjugating machineries operate under different physiological conditions or in different cells.

Carrier Proteins↗
PubMed1999

Dobutamine stress echocardiography at 7.5 mg/kg/min using color tissue Doppler imaging M-mode safely predicts reversible dysfunction early after reperfusion in patients with acute myocardial infarction.

Dobutamine stress echocardiography (DSE) is widely used to predict reversible left ventricular dysfunction, but evaluation by this method is subjective. The recently developed color tissue Doppler imaging (TDI) M-mode may permit objective and quantitative assessment of changes in wall motion induced by DSE. We tested the hypothesis that this new method can detect sensitively reversible dysfunction in the post-myocardial infarction setting. DSE with color TDI M-mode and conventional DSE were performed to predict reversible dysfunction in 53 patients at a mean of 3 days after infarction using 7.5 and 10 microg/kg/min of dobutamine. Follow-up regular echocardiography (4 weeks later) was used as the reference technique to define reversible dysfunction segments. To predict reversible dysfunction segments, the standard segmental wall motion score change on conventional DSE and the ratio of the segmental wall velocity difference at rest versus stress (7.5 and 10 microg/kg/ min) on DSE with color TDI M-mode (7.5-TDI-M and 10-TDI-M, respectively) were used. With 7.5 microg/kg/min of dobutamine, the sensitivity for predicting reversible dysfunction using color TDI M-mode (7.5-TDI-M) was significantly higher than that of conventional DSE (89% vs 73%, p <0.05) whereas specificities and predictive values were almost identical. With a 10-microg/kg/min dose, color TDI-M mode (10-TDI-M) and conventional DSE were not significantly different in predicting reversible dysfunction. With use of color TDI-M mode, regional wall motion during DSE was analyzed objectively and quantitatively. Moreover, combined TDI-M and conventional data were slightly superior to either mode alone. There were no arrhythmias during 7.5 microg/kg/min of dobutamine, but 9 arrhythmias occurred during the 10-microg/kg/min dose in patients with acute myocardial infarction. In conclusion, color TDI M-mode permits objective and quantitative assessment of regional ventricular wall motion and gives additional information for detecting reversible dysfunction in DSE. Improvement of sensitivity at a lower dose of dobutamine with color TDI-M mode may increase the safety of DSE in the post-myocardial infarction setting.

Angioplasty, Balloon, Coronary↗
PubMed1999

4F2 (CD98) heavy chain is associated covalently with an amino acid transporter and controls intracellular trafficking and membrane topology of 4F2 heterodimer.

4F2, also termed CD98, is an integral membrane protein consisting of a heavy chain linked to a light chain by disulfide bond. We have generated a monoclonal antibody to the mouse 4F2 light chain and cloned the cDNA. It encodes a mouse counterpart of rat L-type amino acid transporter-1, and induces system L amino acid transport in Xenopus oocytes in the presence of 4F2 heavy chain. Transfection studies in mammalian cells have indicated that the 4F2 heavy chain is expressed on the plasma membrane on its own, whereas the 4F2 light chain can be transported to the surface only in the presence of 4F2 heavy chain. 4F2 heavy chain is expressed diffusely on the surface of fibroblastic L cells, whereas it is localized selectively to the cell-cell adhesion sites in L cells expressing cadherins. These results indicate that the 4F2 heavy chain is associated covalently with an amino acid transporter and controls the cell surface expression as well as the membrane topology of the 4F2 heterodimer. Although 4F2 heavy and light chains are expressed coordinately in most tissues, the light chain is barely detected by the antibody in kidney and intestine, despite the presence of heavy chain in a complex form. The results predict the presence of multiple 4F2 light chains.

Amino Acid Transport Systems↗
PubMed1999

Preoperative cervical cytology in endometrial carcinoma and its clinicopathologic relevance.

OBJECTIVE: The aim of this study was to assess the significance of malignant or suspicious cervical cytology in preoperative identification of poor prognostic factors in endometrial carcinoma and to determine whether preoperative abnormal cervical cytology is an independent prognostic factor for endometrial carcinoma. METHODS: We evaluated the correlation between preoperative cervical cytology and postoperative clinicopathologic findings, sites of metastasis, and receptor status from 99 surgically staged patients with endometrial carcinoma. RESULTS: Sixty-eight patients (68.7%) had normal cervical cytology, 1 (1.0%) had atypical cytology suspicious for malignancy, and 30 (30.3%) had malignant cytology on preoperative cervical cytology. Malignant and suspicious cervical smears were statistically correlated with surgical stage (P = 0.001), histopathology (P = 0.010), tumor grade (P = 0.012), depth of myometrial tumor invasion (P = 0.001), cervical involvement (P = 0. 01), lymph node metastases (P = 0.002), adnexal metastases (P = 0. 012), progesterone receptor (P = 0.007), and estrogen receptor (P = 0.031). No association was found between preoperative cervical cytology and patients' age or peritoneal cytology. Univariate analysis showed that cervical cytology was related to survival (P = 0.018). However, multivariate analysis of cervical cytology, stage, grade, and myometrial invasion showed that preoperative cervical cytology was not a significant prognosticator for survival. CONCLUSION: Patients with endometrial carcinoma who have malignant or suspicious cytology detected by preoperative cervical cytology are at increased risk of having known poor prognostic factors. However, positive preoperative cervical cytology itself does not appear to be an independent prognostic factor and probably should not influence treatment decisions in endometrial cancer.

Adult↗
PubMed1999

Prognostic significance of progesterone receptor immunohistochemistry for lymph node metastases in endometrial carcinoma.

OBJECTIVE: The aim of this study was to determine whether progesterone receptor (PR), estrogen receptor (ER), p53 protein, and proliferating cell nuclear antigen (PCNA) expression constitute independent prognostic factors for lymph node metastases in endometrial carcinoma using immunohistochemical techniques on hysterectomy and biopsy specimens. METHODS: We evaluated the correlation between lymph node metastases and PR/ER immunohistochemistry, p53/PCNA expression, age, tumor grade, myometrial tumor invasion, cervical involvement, and ovarian metastases in a series of 99 cases of primary endometrial carcinoma surgically staged with systemic pelvic lymphadenectomy and para-aortic lymph node biopsy. RESULTS: Lymph node metastases from endometrial carcinoma were statistically correlated with negative PR immunohistochemistry (P = 0.001), intense p53 expression (66% or more of the tumor cells stained, P = 0.003), deep myometrial tumor invasion (greater than one-half, P = 0.001), and cervical involvement (P = 0.001). Tumor grade showed borderline statistical significance for lymph node metastases (P = 0.058). On multivariate analysis, negative PR, intense p53 expression, and cervical involvement were significant prognostic variables for lymph node metastases (P = 0.0001, 0.0023, and 0.002, respectively). Immunohistochemical study indicated that the PR status on preoperative biopsy specimens and hysterectomy specimens was in good agreement, but p53 status was not. Age, ovarian metastases, ER immunohistochemistry, and PCNA expression were not significantly related to lymph node metastases. CONCLUSION: PR immunohistochemistry appeared to be the most powerful prognostic factor associated with lymph node metastases in endometrial carcinoma, independent of other clinicopathological parameters.

Adult↗
PubMed1999

Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1.

Receptor desensitization is accomplished by accelerated endocytosis and degradation of ligand-receptor complexes. An in vitro reconstituted system indicates that Cbl adaptor proteins directly control downregulation of the receptor for the epidermal growth factor (EGFR) by recruiting ubiquitin-activating and -conjugating enzymes. We infer a sequential process initiated by autophosphorylation of EGFR at a previously identified lysosome-targeting motif that subsequently recruits Cbl. This is followed by tyrosine phosphorylation of c-Cbl at a site flanking its RING finger, which enables receptor ubiquitination and degradation. Whereas all three members of the Cbl family can enhance ubiquitination, two oncogenic Cbl variants, whose RING fingers are defective and phosphorylation sites are missing, are unable to desensitize EGFR. Our study identifies Cbl proteins as components of the ubiquitin ligation machinery and implies that they similarly suppress many other signaling pathways.

Caenorhabditis elegans Proteins↗
PubMed1999

Development of a compact computed tomographic apparatus for dental use.

OBJECTIVE: To describe a compact computed tomographic apparatus (Ortho-CT) for use in dental practice. METHODS: Ortho-CT is a cone-beam-type of CT apparatus consisting of a multifunctional maxillofacial imaging machine (Scanora, Soredex, Helsinki, Finland) in which the film is replaced with an X-ray imaging intensifier (Hamamatsu Photonics, Hamamatsu, Japan). The region of image reconstruction is a cylinder 32 mm in height and 38 mm in diameter and the voxel is a 0.136-mm cube. Scanning is at 85 kV and 10 mA with a 1 mm Cu filter. The scan time is 17 s comparable with that required for rotational panoramic radiography. A single scan collects 512 sets of projection data through 360 degrees and the image is reconstructed by a personal computer. The time required for image reconstruction is about 10 min. RESULTS: The resolution limit was about 2.0 lp mm-1 and the skin entrance dose 0.62 mGy. Excellent image quality was obtained with a tissue-equivalent skull phantom: roots, periodontal ligament space, lamina dura, and cancellous bone were clearly visualized. CONCLUSION: Ortho-CT provides three-dimensional images of excellent quality for dental use at a low entrance dose.

Humans↗