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Biomedical subjects

H Gonda

Publications and source records attributed to H Gonda.

At least 19 recordsLinked to original sources

Heritable translocations induced by dermal exposure of male mice to acrylamide.

Acrylamide (AA) is an important industrial chemical used mainly in the production of polymers. It can be absorbed through the skin. AA was shown to be a germ cell clastogen that entails a genetic risk for exposed workers. The genetic risk calculation was based on mouse heritable translocation test data obtained after acute intraperitoneal (ip) exposure (Adler et al., 1994). To obtain a correction factor between ip and dermal exposure, dominant lethal and heritable translocation tests were carried out with dermal exposure of male mice to AA. In the dominant lethal test, male (102/El x C3H/El)F1 mice were exposed by dermal application to the shaved backs of 50 mg/kg AA per day on five consecutive days or to five daily ip injections of 50 mg/kg AA. One day after the end of exposure, the males were mated to untreated females of the same hybrid stock for four days and females were changed every four days for a total of five matings. Dominant lethal effects were found during matings 1-3. For ip exposure, these values were 81.7, 85.7 and 45.4%, respectively; for dermal exposure the corresponding values were 22.1, 30.6 and 16.5%, respectively. In the heritable translocation assay, male C3H/El mice were treated with five dermal exposures of 50 mg/kg AA and mated 1.5-8.5 days after the end of exposure to untreated female 102/El mice. Pregnant females were allowed to come to term and all offspring were raised to maturity. Translocation carriers among the F1 progeny were selected by a sequential fertility testing and cytogenetic analysis including G-band karyotyping and M-FISH. A total of 475 offspring were screened and 41 translocation carriers were identified. The observed translocation frequency after dermal exposure was 8.6% as compared to 21.9% after similar ip exposure (Adler, 1990). The calculated ratio of ip vs. dermal exposure of 0.39 can be applied to obtain a more realistic calculation of genetic risk for dermally exposed workers.

Acrylamide↗

DNA polymerase beta is not essential for the formation of palindromic (P) region of T cell receptor gene.

Formation of palindromic (P) region at the variable (V)-diversity (D)-joining (J) junction in DNA polymerase beta (pol-beta) deficient mice were investigated by sequencing of reverse transcriptase-polymerase chain reaction (RT-PCR) products of mRNAs encoding the beta chain of T cell receptor (TCR). Total 42 and 43 cDNA clones encoding V(beta8)-D(beta)-J(beta)-C(beta) from E18.5 embryonic thymocytes of pol-beta gene knocked-out and wild type control mouse, respectively, were sequenced. Among them five and six clones from pol-beta knocked-out and wild type, respectively, have P insertions of two nucleotides. This result unequivocally indicates that pol-beta, which is one of the repair-type DNA polymerases most abundantly expressed in thymus and spleen, is not essential for the formation of P region.

Animals↗

Histone acetylation determines the developmentally regulated accessibility for T cell receptor gamma gene recombination.

Variable/diversity/joining (V[D]J) recombination of the T cell receptor (TCR) and immunoglobulin (Ig) genes is regulated by chromatin accessibility of the target locus to the recombinase in a lineage- and stage-specific manner. Histone acetylation has recently been proposed as a molecular mechanism underlying the accessibility control. Here, we investigate the role for histone acetylation in the developmentally regulated rearrangements of the mouse TCR-gamma gene, wherein predominant rearrangement is switched from Vgamma3 to Vgamma2 gene during the fetal to adult thymocyte development. Our results indicate that histone acetylation correlates with accessibility, as histone acetylation at the fetal-type Vgamma3 gene in accord with germline transcription is relatively high in fetal thymocytes, but specifically becomes low in adult thymocytes within the entirely hyperacetylated locus. Furthermore, inhibition of histone deacetylation during the development of adult bone marrow-derived thymocytes by a specific histone deacetylase inhibitor, trichostatin A, leads to elevated histone acetylation, germline transcription, cleavage, and rearrangement of the Vgamma3 gene. These data demonstrate that histone acetylation functionally determines the chromatin accessibility for V(D)J recombination in vivo and that an epigenetic modification of chromatin plays a direct role in executing a developmental switch in cell fate determination.

Acetylation↗

Targeting of Krüppel-associated box-containing zinc finger proteins to centromeric heterochromatin. Implication for the gene silencing mechanisms.

Krüppel-associated box-containing zinc finger proteins (KRAB-ZFPs) repress transcription via functional interaction with the corepressor KRAB-associated protein-1 (KAP-1). KAP-1 directly interacts with heterochromatin protein 1 (HP1), a dose-dependent regulator of heterochromatin-mediated silencing. Here we show that two KRAB-ZFPs that we previously identified, KRAZ1 and KRAZ2, are targeted to foci of centromeric heterochromatin containing HP1alpha through the interaction with KAP-1. Centromeric targeting potential of KRAZ1 and KAP-1 is strictly correlated with their silencing activities; a KRAB mutant of KRAZ1 that is unable to bind KAP-1 and KAP-1 deletions unable to bind HP1 cannot localize to centromeric foci nor repress transcription. We provide evidence that this correlation is likely to be functionally relevant. First, overexpression of the VP16 transactivation domain fused with the KAP-1 deletion that binds to KRAB but not to HP1 leads to dramatic redistribution of KRAZ1 from centromeric foci and simultaneously converts KRAZ1-mediated silencing into strong transcriptional activation. Second, a specific inhibitor of histone deacetylases, trichostatin A, effectively redistributes KRAZ1 and KAP-1 from centromeric foci and partially relieves their silencing activities. These data strongly suggest that KRAB-ZFPs/KAP-1 silence transcription by dynamic recruitment of the target locus to the specific gene silencing compartment, centromeric heterochromatin, in a histone deacetylase-dependent manner.

3T3 Cells↗

[A survival case of severe Legionella longbeachae pneumonia].

A 56-year-old Japanese male was admitted to Toyohashi Municipal Hospital because of fever, cough, and dyspnea. Chest X-ray film showed bilateral alveolar infiltrates. He suffered from severe hypoxemia and was given a diagnosis of acute respiratory distress syndrome. He was also complicated with disseminated intravascular coagulation and pseudomembranous colitis. He fully recovered by intensive treatment with antibiotics, mechanical ventilation and endotoxin eliminating therapy. Legionella longbeachae was isolated from his respiratory specimens and was regarded as the etiologic agent of his pneumonia.

Humans↗

[A clinical study on patients detected Pasteurella multocida from sputum].

We reported ten cases, (four female and six male), whose sputum cultures positive for Pasteurella multocida from 1990 to 2000. In the past eleven years increasing numbers of cases have appeared in our hospital. The majority of the cases with P. multocida possessed some underlying pulmonary diseases (seven cases, 70%), inactive lung tuberculosis or bronchiectasis. There were compromised hosts such as high ages person, steroids dependent person and diabetes mellitus patients. P. multocida was almost susceptible to antibioticus (penicillin and cephalosporins), although some erythromycin resistant strains were identified. The cats' oral cavities in our two cases were cultured and P. multocida were isolated. In our survey the prevalence of this organism is as high as 85% in cats. Our data suggests that patients who are in the high infection risk category are easily infected to P. multocida.

Adolescent↗

1-Aminobenzotriazole inhibits acrylamide-induced dominant lethal effects in spermatids of male mice.

Acrylamide (AA) is a germ cell mutagen and induces clastogenic effects predominantly in spermatids of mice. The mechanism of AA clastogenicity has been a matter of dispute. Since the reactivity of AA with DNA is low but is high with proteins containing SH groups, it was suggested that protamine alkylation could be the mechansim of clastogenicity by AA in spermatids. This was substantiated by the observation that the time course of protamine alkylation and dominant lethal effects in spermatids of mice induced by AA was strictly parallel. Another suggestion was that AA may be metabolized by cytochrome P-450 to the epoxide glycidamide (GA), which is then the ultimate DNA-reactive clastogen. This suggestion was based on the similarity of the stage specificity pattern for dominant lethality and heritable translocation induction by AA and GA. To test this latter assumption, 1-aminobenzotriazole (ABT), an inhibitor of P-450 metabolism, was used in the present experiments. Male mice were pretreated with ABT (3x50 mg/kg) on three consecutive days followed by AA treatment (125 mg/kg) on day 4. Parallel groups of animals were treated with AA (125 mg/kg), ABT (3x50 mg/kg) or with the solvent double-distilled water. The experiment was repeated once with slightly varied mating parameters. The results of both experiments showed that ABT inhibited or significantly reduced the AA-induced dominant lethal effects. Thus, the present data support the hypothesis that the AA metabolite GA is the ultimate clastogen in mouse spermatids.

Acrylamide↗

Mutual education between hematopoietic cells and bone marrow stromal cells through direct cell-to-cell contact: factors that determine the growth of bone marrow stroma-dependent leukemic (HB-1) cells.

A stroma-dependent cell line (HB-1) was established from myelogenous leukemic cells of CBA/N mouse. Characterization of the cells showed that HB-1 proliferated on hematopoietic supportive stromal cells (MS-10), but did not survive or proliferate on hematopoietic nonsupportive cells (MS-K). Direct contact between HB-1 and MS-10 appears to be necessary for HB-1 to proliferate on MS-10. We found that interleukin-1alpha (IL-1alpha) produced by MS-10 plays a major role in the survival and proliferation of HB-1. IL-11 did not support the proliferation of HB-1 cells by itself, but enhanced the proliferation of HB-1 cells in the presence of IL-1alpha. The expression of IL-1alpha and IL-11 was induced in MS-10 by the direct contact with HB-1 cells, and the expression of IL-1 receptor type I (IL-1RI) and interleukin-11 receptor (IL-11R) was induced in HB-1 cells by the attachment of the cells to MS-10. These findings show the existence of two-way interactions between HB-1 and MS-10.

Acute Disease↗

Dose response study for 1,3-butadiene-induced dominant lethal mutations and heritable translocations in germs cells of male mice.

Butadiene (BD) and its metabolites have extensively been studied in the EU sponsored research project "Multi-endpoint analysis of genetic damage induced by 1,3-butadiene and its major metabolites". Within this project a dominant lethal test and a heritable translocation test were performed with male mice to study the dose-response relationships for the respective endpoints. BD concentrations of 130 and 500 ppm were tested in the dominant lethal assay by exposing male mice on 6 h/day for five consecutive days resulting in doses of 3900 and 15,000 ppmh, respectively. Males were mated for four consecutive weeks at a ratio of 1:2 to untreated females. A positive dominant lethal effect was observed in the first mating week in the experiment with 15,000 ppmh but no dominant lethality was found with the lower dose of 3900 ppmh. The present dominant lethal data have to be viewed together with the data already published for a BD dose of 39,000 ppmh (1300 ppm at 6 h/day on 5 consecutive days) [1]. The main difference between results with the highest and the middle dose is that mating weeks one and two (sperm and late spermatids) showed an effect at 39,000 ppmh while only mating week one (sperm) showed an effect at 15,000 ppmh. In the heritable translocation assay, males mice were exposed with a BD dose of 15,000 ppmh and mated for one week to untreated females. Among 434 F1 offspring, we found 5 translocation carriers (1.15% vs. 0.05% in the historical control, p < 0.001). In the previous heritable translocation experiment with a BD dose of 39,000 ppmh of DB exposure, 2.7% of the offspring carried a reciprocal translocation [2]. These data can be used for quantification of genetic risk. The dose response for BD-induced heritable translocations in sperm and late spermatids of mice was linear (Y = 0.05 + 6.9 x 10(-5)X) and a doubling dose of 725 ppmh could be calculated.

Animals↗

[An autopsy case of chronic granulomatous disease diagnosed by biopsy].

This report concerns a male patient aged 25 years, diagnosed at the age of 12 years as suffering from chronic granulomatous disease. This patient had p47-phox deficiency. He was admitted to this hospital because of fever and dyspnea accompanied by right spontaneous pneumothorax. He failed to respond to medical treatment. He died from respiratory failure four months after admission. Autopsy demonstrated pigmented lipid histiocytes characteristic of CGD. These characteristic pigmented cells were distributed in the spleen, liver, lymph nodes and in the small intestine. As for the nature of the pigment, lipofuschin-like compound were identified. Granulomatous component was seen in the mucosa of the stomach obtained by operation. The presence and characteristic distribution of such pigmented macrophages in tissue in young adults may suggest the diagnosis of CGD.

Adult↗

Two cases of recurrent pulmonary metastasis resected after operation for gastric cancer.

It is said that the prognosis is poor in cases with recurrent pulmonary metastasis after operation for gastric cancer. In this article, 2 cases with nodular type of pulmonary metastasis resected after operation for gastric cancer and surviving well are reported by the authors. Case 1: 57-year-old female. The patient underwent a total gastrectomy for the 3'type of cardiac cancer. As the serum levels of tumor markers increased and the chest X-ray examination revealed a mass lesion in the right lung (S10), the operation for the lesion under the diagnosis of metastatic lung cancer was performed 1 year and 2 months after gastrectomy. The patient died of pulmonal and pleural metastasis 4 years and 7 months after the first operation. Case 2: 65-year-old male. The patient underwent a subtotal gastrectomy for the 5' type of gastric cancer. Chest X-ray examination for follow-up study revealed a mass lesion in the left lung (S5). The patient underwent a left pulmonary superior lobe resection 2 years and 9 months after gastrectomy. The patient is still alive 6 years after the first operation. Surgical treatment must be actively considered for nodular type of metastatic lung cancer after operation for gastric cancer.

Adenocarcinoma↗

[Malignant fibrous histiocytoma of the lung].

A 68-year-old man had a malignant fibrous histiocytoma of the lung that was found at autopsy. The patient was admitted to our hospital because of exertional dyspnea. A chest X-ray film and chest CT scan showed atelectasis in the left upper lobe. Examination with a fiberoptic bronchoscope revealed a necrotic mass in the left mainstem bronchus. Microscopic examination of a biopsy specimen disclosed several atypical giant cells but was not diagnostic. He underwent chemotherapy with CBDCA, IFM and VP-16, because a malignant tumor of the lung was strongly suspected. After three cycles of chemotherapy, the tumor had shrunk, as demonstrated on repeated bronchoscopy. The patient's condition improved temporarily, but he began to complain of dyspnea, and died of respiratory insufficiency despite radiotherapy. Postmortem examination was done. The tumor in the lung was mainly composed of spindle-shaped fibroblast-like cells and several pleomorphic giant cells with multiple nuclei, with storiform and fascicular patterns. Immunohistochemically, these tumor cells were shown to contain vimentin, alpha-1-antitrypsin, and LN-5. These findings were compatible with malignant fibrous histiocytoma of the lung.

Aged↗

[Effects of cepharanthin on leukopenia and thrombocytopenia induced by chemotherapy in lung cancer patients].

We studied the effects of Cepharanthin (CEP) on bone marrow suppression induced by chemotherapy in 18 primary lung cancer patients (14 NSCLC, 4 SCLC). NSCLC patients received IP (IFM+CDDP) therapy and SCLC patients received ION (IFM+VCR+ACNU) therapy. For the control, we chose the first course and we administered CEP (1 mg/kg) during the second course. The rate of leukopenia and neutropenia was significantly lower during the CEP course than during the control (p less than 0.01). The recovery rate (at 3 weeks) of leukopenia and neutropenia was significantly higher during the CEP course than during the control (p less than 0.05). But, obvious effects of CEP for lymphopenia and thrombocytopenia were not obtained. Side effects by CEP were not observed in this study. These data suggest that the large dose of CEP contributes to the prevention of leukopenia, especially neutropenia, in patients who receive a sufficient amount of anticancer drugs.

Adult↗

[A case of bronchocentric granulomatosis presenting as a tumorous shadow on chest X-ray film].

A 57-year-old woman was admitted to our hospital with cough, sputum and abnormal chest X-ray. In summer, 1989, she developed cough which gradually worsened in autumn. In November, the chest X-ray revealed a tumorous shadow in the left suprahilar region. On admission, there were no symptoms of bronchial asthma. Chest X-ray revealed a subpleural tumorous shadow in the left upper lung field. X-ray findings suggested that the tumorous shadow in the suprahilar region moved to the left peripheral upper lung field. Left B1+2 orifice obstruction with necrotic tissue was seen on fiberoptic bronchoscopy. Transbronchial biopsies failed to yield specific diagnostic findings, except for bronchitis with exudate containing eosinophils. In February, 1990, she developed hemosputum and left chest pain. Chest X-ray showed consolidation in the left apical lung field. Left upper lobectomy was performed. Histological examination disclosed many granulomas with central necrosis around the bronchi, and aspergillus hyphae were seen. These findings are compatible with bronchocentric granulomatosis without asthma.

Bronchial Diseases↗

[Two cases of human chorionic gonadotropin-producing large cell carcinoma of the lung accompanied with gynecomastia].

Two cases of human chorionic gonadotropin (HCG)-producing lung carcinoma are reported. Both were male, aged 66 and 65, respectively histological examination of percutaneous lung biopsy revealed large cell carcinoma. The patients both developed bilateral gynecomastia during their clinical course. Endocrine function tests demonstrated high levels of HCG, HCG-beta, luteinizing hormone, estrone, estradiol, progesterone in the blood. They were given only anticancer chemotherapy with no effect and died. Autopsy revealed extensive metastases of lung cancer and the presence of HCG in tumor cells was demonstrated by immunohistochemical technique in both cases.

Aged↗

[A clinical study on ceftazidime in the treatment of intractable respiratory infections].

Ceftazidime (CAZ) was administered to 51 patients (37 males, 14 females) with respiratory infections including severe cases, accompanied by various underlying respiratory diseases. The clinical efficacy and side effects of CAZ were investigated. The mean age and body weight of these 51 cases were 62.6 years and 48.0 kg, respectively. CAZ was administered by intravenous drip infusion (daily dose of 2-4 g) for a mean of 14.7 days to a mean total dose of 56.7 g. Clinical efficacy rates were 64% (18 of 28 cases), 80% (16 of 20 cases) and 67% (2 of 3 cases) for airway and intermediary regional infections, pneumonia (including lung abscess) and pyothorax, respectively. In the bacteriological study, efficacy rates and bacterial eradication rates were 69% and 67%, 33% and 20%, 100% and 100%, and 100% and 100% for infections caused by Pseudomonas aeruginosa (13 cases), Staphylococcus aureus (6 cases), Streptococcus pneumoniae (6 cases) and Klebsiella pneumoniae (4 cases), respectively, and bacterial eradication was achieved in both of 2 cases of Peptostreptococcus anaerobius and 2 cases of Haemophilus influenzae, and 1 case each of Peptococcus sp., Fusobacterium necrophorum and Serratia marcescens. Side effects observed were eruption in 1 case (2%) and elevated GOT, GPT and Al-P values in 1 case (2%), but these cases tended to recover after CAZ treatment was discontinued.

Adult↗