Accelerated accumulation of methylmercury in the rat fetus at the late pregnant stage.
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Biomedical subjects
Publications and source records attributed to M Ohsawa.
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We redirect attention to contributions to the energization, of the active transport of amino acids in the Ehrlich cell, beyond the known energization, by down-gradient comigration of Na+, beyond possible direct energization by coupling to ATP breakdown, and beyond known energization by exchange with prior accumulations of amino acids. We re-emphasize the uphill operation of System L, and by prior depletion of cellular amino acids show that this system must receive energy beyond that made available by their coupled exodus. After this depletion the Na+-indepdendent accumulation of the norbornane amino acid, 2-aminobicycloheptane-2-carboxylic acid becomes strongly subject to stimulation by incubation with glucose. Energy transfer between Systems A and L through the mutual substrate action of ordinary amino acids was minimized although not entirely avoided by the use of amino acid analogs specific to each system. When 2,4-dinitrophenol was included in the depleting treatment, and pyruvate, phenazine methosulfate, or glucose used for restoration, recovery of uptake of the norbornane amino acid was independent of external Na+ or K+ levels. Restoration or the uptake of 2-(methylamino)isobutyric acid was, however, decreased by omission of external K+. Contrary to an earlier finding, restoration of uptake of each of these amino acids was associated with distinct and usually correlated rises in cellular ATP levels. ATP addition failed to stimulate exodus of the norbornane amino acid from plasma membrane vesicles, although either NADH or phenazine methosulfate did stimulate exodus. ATP production and use is thus associated with transport energization although evidence for a direct role failed to appear.
We have carried out serum assays for myoglobin in parallel with the determination of serum CPK activity to assess its usefulness in raising the detectability rate of Duchenne muscular dystrophy carriers. Of the 14 carriers, ten (71.4%) had high serum levels of myoglobin and nine (64.3%) showed increased serum CPK levels. Either parameter revealed elevation in 11 (78.6%) of the 14 cases studied. Serum myoglobin determination is of noticeable value in the detection of Duchenne muscular dystrophy carriers.
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An optical feeler measuring technique was introduced for evaluating the dimensional accuracy of indirect stone models. It presents the following advantages being able to measure the diameter of specimens in detail at various heights, indicating good reproducibility of the data; and hardly injuring the surface of the stone casts.
Out of 13 patients with congenital muscular dystrophy myoglobinemia was proven in four, and nine of 13 cases of Duchenne dystrophy showed myoglobinemia by counterimmunoelectrophoretic technique. Serum myoglobin was positive in 14 out of 15 patients whose serum creatinine phosphokinase (CPK) levels rose above 2500 units, whereas positive myoglobinemia was obtained in only one patient in eleven with lower CPK levels. All the myoglobinemic patients were less than 5 years of age in the case of congenital muscular dystrophy and less than 9 years of age in the case of Duchenne dystrophy. Thus, the leakage of myoglobin into the serum from the damaged muscle seemed closely correlated to the age of the patients and level of serum CPK, but not to the type of disease.
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It has been suggested that oxidative stress plays a pathogenic role in idiopathic interstitial pneumonias. Macrophage- or neutrophil-derived oxidants seem to be important sources of oxidative stress in this group of inflammatory disorders. Recent experimental studies have revealed that oxidative injury during inflammation or apoptosis can change phosphatidylcholine of cell membrane into its oxidized form, which serves as a ligand for macrophage scavenger receptor CD36. Recently, we developed a monoclonal antibody against oxidized phosphatidylcholine. Using this novel antibody, we performed an immunohistochemical investigation to clarify the localization of oxidized phosphatidylcholine in lung tissues of idiopathic interstitial pneumonias and a relationship between oxidized phosphatidylcholine localization and CD36 expression. Lung specimens obtained from patients with desquamative (n = 8) or usual interstitial pneumonia (n = 15) were studied. Thirteen normal lung tissues were also examined as controls. Antibodies against oxidized phosphatidylcholine, CD36, epithelial cells, macrophages, and neutrophils were used as primary antibodies. The positive cell number was counted by computer-aided morphometry. While there were no oxidized phosphatidylcholine-positive cells in normal lungs, lungs of desquamative or usual interstitial pneumonia contained large numbers of oxidized phosphatidylcholine-positive cells in the alveolar spaces. Double-staining analysis revealed that most oxidized phosphatidylcholine-positive cells were macrophages. The oxidized phosphatidylcholine-positive cells were increased in association with the increase in the densities of macrophages (Rs = 0.87, p < 0.0001) and neutrophils (Rs = 0.89, p < 0.0001). Accumulated macrophages also showed distinct CD36 expression. These findings suggest that oxidative stress and the related product, oxidized phosphatidylcholine, play an important role in the pathophysiology of idiopathic interstitial pneumonias.
Inducibility of chromosomal aberrations and cytotoxicity in cultured Chinese hamster cells by cadmium chloride (CdCl2) was investigated under 3 different treatment conditions: (i) 2-h treatment in MEM medium supplemented with 10% fetal bovine serum (MEM + 10% FBS) or (ii) in HEPES-buffered Hanks' solution (HEPES-Hanks), and (iii) continuous treatment for 24 h in MEM + 10% FBS. Two-h treatment with CdCl2 in HEPES-Hanks or continuous treatment for 24 h in MEM + 10% FBS was respectively 2 or 3 times more cytotoxic than 2-h treatment with the metal in MEM + 10% FBS. Continuous treatment for 24 h with a CdCl2 concentration in excess of 5 X 10(-6) M was too toxic to the cells to allow chromosomal analysis, and moreover, only a slight increase in incidence of chromosomal aberrations was observed at a concentration of 5 X 10(-6) M CdCl2. In contrast, a marked and concentration-dependent increase in incidence of chromosomal aberrations was observed after post-treatment culture for 22 h follows 2-h treatment with 1 X 10(-6) M to 5 X 10(-5) M of CdCl2 in both MEM + 10% FBS and HEPES-Hanks. Two-h treatment with cadmium in HEPES-Hanks was approximately 3 times more potent for the induction of chromosomal aberrations than that in MEM + 10% FBS. Types of aberrations induced by CdCl2 mainly consisted of chromatid gaps and breaks, although a few exchanges, dicentrics and fragmentations were observed at high concentrations of cadmium. Increase in incidence of tetraploidy was also observed with a concentration dependency after 2-h treatment with CdCl2. Potency of CdCl2 to induce chromosomal aberrations after 2-h exposure was comparable to that of benzo[a]pyrene activated with S9 at equitoxic concentrations. Two-h treatment with cadmium markedly inhibited incorporation of [3H]thymidine, even at concentrations at which incorporation of [3H]uridine or [3H]leucine was less inhibited. However, the inhibition of [3H]thymidine incorporation by cadmium was reversible and the incorporation restored to the control level during 2-6 h of post-treatment incubation. These findings suggest that restoration of DNA synthesis after cadmium exposure is required for the efficient detection of chromosomal aberrations induced by the metal.
The effect of cadmium (Cd) on the lymphocyte subpopulation in peripheral blood and spleen was studied in ICR mice given a daily subcutaneous injection of 0.5 and 1.0 mg Cd/kg body weight for 5 days or mice fed with the drinking water containing 3, 30 and 300 ppm Cd for 10 weeks. The reduction of blood B lymphocytes observed in Cd-injected mice was accompanied by the increase of the number of splenic B lymphocytes. On the other hand in Cd-fed mice the reduction of blood T lymphocytes was found and associated with the increase of the number of splenic T lymphocytes. These findings suggest that circulating lymphocytes may redistribute differentially in lymphoid organs responded to the Cd exposure.
As a result of a systematic review of non-Hodgkin's lymphoma of the gastrointestinal tract (GI) at the Yonsei University, Seoul, Korea and the Osaka University, Osaka, Japan, we found an extramedullary plasmacytoma in 5 of a total of 78 cases (6.4%) in Korea and 1 of 136 cases (0.7%) in Osaka, which represents an approximately 9-fold difference in frequency. The presence of the Epstein-Barr virus (EBV) genome was examined in paraffin-embedded specimens from the 5 cases with GI plasmacytoma from Korea together with 17 patients collected by a nationwide study in Japan. There were no clinical findings suggestive of the presence of immunodeficiency in these Korean and Japanese patients. There were no prominent differences in the age distribution or sex ratio between the patients of the two countries. Histologically, the proliferation of mature plasma cells was almost monomorphous with occasional bi- or multinucleated forms. The immunohistochemistry revealed a restricted cytoplasmic expression of immunoglobulin light chain, kappa type in 8 cases and lambda type in 14. A polymerase chain reaction of preserved DNA from 4 Korean and 16 Japanese patients found that only 2, both Korean, were positive for EBV of subtype A. The difference in the frequency of EBV positivity between Korean and Japanese cases was significant (p < 0.05). In situ hybridization revealed positive signals in the nucleus of the tumor cells. IHC revealed that the tumor cells in these two cases were positive for latent membrane protein-1 and EB nuclear antigen-2, showing latent infection of EBV. These findings suggest a close association of EBV and Korean GI plasmacytoma, and might partly explain the remarkable number of cases in this country.
Previous epidemiological studies showed an increased risk for the development of renal cell carcinoma (RCC) after adjuvant therapy or simultaneous discovery of non-Hodgkin's lymphoma (NHL). However, clinicopathological features of NHL complicated by RCC are not well known. We summarized the clinicopathological features of 42 cases with malignant lymphoma complicated by renal tumors collected in a nationwide study in Japan. There were 27 males and 15 females, and the age at initial diagnosis of NHL ranged from 51 to 85 years (median 69 years). The clinical stages of NHL were stage I in 13 patients, stage II in 8, stage III in 8 and stage IV in 13 patients. RCC was simultaneously detected in 4 patients, within 1 year after the diagnosis of NHL in 20 and after more than 1 year in 13 patients. In the remaining 3 patients, NHL was diagnosed 1 year (2 cases) or 6 years (1 case) after nephrectomy. Histologically, all but 2 cases of NHL were diagnosed as diffuse lymphoma, with the large-cell type being the most common. The remaining 2 cases were follicular lymphoma. NHL in 35 cases (85%) were immunophenotyped as B cell type and 4 (10%) as T cell type. Renal tumors in all but 2 cases were classified as RCC: clear-cell type in 29, chromophobic type in 3, chromophilic type in 7 and Bellini duct carcinoma in 1 case. All RCC showed a cellular malignancy of grade II or III. When compared to sporadic autopsy cases of NHL in Japan, the frequency of extranodal lymphoma and B cell type was higher in the current cases (p = 0.06). In addition, leiomyosarcoma occasionally occurred among complicated renal tumors.
Local recurrence of tumor is a common phenomenon in soft tissue sarcoma (STS) and may be accompanied by an increase in malignant potential. In the present study, an increase of proliferative activity in recurrent tumors compared to primary tumors was observed using a silver stain for nucleolar organizer regions (AgNOR), and its implication for predicting prognosis is assessed. 44 patients with STS showing local tumor recurrence were selected. Local recurrence was defined as new tumor growth more than 2 months after the initial surgery in the same region where the primary tumor occurred. All patients received surgery, followed in 11 patients by adjuvant radiotherapy and/or chemotherapy. The histologic subtype was malignant fibrous histiocytoma in 22 cases, synovial sarcoma in 5, leiomyosarcoma in 4, liposarcoma in 3, malignant schwannoma in 3, and others in 7. The interval between initial surgery and local recurrence ranged from 2 to 72 months. No patients changed from one histological subtype to another. Histological changes included an increase in mitosis, cellularity, and sclerosis in 43.2, 31.8, and 27.3%, respectively. The AgNOR count (mean +/- SD) in recurrent tumors (7.22 +/- 2.59) was significantly higher than that in primary tumors (5.58 +/- 2.28; p < 0.0057), clearly showing a tendency for an increase in proliferative activity during recurrence. The 5-year survival rate of patients with a marked increase (> 4) in AgNOR count (16.7%) was worse than with minor to moderate increases (60.0%; p < 0.02). Marked AgNOR increase was more frequently observed in the tumors located in the head and neck and retroperitoneum (40%) than in other sites (9%). Irrespective of the primary site of tumors, a marked AgNOR increase resulted in an unfavorable prognosis. Multivariate analysis of change in histologic factors including AgNOR, cellularity, mitotic counts, pleomorphism, myxoid change, necrosis, sclerosis, and tumor size showed that increase of AgNOR counts was significant (p < 0.05). The present findings suggest that AgNOR counts can be used as a prognostic factor in recurrent STS.
The significance of neovascularization for tumor growth and metastasis has recently been postulated for human cancers; increased microvessel density correlates with increased frequency of metastasis. In the present study, microvessel density was examined in 42 cases of malignant fibrous histiocytoma (MFH). Microvessels were defined as lumens surrounded by anti-factor-VIII-related antigen (FVIII-RA)-antibody-stained endothelium, and counted in a x 400 field. The number of microvessels varied from 4 to 79 (median 14.5). When cases were divided into groups with less than or greater than 20 microvessels, there were no prominent differences in age distribution, sex ratio, size of tumor, depth of tumor, and histologic subtypes between the two groups. The number of microvessels in 19 cases with and 22 cases without metastasis was 19.4 +/- 14.9 and 19.6 +/- 17.4, respectively. Angiogenesis is apparently not a key factor in the formation of metastasis by MFH.
Information on prognostic factors is essential to establish appropriate therapeutic modalities for soft tissue sarcoma (STS). To evaluate the biological nature and prognostic factors of STS, p53 and bcl-2 expression was immunohistochemically studied on paraffin-embedded sections from 70 patients with STS in the extremities and trunk. In addition, the degree of apoptosis was examined by in situ end-labeling. Histologic diagnoses in these cases were malignant fibrous histiocytoma in 29 cases, liposarcoma in 11, synovial sarcoma in 11, leiomyosarcoma in 5, malignant neurogenic tumor in 5, and others in 9. Tumor cells in 31 of 70 cases (44%) showed positive nuclear staining for p53 protein. There was no correlation between p53 expression and tumor size, histologic grade, argyrophilic nucleolar organizer region (AgNOR) count, cellularity and extent of neerosis. Expression of p53 did not correlate with survival of patients. Tumor cells in 24 of 56 cases (43%) were positive for bcl-2 protein expression. The frequency of bcl-2 expression in the tumor cells showed a direct proportion to tumor size (> or = 10 vs. < 10 cm) but inverse proportion to AgNOR counts and cellularity. The 5-year survival rate in patients with bcl-2-positive tumors (87%) was more favorable than in those with bcl-2-negative tumors (53%; p < 0.05). The frequency of apoptosis in low-grade STS was significantly higher than that in the intermediate and high-grade STS (p < 0.001). Extent of necrosis, a well-known prognostic indicator in STS, was not correlated with the frequency of apoptosis. Multivariate analysis showed that cellularity, bcl-2 and AgNOR counts were independent prognostic factors in patients with STS. The current study revealed that STS with a higher expression of bcl-2 had lower proliferative activity and larger size than those without. Immunohistochemical detection of bcl-2 is useful for predicting prognosis in patients with STS.