Biomedical subjects
Publications and source records attributed to N Tsukamoto.
This paper discusses a modified surgical and prosthodontic protocol to place implants in the completely edentulous patient. Methods for presurgical, prosthodontic workup, impression transfer technique, provisionalization, and attachment placement are also discussed.
We preliminarily studied screening for prostatic diseases in one-day total health check-up by employing prostate specific antigen (PSA), international prostate symptom score (IPSS) and quality of life (QOL) index. From January 6 to March 31, 1998, a total of 390 men were included in this study, whose age ranged from 50 to 78 years with the mean of 57.5 years. The questionnaires, IPSS and QOL index, were mailed to the participants in advance. PSA (IMx: Dainapack) was measured at the end of the health check-up and the results of tests were explained on the same day. Participants who showed more than 8 points in IPSS, more than 4 points in QOL index and/or more than 4.1 ng/ml in PSA were given a referral to urologists of corresponding hospitals for further examination. A total of 116 men (29.7%) were judged to need thorough examination. Among 106 men who were referred to urologists, only 34 (32.1%) had visited the urologists by the end of July 1998. Two men (0.51% in all participants) were diagnosed with prostate cancer, 10 received some pharmacotherapy, and 2 underwent transurethral resection of prostate. The results indicate that screening for prostatic diseases in total health check-up is useful, even in an institute without staff urologists, in close association with urologists.
Rap1 GTPase is activated by a variety of stimulations in many types of cells, but its exact functions remain unknown. In this study we have shown that SPA-1 interferes with Rap1 activation by membrane-targeted C3G, C3G-F, in 293T cells through the GTPase activating protein (GAP) activity. SPA-1 transiently expressed in HeLa cells was mostly localized at the cortical cytoskeleton and induced rounding up of the cells, whereas C3G-F conversely induced extensive cell spreading. Conditional SPA-1 overexpression in HeLa cells by tetracycline-regulative system suppressed Rap1 activation upon plating on dishes coated with fibronectin and resulted in the reduced adhesion. When SPA-1 was conditionally induced after the established cell adhesion, the cells gradually rounded up and detached from the dish. Both effects were counteracted by exogenous fibronectin in a dose-dependent manner. Retroviral overexpression of SPA-1 in promyelocytic 32D cells also inhibited both activation of Rap1 and induction of cell adhesion by granulocyte colony stimulating factor without affecting differentiation. These results have indicated that Rap1 GTP is required for the cell adhesion induced by both extracellular matrix and soluble factors, which is negatively regulated by SPA-1.
G protein-coupled receptors are commonly thought to bind their cognate ligands and elicit functional responses primarily as monomeric receptors. In studying the recombinant gamma-aminobutyric acid, type B (GABAB) receptor (gb1a) and a GABAB-like orphan receptor (gb2), we observed that both receptors are functionally inactive when expressed individually in multiple heterologous systems. Characterization of the tissue distribution of each of the receptors by in situ hybridization histochemistry in rat brain revealed co-localization of gb1 and gb2 transcripts in many brain regions, suggesting the hypothesis that gb1 and gb2 may interact in vivo. In three established functional systems (inwardly rectifying K+ channel currents in Xenopus oocytes, melanophore pigment aggregation, and direct cAMP measurements in HEK-293 cells), GABA mediated a functional response in cells coexpressing gb1a and gb2 but not in cells expressing either receptor individually. This GABA activity could be blocked with the GABAB receptor antagonist CGP71872. In COS-7 cells coexpressing gb1a and gb2 receptors, co-immunoprecipitation of gb1a and gb2 receptors was demonstrated, indicating that gb1a and gb2 act as subunits in the formation of a functional GABAB receptor.
CD40 signaling modulates the immune response at least in part by activation of nuclear factor kappaB (NFkappaB). It has been shown that two distinct domains in the CD40 cytoplasmic tail (cyt), namely cyt-N and cyt-C, independently activate NFkappaB. Although four members of the tumor necrosis factor receptor-associated factor (TRAF) family, including TRAF2, TRAF3, TRAF5, and TRAF6, bind to the CD40 cyt, how each TRAF protein contributes to the NFkappaB activation by CD40 is not clear. Here we report that TRAF2, TRAF3, and TRAF5 bind cyt-C, whereas TRAF6 binds cyt-N. cyt-N is conserved poorly between human and mouse CD40, while cyt-C is highly conserved. However, single aa substitution of Glu-235 in cyt-N of human CD40 with Ala abolishes the binding of TRAF6 to cyt-N and NFkappaB activation by cyt-N. Conservation of this Glu between mouse and human CD40 strongly suggests that TRAF6 could link cyt-N to signals essential for CD40-mediated immune response. Furthermore, NFkappaB activation by cyt-C is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by cyt-N, consistent with the result that NFkappaB activation by TRAF2 and TRAF5 is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by TRAF6. These results indicate that NFkappaB activating signals emanating from cyt-N and cyt-C are mediated by the different members of the TRAF family and could be regulated in a distinct manner.
It is sometimes reported that the immunological abnormalities in myelodysplastic syndromes (MDS) induce autoimmune disease (i.e., acute systemic vasculitic syndrome, chronic cutaneous vasculitis, polyneuropathy, relapsing polychondritis, and steroid-responsive pulmonary disorders). We investigated the clinical features of patients with MDS accompanied by nephrotic syndrome. We enrolled 125 patients with MDS who were admitted between January 1979 and May 1996 in this study. The renal function was assessed based on the laboratory data and the findings at the physical examination. The diagnoses of nephrotic syndrome and glomerular disease were established when 24-hr urinary excretion was more than 3.5 g and serum total protein was less than 6.0 g/dl, and when the 24-hr protein excretion was more than 1.5 g. Five patients (4%) had glomerular disease, and three (2.4%) had nephrotic syndrome. Of the five patients with glomerular disease, two had refractory anemia (RA), and three had chronic myelomonocytic leukemia (CMMOL). Three of the total 11 patients with CMMOL were diagnosed as having nephrotic syndrome. Among the CMMOL patients, those with nephrotic syndrome showed higher absolute monocyte numbers than did those without nephrotic syndrome (8830 +/- 4677/microl vs. 3061 +/- 2887/microl, P = 0.03). One CMMOL patient was treated with VP-16 and hydroxyurea. As the white blood cell count in this patient decreased, the 24-hr urine protein excretion and the serum tumor necrosis factor alpha level decreased. The relationship between nephrotic syndrome and CMMOL was not clear. High monocyte count and the serum cytokines in MDS patients may play a partial role in the evolution of glomerulonephritis, and CMMOL may be closely related to nephrotic syndrome.
Carcinosarcoma of the uterus is a highly aggressive neoplasm. However, the angiogenesis of this neoplasm is still unknown. This is the first study to examine the differences in angiogenesis between the epithelial and mesenchymal elements of this biphasic neoplasm. Surgical specimens from 21 primary uterine carcinosarcomas were histopathologically evaluated, and then immunohistochemically analyzed for tumor angiogenesis, using an anti-vascular endothelial growth factor (VEGF) antibody. The microvessel density (MVD) was also measured in each element of these neoplasms, using anti-CD34 monoclonal antibody. The MVD in the epithelial element was found to be higher than that of the mesenchymal element in 20 of 21 (95.2%) primary tumors. The epithelial elements showed a higher MVD (mean, 81.6 +/- 41.1) than the mesenchymal elements (mean, 36.7 +/- 23.8) in these primary tumors (P < .0001). Moreover, the epithelial elements showed a higher VEGF expression (mean, 0.78 +/- 0.23) than the mesenchymal elements (mean, 0.37 +/- 0.20) (P < .0001). The tumors with lymph-vascular invasion showed a higher VEGF expression (n = 17; mean, 0.85 +/- 0.17) than the tumors without lymph-vascular invasion (n = 4, mean, 0.47 +/- 0.12) (P < .01). Microscopically, neither lymph-vascular space invasion nor metastatic tumors consisted of sarcoma alone in this series. In addition, a decrease in the VEGF expression was found in the transitional areas between carcinomatous and sarcomatous elements in all 10 homologous and 4 heterologous tumors evaluated. These results suggest that the tumor angiogenesis in the epithelial element may be more active than that of the mesenchymal element and also substantiated the high metastatic potential of the epithelial element in uterine carcinosarcoma. Based on these findings, carcinoma cells thus may play a key role in the angiogenesis of this biphasic neoplasm.
The morphology of myeloma cells is reported to be one of the prognostic factors in multiple myeloma (MM) patients. We analyzed the prognostic factors, including morphological classification, in 292 patients with MM in order to select poor-risk patients who should be considered candidates for early intensive chemotherapy, including stem cell transplantation. Multivariate analysis was applied to 90 patients diagnosed between 1989 and 1996, because serum beta-2-microglobulin (beta2M) has been measured regularly since 1989, and showed that serum albumin, serum beta2M, and the morphology of myeloma cells predicted survival. According to these factors, patients were divided into 3 risk groups; a high-risk group (14%), a intermediate-risk group (46%) and a low-risk group (40%). There were significant differences between survival times in these 3 groups (median survival: high-risk, 16; intermediate-risk, 22; and low-risk, 44 months).
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The clinical outcome of 3 myelodysplastic syndrome (MDS) patients with polyclonal hematopoiesis is reported. All patients were heterozygous for the phosphoglycerate kinase (PGK) gene. The presence of polyclonal hematopoiesis was determined by the X-chromosome-linked restriction fragment length polymorphism-methylation method using the PGK gene as a marker. The patients were initially diagnosed as having refractory anemia (RA), RA with ring sideroblasts (RARS), and RA with an excess of blasts (RAEB), respectively. Their pancytopenia persisted during the follow-up period of 11.4 years for the RA patient, 19.5 years for the RARS patient and 0.8 years for the RAEB patient. Although the RARS patient continues to be in good health, leukemic transformation occurred in the other 2 patients. A karyotype change from 46,XX to 45,XX,t(3;21),-7 was observed at the time of disease progression in the RA patient. The coexistence of a monoclonal MDS clone and normal bone marrow cells is thought to be the most probable reason for the polyclonal hematopoiesis of these patients.
We report the performance and our impression of five patient-controlled analgesia (PCA) drug delivery devices commercially available; Atom PCA Pump 500, AP-II, Deltec CADD-PCA 5800, Sabratek 6060 and Verifuse. Each of these devices has unique features for PCA. However, these devices still leave some room for improvement. Especially, we hope that future devices will be lighter to carry and use dry batteries more economically. In order to use these devices effectively for the management of pain, it is important to understand their characteristics.
The objective of this study was to examine the feasibility of soft-copy (CRT) reading and suitable compression. Forty abdominal CT images with a space-occupying lesion (SOL) in liver and 40 normal images were selected for receiver-operating-curve (ROC) analysis. Each image was compressed by JPEG extended mode into 1/10 its original capacity, and then an expanded image was printed on film. Ten radiologists evaluated the presence of liver SOLs (primary and secondary tumors) on soft-copy (CRT) and hard-copy (film) images. Each radiologist reviewed four types of images (original and compressed hard-copy and original and compressed soft-copy images). Values of the area under the curve in the various ROC analyses were 0.858 (FILM) and 0.842 (CRT) for original images and 0.879 (FILM) and 0.846 (CRT) for compressed images. The results of ROC analysis showed better reading performance with hard-copy than soft-copy images, but the difference was not statistically significant. Compressed images showed a higher value (0.879) than original images (0.858), a difference that was statistically significant (p < 0.029) by the paired t-test but not by the jackknife method. The results indicate that soft-copy reading is a clinically acceptable alternative to hard-copy reading. We have had no difficulty in reading abdominal CT images compressed to 1/10 of the original size by the JPEG method. This study was supported in part by a grant from the Japanese Ministry of Health and Welfare.
A 47-year-old woman presented with severe neutropenia accompanied by diplopia and orbital pain. Her bone marrow was normal except for the absence of segmented neutrophils. Because the administration of granulocyte colony-stimulating factor (G-CSF) at a dose of 1 microgram/kg/day was not sufficiently effective and neutropenia developed, the patient was admitted to our hospital. Physical examination revealed painful ophthalmoplegia and hypoalgesia in the first region of trigeminal nerve, suggestive of Tolosa-Hunt syndrome. Severe neutropenia was observed in both peripheral blood and bone marrow, together with mild anemia and thrombocytopenia. The life span of red cells and platelets was shortened. High PAIgG levels, a positive Coombs test, and a positive test for anti-NA1 antibody suggested that blood cells were being destroyed by an autoimmune mechanism. Corticosteroid hormone therapy preceded by the administration of G-CSF at 5 micrograms/kg/day was effective for both neutropenia and in improving the patient's neurological findings.
The development of gynecologic oncology in the U.S.A. was briefly reviewed and the differences in treatment approaches to gynecologic cancers between Japan and U.S.A. were described. In 1969, the Society of Gynecologic Oncologists was organized and the subspecialty of gynecologic oncology was created as a subsidiary division of the American Board of Obstetrics and Gynecology in 1970. In the same year the Gynecologic Oncology Group, which is a national collaborative research group, was established. It was decided that a gynecologic oncologist should have training and skills in all effective forms of treatment of gynecologic cancers: radical pelvic surgery, radiation therapy and chemotherapy. This subspecialty was a real success and became the model for such systems throughout the world. The role of the gynecologic oncologist is being recognized by the public in the U.S.A. Treatment approaches to cervical cancer, endometrial cancer and ovarian cancer in the U.S.A., which are different from ours, are also briefly described.
Elevation of activity and mRNA level of a cytosolic aldehyde dehydrogenase-1 (ALDH1), which oxidizes aldophosphamide, was previously observed in a cyclophosphamide-resistant murine leukemia cell line. However, changes in other enzyme(s) which may detoxify the drug or produce anti-alkylating agent(s), have not been examined. The human leukemia cell line, K562, was made 30-fold resistant against 4-hydroperoxycyclophosphamide (4HC) by exposing the cells to increasing concentrations of the drug. Resistance against cisplatin was also increased by about 3-fold. Activities of glucose-6-phosphate dehydrogenase (G6PD) and ALDH1 were elevated more than 7-fold in the resistant cells. The mRNA level of the two enzymes was also proportionally elevated. The concentration of reduced glutathione (GSH) was higher in the resistant cells (i.e., 21.1 versus 4.68 nmole per 10(6) cells), while activities of gamma-glutamylcysteine synthetase and glutathione synthetase, and the expressions of other human ALDH genes were not increased in the resistant cells. These findings suggest that the acquired resistance against 4HC is a consequence of transcriptional activation of two genes, i.e., one encoding the G6PD, a major enzyme regenerating anti-alkylating GSH, and the other encoding ALDH1, which has a high activity for oxidation of aldophosphamide derived from 4HC.
BACKGROUND: The pathogenesis of impaired water excretion in liver cirrhosis has not been fully elucidated. METHODS: We induced an intravenous water overload of 20 ml/kg body weight in 10 cirrhotics without ascites (CLC), 11 cirrhotics with ascites (DLC), and 10 normal subjects (N) and investigated the relationship of plasma levels of substance P (SP), norepinephrine (NE), and antidiuretic hormone (ADH) to impaired water excretion. RESULTS: Free water clearance (CH2O) was lower in DLC (mean, 2.7 ml/min) than in N (8.3 ml/min; P < 0.001) and CLC (6.9 ml/min; P < 0.001). In DLC the creatinine clearance (CCr), maximal urine flow rate/CCr, (CH2O + CNa)/CCr, and mean arterial pressure (MAP) were significantly lower than in N and CLC. There was a progressive increase in basal SP, from lowest in N to CLC, to highest in DLC. Basal NE increased in CLC and DLC. Basal ADH did not differ among N, CLC, and DLC. In cirrhotics CH2O was correlated positively with serum albumin and cholinesterase and negatively with the retention rate of indocyanine green at 15 min. Basal SP was negatively correlated with CH2O (r= -0.71: P < 0.001) and MAP (r= -0.56; P < 0.005). Basal NE was correlated positively with basal SP (r= 0.67, P < 0.01 ). CONCLUSIONS: Decreased CH2O is closely related to the severity of the liver disturbance. Decreased CCr and reduced delivery of filtrate to the ascending limb of the loop of Henle secondary to an increased sodium reabsorption in the proximal tubule may play an important role in the impairment of water excretion. The increase in SP, which has a potent vasodilatory action, and the associated enhanced activity of the sympathetic nervous system may be responsible for the mild or moderate impairment of water excretion in the absence of nonosmotic hypersecretion of ADH in cirrhotics with ascites.
We report a case of peripheral primitive neuroectodermal tumor (pPNET), which belongs to the PNET/Ewing's sarcoma family, arising in the left ovary of a 29-year-old woman. Microscopically, the tumor was composed of solid nests and sheets of monotonous, primitive, small round cells with a few rosettes, making it difficult to distinguish from small cell carcinoma of the ovary. Immunohistochemically, the tumor cells showed intense cell-membranous immunoreactivity for MIC2 protein (CD99). A short-term cell culture and karyotypic analysis revealed the tumor to possess a balanced t(11;22)(q24;q12) chromosomal translocation that is highly specific for tumors of the PNET/Ewing's sarcoma family. In addition, EWS/FLI-1 chimeric mRNA that originated from the characteristic chromosomal translocation was detected by reverse transcription-polymerase chain reaction. These results confirmed the diagnostic validity of the present tumor being a pPNET, thus raising the possibility that in the past, pPNETs which have arisen in the ovary may have been mistakenly diagnosed as small cell carcinomas of the ovary.
Mouse Spa-1 gene with a region homologous to the human rap1GAP gene is transcriptionally induced in the lymphocytes by mitogenic stimulation. Herein we have cloned a cDNA for its human counterpart. SPA-1 cDNA encodes a 130-kDa protein (p130(SPA-1)) consisting of proline-rich regions and rap1GAP-related domain followed by a coiled-coil stretch. Baculovirally expressed p130(SPA-1) exhibited GTPase-activating protein (GAP) activity for Rap1 and Rap2, but not for Ras, Rho, Cdc42, Rac, and Ran, with comparable specific activity to the rap1GAP gene product (p85/95(rap1GAP)). In the cells, p130(SPA-1) was mostly localized at the perinuclear membranous region co-localizing with Rap1 and Rap2. Expression of SPA-1 and rap1GAP genes tended to be segregate in various tissues, lymphoid tissues expressing abundant SPA-1 transcript without rap1GAP, while those such as brain, kidney, and pancreas exhibiting rap1GAP mRNA with little SPA-1. Promyelocytic HL-60 cells, which expressed p130(SPA-1) with little p85/95(rap1GAP) in uninduced state, showed progressive decline in p130(SPA-1) and conversely drastic increase in p85/95(rap1GAP) as they ceased from proliferation and differentiated into macrophages by 12-O-tetradecanoylphorbol-13-acetate. These results suggested that products of SPA-1 and rap1GAP genes, albeit comparable GAP activity for Rap1 and Rap2, functioned in the distinct contexts depending on cell types and/or states.