Biomedical subjects
Publications and source records attributed to G Ueda.
Pulmonary arterial pressure of treadmill-running rats became significantly higher than the sedentary control level, while systemic arterial pressure did not rise. The rise of pulmonary arterial pressure seemed to be accompanied with the increase of cardiac output.
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In order to estimate the clinical significance of sialyl Tn (STN) antigen, the antigen was measured with an "STN" Otsuka Kit in sera from patients with various gynecologic tumors and healthy women. The antigen in ovarian fluid was also determined. Furthermore, the amount of serum STN antigen was serially checked in the patients with increased serum STN to evaluate the correlation between serum STN and the response to treatment. Results obtained were as follows. 1) Among the patients with uterine myoma, uterine malignancies and benign ovarian tumors, the incidence of increased serum STN antigen was low. 2) Among the patients with ovarian malignancies, serum STN antigen was significantly increased in the following order: Clinical stage I (18%) stage II (22%) stage III (68%). 3) The highest STN value was observed in the cyst fluid from ovarian malignancies. 4) The serum STN concentration was correlated with the effect of treatment. Interestingly, the increase in serum STN preceded the clinical detection of recurrence in one case. Thus STN appears to be a useful marker for monitoring ovarian malignancies.
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Despite cis-platin-based combination chemotherapy with initially high response rates in advanced ovarian cancer, the overall survival rate remains unsatisfactory. This prompted us to design a new systematic approach using a combination chemotherapy consisting of cis-platin, adriamycin and cyclophosphamide (PAC), namely cyclic-PAC chemotherapy: Three-step chemotherapies consisting of 3 courses of the PAC regimen in each step were administered for 18 months to patients with Stage Ic-IV, after cytoreductive surgery and chemotherapy. In the present study, the survival rate with the cyclic-PAC chemotherapy was compared to that with short course-PAC and FAM (5-Fu, Alkylating agent and Mitomycin C) chemotherapies. The cyclic-PAC, PAC and FAM groups included 24 cases, 31 cases and 30 cases, respectively. Treatment of Stage Ic-IV diseases by cyclic-PAC improved the outcome (66% 3-year survival rate) compared to PAC and FAM groups (PAC 35% and FAM 30% 3-year survival rates), while no difference was observed between PAC and FAM. The outcome for patients with Stage III. IV was also superior for the cyclic-PAC group compared to the PAC and FAM groups (cyclic-PAC 54%, PAC 18% and FAM 13% 3-year survival rates). Cyclic-PAC chemotherapy is capable of dramatically improving the long-term survival rate of ovarian cancer patients.
Cerebral edema occurs in fatal cases of acute mountain sickness. Dexamethasone, commonly used to treat cerebral edema due to other causes, also reduces the symptoms of acute mountain sickness when given prophylactically. However, the efficacy of dexamethasone in the treatment of established acute mountain sickness remains uncertain. To investigate this question, we exposed six men in a hypobaric chamber to a simulated altitude of 3700 m (barometric pressure, 64 kPa [481 mm Hg]) for 48 hours on two occasions. Acute mountain sickness was diagnosed with use of a symptoms questionnaire, and dexamethasone (4 mg every six hours) or placebo was then given in a randomized, double-blind, crossover fashion. Dexamethasone reduced the symptoms of acute mountain sickness by 63 percent (P less than 0.05), whereas placebo had a minimal effect (reduction by 23 percent; P not significant). In spite of this response, one subject had mild cerebral edema on brain CT after both placebo and dexamethasone. Dexamethasone had no effect on fluid shifts, oxygenation, sleep apnea, urinary catecholamine levels, the appearance of chest radiographs or perfusion scans, serum electrolyte levels, hematologic profiles, or the results of psychometric tests. Dexamethasone treatment was complicated by mild hyperglycemia in all subjects (mean [+/- SE] glucose level, 7.3 +/- 1.3 mmol per liter [132 +/- 23 mg per deciliter]). We conclude that dexamethasone effectively reduces the symptoms of acute mountain sickness. However, it did not improve objective physiologic abnormalities related to exposure to high altitudes. We therefore recommend that dexamethasone be used only when descent is impossible, or to facilitate cooperation in evacuation efforts.
In order to estimate the clinical significance of sialyl Lewis Xi (SLXi) antigen, the antigen was measured with an "FH-6" Otsuka Kit in sera from patients with various gynecologic tumors and healthy women. The antigen in ovarian cyst fluids was also determined. Furthermore, serum SLXi antigen levels were serially followed up in the patients with elevated serum SLXi levels to evaluate the correlation between serum SLXi levels and the response to treatment. Results obtained were as follows. 1) Among the patients with uterine myoma, uterine malignancies and benign ovarian tumors, the incidence of elevated serum SLXi antigen levels was very low. 2) Among the patients with ovarian malignancies, serum SLXi antigen levels was significantly increased in the following order: clinical stage I (38%), stage II (50%) and stage III (65%). 3) The high SLXi value was observed in the cyst fluid from all ovarian mucinous adenomas and all ovarian cancers. In addition SLXi antigen level was significantly higher in the cyst fluid of mucinous adenocarcinomas than that of serous cystadenocarcinomas. 4) Serum SLXi values were correlated with the effect of treatment. Interestingly, the elevation of serum SLXi levels preceded the clinical detection of recurrence by 3 month in a case. Thus SLXi antigen appears to be a useful marker for monitoring of ovarian malignancies, especially of mucinous adenocarcinomas.
Various gynecologic tumors with argyrophilia were studied immunohistochemically for chromogranin using two antibodies, antichromogranin and antineuroendocrine. Of seven small cell carcinomas of the cervix, four were immunoreactive with antichromogranin and seven with antineuroendocrine. Argyrophil cells of six cervical adenocarcinomas were all immunoractive with both antibodies. Type I argyrophil cells of 20 endometrial carcinomas were likewise stained positively. However, of the 30 endometrial carcinomas with type II argyrophil cells, 19 showed positive immunoreactivity for chromogranin and 22 for neuroendocrine. Of the ovarian tumors tested, argyrophil cells of 11 mucinous tumors, three carcinoid tumors, and the pancreatic tissue of a malignant mixed germ cell tumor were all chromogranin- and neuroendocrine-immunoreactive. Type I argyrophil cells of five endometrioid carcinomas of the ovary were also immunoreactive with both antibodies. Of the 13 endometrioid carcinomas with type II argyrophil cells, only four showed positive immunoreactivity for chromogranin and only five for neuroendocrine. In conclusion, both antichromogranin and antineuroendocrine detect the specific neuroendocrine markers in close association with argyrophilia in gynecologic tumors, the latter being more sensitive for small cell carcinoma of the cervix, and for type II argyrophil cells in adenocarcinoma of the endometrium and endometrioid carcinoma of the ovary.
Autoimmune-prone NZB and NZB x NZW F1 mice have a large amount of autoantibodies cytotoxic for thymocytes (natural thymocytotoxic autoantibodies, NTA). We established two distinct monoclonal NTAs (NTA260 and NTA204) from a NZB mouse that react with the majority, but not all of these thymocytes. Flow cytometry analysis showed that NTA260 is positive on subpopulations of peripheral T cells from young mice, in which approximately 65% of CD4+ and 85% of CD8+ T cells were NTA260+. NTA260 also reacted with brain tissues of mice and rats, including Purkinje cells in the cerebellum. Western blot analysis showed that the molecular weight of NTA260 antigen was 55 kDa. In contrast to NTA260, NTA204 reacted with peripheral B cells but not with peripheral T cells in mice. NTA204 also reacted with peripheral blood granulocytes and bone marrow myeloid cells from both mice and rats. An immunofluorescence inhibition assay revealed the presence of autoantibodies with specificities of each NTA260 and NTA204 in the sera from NZB mice. As a selective decline in the subset of NTA260+ T cells but not NTA204+ B cells was observed with aging of NZB and NZB x NZW F1 hybrid mice, NTA260 is at least partly related to the observed immunological abnormalities of T cells in these autoimmune-prone New Zealand mice.
The distribution of colon--ovarian tumor antigen (COTA) and colon-specific antigen (CSA) was studied immunohistochemically in gynecologic tumors. The antigens were absent in the serous benign tumors of the ovary and in the normal ovarian tissues, whereas they were detected in some of the mucinous benign tumors. COTA and CSA were present and similarly distributed in most malignant epithelial tumors of the ovary, with their expression increasing with malignancy. Both antigens were almost completely absent in normal glands of the endometrium, but were expressed in many of the endometrial adenocarcinomas. Adenocarcinomas of the cervix were strongly positive for both antigens, and they were also detected in some of the normal cervical glands. However, no relationship was found between the expression of the two antigens and that of argyrophilia, an intestinal metaplasia.
Small-cell and poorly differentiated carcinomas of the cervix were studied immunohistochemically for several neuroendocrine and epithelial markers. Neuroendocrine markers were frequently expressed in small-cell carcinomas with argyrophilia; of the seven such tumors, four were immunoreactive with anti-chromogranin, seven with antineuroendocrine, five with anti-Leu 7, and seven with anti-neuron-specific enolase. Only neuron-specific enolase, however, was expressed in two of the three small-cell carcinomas without argyrophilia. On the other hand, one of the epithelial markers, epithelial membrane antigen, was strongly positive in all three small-cell carcinomas without argyrophilia and all seven poorly differentiated carcinomas, while it was expressed only weakly and focally in all small-cell carcinomas with argyrophilia except in one case. In conclusion, it is suggested that the immunohistochemical demonstration of several neuroendocrine markers may be helpful in diagnosing neuroendocrine carcinoma of the cervix as a supplement to conventional light microscopy, silver staining, and electron microscopy.
A murine monoclonal antibody, MCA-97, was prepared against a human endometrial adenocarcinoma cell line. In a cellular enzyme-linked immunospecific assay, the MCA-97 antibody reacted with all adenocarcinoma cell lines tested, including four endometrial adenocarcinoma lines. The antigen defined by MCA-97 was estimated to be a nonsialylated high-molecular-weight glycoprotein containing galactose and N-acetylglucosamine in its determinant. In immunoperoxidase staining of formalin-fixed, paraffin-embedded sections, MCA-97 reacted with most endometrial adenocarcinomas and ovarian endometrioid-type adenocarcinomas, and also reacted with normal glandular epithelium of the female genital and gastrointestinal tracts. However, it was mostly unreactive with squamous cell carcinoma and ovarian serous adenocarcinoma tissues. By the reversed passive hemagglutination method, the antigen defined by MCA-97 was detected in the sera of one-third of patients with endometrial adenocarcinomas, and in half of those with ovarian endometrioid adenocarcinomas. The antigen was not demonstrable in the sera of most normal female volunteers. Thus, MCA-97 monoclonal antibody has potential clinical applications in diagnostic serology and pathology.
Pancreatic secretory trypsin inhibitor (PSTI) is a specific trypsin inhibitor secreted by the acinar cells of the pancreas. Serum levels of immunoreactive PSTI have been reported elevated in patients with various malignancies including gynecologic tumors. The immunohistochemical localization of PSTI is studied in the comparison with argyrophilia and amylase immunoreactivity on 100 ovarian tumors, 35 endometrial carcinomas, and 34 cervical carcinomas. PSTI was noted in 19 of 85 common epithelial tumors of the ovary, being most frequently in mucinous tumors and less in endometrioid, but only occurred in immature pancreatic tissue of 1 of 15 germ cell tumors tested. In the uterus, 5 of 19 adenocarcinomas of the endometrium and 3 of 10 adenocarcinomas of the cervix were positive for PSTI immunoreactivity. PSTI was found more frequently in the tumors with argyrophil cells, especially of type I, but was related to the intestinal metaplasia and exocrine secretion rather than argyrophilia itself, judging from the different localization of PSTI and argyrophilic granules. No relationship was observed between amylase and PSTI immunoreactivity.
The role of charged sites on the permeability characteristics of the pulmonary microvascular barrier were investigated using chronically instrumented unanesthetized sheep. In one series of experiments we studied the effects of the cationic amphiphile, dodecyl trimethylamine (DTA; 297 mol wt), and the anionic amphiphile, SDS (288 mol wt), on lung lymph flow rates (Ql), lung lymph to plasma protein ratios (L/P), pulmonary hemodynamics, and systemic hemodynamics. DTA significantly increased both Ql and L/P, whereas SDS had a more modest and transient effect on these variables. In a second series of experiments the polycations polybrene and poly-l-lysine were found to have very similar effects as those of DTA. In another series of experiments we tested the pretreatment inhibition potential of chlorpheniramine (an H1 receptor antagonist), dibutyryl-cyclic AMP (db-cAMP), and the calcium channel antagonists verapamil and nifedipine on polybrene-induced lung injury. We found that only verapamil and db-cAMP significantly attenuated the permeability effects of polybrene. We conclude that both cationic amphiphiles and polycations cause hemodynamic and permeability alterations in the pulmonary circulation of unanesthetized sheep. In addition, the permeability alterations induced by polybrene can be modulated by intracellular calcium and/or cAMP levels.
Wood mice (Apodemus argenteus) were trapped live at three different altitudes (below 1,000, 1,900, and 2,400 m) during a 1-year period (Feb. 1984-Jan. 1985). After remaining at the trapped locations for 10-14 days, they were transferred into a climatic chamber at an altitude of 610 m. Oxygen consumption (VO2) and colonic temperature (Tco) were measured at chamber temperatures (Ta) of five steps (30, 20, 10, 0, and -10 degrees C) in freely moving conditions. In response to Ta of 0 degrees C for the mice trapped in winter when their mean local habitat temperature (Te) were lower than 0 degrees C, there was a significant inverse correlation between VO2 and Te (r = -0.70, p less than 0.001) whereas no significant correlation (r = 0.23) was observed in the mice trapped in other seasons when Te was higher than 0 degrees C. The correlation between Tco and Te was significant (r = -0.66, p less than 0.001) over the entire range of Te. The pelt weight of the mice trapped at Te higher than 0 degrees C had a significant inverse correlation with Te (r = -0.65, p less than 0.001), but not in the mice trapped at Te lower than 0 degrees C. After measurement of VO2 and Tco at Ta of 0 degrees C, the mice who had lived in colder habitats (below 0 degrees C) showed 0% mortality, whereas the mortality of the populations which had lived in warmer habitats was 13%. These results suggest that, in wood mice, adaptation to severe cold is established by an enhanced thermogenesis and by an increased insulation of the pelt in moderate cold.
We carried out an experiment to analyze morphological differences in hearts of rats well adapted and poorly adapted to chronic hypoxia. Male and female Wistar rats, 1 week, 4 weeks and 9 weeks old, were employed on the assumption that adaptive ability was dependent on age and sex. These rats were raised at an altitude of 2,400 m and were kept for 7 to 9 weeks. Control groups were maintained at an altitude of 600 m during the same period of time. Each group consisted of 4 to 6 rats. At the end of the experiment, body weight, heart weight, ratio of heart weight to body weight and hematocrit were measured, and ventricular wall thickness, myocardial fiber diameter, capillary supply and mitochondria were morphometrically studied. Of the 6 experimental groups, the 4-week-old male rats (M2) had the highest body weight, as compared with the other experimental groups. In addition, relative to these other experimental groups, the following features were found for M2. Heart weight was intermediate, heart weight/body weight ratio was low and hematocrit was also low. Ventricular wall thickness was intermediate in the right ventricle (RV) and interventricular septum (IVS) but was thin in the left ventricle (LV). Myocardial fiber diameter was intermediate in the RV, large in the IVS and small in the LV. Capillary supply was intermediate in the RV and dense in the IVS and LV. Mitochondria were small but cristal density and percentage area, estimated from electron micrographs, were found to be high.(ABSTRACT TRUNCATED AT 250 WORDS)
To examine the role of barometric pressure in high-altitude pulmonary edema, we randomly exposed five unanesthetized chronically instrumented sheep with lung lymph fistulas in a decompression chamber to each of three separate conditions: hypobaric hypoxia, normobaric hypoxia, and normoxic hypobaria. A combination of slow decompression and/or simultaneous adjustment of inspired PO2 provided three successive stages of simulated altitudes of 2,600, 4,600, and 6,600 m during which hemodynamics and lymph flow were monitored. Under both hypoxic conditions we noted significant and equivalent elevations in pulmonary arterial pressure (Ppa), cardiac output, and heart rate, with left atrial and systemic pressures remaining fairly constant. Normoxic hypobaria was also accompanied by a smaller but significant rise in Ppa. Lymph flow increased to a highly significant maximum of 73% above base line, accompanied by a slight but significant decrease in lung lymph-to-plasma protein ratio, only under conditions of combined hypobaric hypoxia but not under equivalent degrees of alveolar hypoxia or hypobaria alone. Arterial hypoxemia was noted under all three conditions, with arterial PO2 being uniformly lower under hypobaric conditions than when identical amounts of inspired PO2 were delivered at normal atmospheric pressure. We therefore hypothesize that alveolar pressure significantly alters the Starling forces governing transcapillary fluid flux in the lung and may affect the alveolar-arterial gradient for O2 as well.
This study investigated the effects of a thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (ketoprofen) on hypoxic pulmonary vasoconstriction in conscious adult sheep in order to evaluate the physiological role of thromboxane and other cyclooxygenase products. In addition, we studied the effects of histamine H1 (chlorpheniramine) and H2 antagonists (cimetidine) on hypoxic pulmonary vascular tone. Hypoxia caused a 37% rise in pulmonary arterial pressure (p less than 0.05) and a 36% increase in pulmonary vascular resistance (p less than 0.05). Pretreatment with intravenous OKY-046 10 mg/kg or ketoprofen 2 mg/kg had no effect on normoxic pulmonary vascular tone and inhibited the increase in plasma TXB2 concentration during hypoxia without affecting the pulmonary pressor response to hypoxia. Cimetidine produced an increase in hypoxic pulmonary vascular tone when individual members of the group were compared, but there was no statistically significant difference when the group was compared to the control study. Chlorpheniramine had no effect on hypoxic pulmonary tone. These data suggest that hypoxic pulmonary vasoconstriction is not mediated by release of TXA2, that hypoxic vascular tone is not modulated by cyclooxygenase products, and that the histamine H2 receptor may play a modulating role in hypoxic pulmonary vasoconstriction in conscious adult sheep.