Biomedical subjects
Publications and source records attributed to S Kobayashi.
We removed a cavernous angioma, making a tunnel between the fourth ventricle and tubercle using the traction-dissection method. Cavernous angioma with such a distribution is extremely rare, and we manipulated the mass differently to minimize surgical damage. Intraoperative findings and technical considerations are made.
OBJECTIVE: To determine the relations between macrophage migration inhibitory factor (MIF), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and cortisol in patients with systemic inflammatory response syndrome (SIRS) and to determine whether their levels correlate with patient survival. DESIGN: Prospective, observational, cohort study. SETTING: General intensive care unit in a university hospital. PATIENTS AND PARTICIPANTS: The study included 17 consecutive patients who met the criteria for SIRS; the patients were classified into subgroups, survivors (n = 8) and nonsurvivors (n = 9); eight healthy volunteers served as control subjects. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Serum MIF, TNF-alpha, IFN-gamma, and cortisol levels were measured serially when the patients were first identified as having SIRS (day 0), and on days 1-4. Except for the high tendency of acute respiratory distress syndrome in nonsurvivors (44%) compared to survivors (13%), there were no differences in the clinical backgrounds of the patients between the two groups. All patients had multiple organ dysfunction syndrome. The values of MIF and TNF-alpha in the nonsurvivors were significantly more elevated than those cytokines measured in the survivors and control subjects. Peak MIF levels significantly correlated with peak TNF-alpha levels (r2 = 0.448, P = 0.002), but did not correlate with peak levels of cortisol and IFN-gamma. Although the levels of IFN-gamma and cortisol showed a marked increase compared to those of the control subjects, we could not find differences in these variables between the survivors and the nonsurvivors. CONCLUSIONS: High MIF and TNF-alpha levels are closely linked with poor outcome in patients with SIRS. MIF and TNF-alpha may act together and have pathogenic roles in SIRS.
We present a case of brain metastasis from malignant mesothelioma with lipomatous change.
It is still difficult to predict whether cancer in patients who undergo curative gastrectomy for gastric cancer will recur and when they will die of recurrence. This study clarified predictive factors related to timing of death from tumor recurrence. A multivariate analysis was used to assess the dependence of death on postoperative tumor recurrence and were the dependence of the timing of death on tumor recurrence. Patients were divided into two groups according to the timing of death: those who died of tumor recurrence less than 2 years after surgery and those who died more than 2 years after surgery. Depth of cancer invasion, regional lymph node metastasis, and tumor size were independently correlated with tumor recurrence after curative gastrectomy. Onlv the depth of cancer invasion independently correlated with the timing of death due to tumor recurrence. It might be possible to predict the timing of death from tumor recurrence by the depth of cancer invasion into the gastric wall.
We previously reported a case of bone marrow infarction attributable to acute graft-versus-host disease (GVHD) in a patient with acute lymphoblastic leukemia after unrelated bone marrow transplantation (BMT). Although the bone marrow infarction-induced arthralgia in this patient improved, severe arthralgia appeared again with exacerbation of chronic GVHD, and the arthralgia was strongly correlated with the clinical course of chronic GVHD, i.e., the course of symptoms such as dermal and hepatic GVHD and ocular dryness. Finally, the patient developed avascular necrosis (AVN) in the right femoral head. Serum interleukin (IL)-6 and IL-10 levels were high at the onset of arthralgia but low during remission, and levels of interferon-gamma were undetectable throughout the period of arthralgia. Based on the clinical course and these data, chronic GVHD was thought to have been the major cause of the AVN. Since IL-10 antagonizes various other cytokines that induce GVHD, the increase in IL-10 might have inhibited the development of GVHD.
This study was designed to investigate the effects of PR-350, a newly developed radiosensitizer, on dihydropyrimidine dehydrogenase (DPD) activity and 5-fluorouracil (5-FU) pharmacokinetics in 8-week-old male Sprague-Dawley rats. In an in vitro study with hepatic cytosol, DPD activity was dose-dependently reduced by PR-350 at 0.5, 1.0, and 2.0 mmol/l to 75.5%, 64.9%, and 61.5%, respectively, of the control values. In an ex vivo study, DPD activities in hepatic cytosols obtained from animals which had received PR-350 over 4 days (200 mg/kg per day) were not significantly different from those in animals which had not. In an in vivo study, none of the pharmacokinetic parameters obtained from the plasma concentration-time profile of 5-FU were significantly altered by single i.v. injections of PR-350 (50, 100, or 200 mg/kg). However, (E)-5-(2)-(bromovinyl)uracil (BVU), a DPD inhibitor, significantly increased the half-life and area under the curve of 5-FU to 238.1% and 323.2%, respectively, of the control values. Administration of PR-350 over 4 days (200 mg/kg per day) did not affect either of these parameters. The administration of PR-350 significantly reduced the clearance (73.5% of control) and volume of distribution (71.0% of control) of 5-FU, but the alterations were much less than those caused by BVU. These results suggest that the effect of PR-350 on 5-FU pharmacokinetics is much less than that of BVU and that the enhancement of 5-FU toxicity by PR-350 is less than we initially anticipated.
PURPOSE: To evaluate the metabolic fate of UCN-01, a signal transduction inhibitor, blood and plasma concentrations, distribution, metabolism and excretion were investigated in rats and dogs after intravenous administration of [3H]UCN-01. METHODS: The radioactivity in plasma, blood and tissues was measured after intravenous administration of UCN-01. In addition, the radioactivity excreted in bile, urine and feces was also determined. RESULTS: The radioactivity in rat and dog plasma disappeared triphasically with terminal half-lives of 21.3 and 27.2 h, respectively. The ratios of the blood-to-plasma concentrations ranged from 0.82 to 1.13 in rats and 0.81 to 1.73 in dogs. From 0.5 to 4 h after giving [3H]UCN-01 to rats, the radioactivity in all tissues except the brain and testes was higher than in plasma. The highest concentration was observed in the lungs followed by the liver and kidneys. The radioactivity was mainly excreted in feces, reaching 96.0% of the radioactivity dose in rats and 78.4% in dogs up to 168 h after injection. Since the biliary excreted radioactivity was 67.2% over 48 h in bile duct-cannulated rats, most of the radioactivity excreted in feces was from biliary radioactivity. There were several metabolites in bile samples, but little UCN-01. CONCLUSIONS: UCN-01 is mainly eliminated by the liver, and there are high concentrations of radioactivity derived from [3H]UCN-01 in all tissues except the brain and testes.
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A total of 268 nonhuman primates (20 species) kept in the Primate Research Institute, Kyoto University, Japan, were surveyed for intestinal amebas. Total positive rates as based on the presence of cysts in the stool following formalin-ether sedimentation were as follows: Entamoeba histolytica/E. dispar, 53%; E. coli, 34%; E. hartmanni, 34%; Iodamoeba buetschlii, 25%; Endolimax nana, 8%; and E. chattoni, 3%. Positive rates were higher in Old World monkeys and lower in New World monkeys. All the 141 E. histolytica/E. dispar-positive animals were Macaca monkeys. The E. histolytica/E. dispar-positive samples were analyzed by polymerase chain reaction (PCR) for identification of E. histolytica and E. dispar. E. dispar DNA was detected in 137 samples, whereas no E. histolytica DNA was seen. Zymodeme analysis and reactivity to monoclonal antibodies of cultured trophozoites also supported the presence of E. dispar and the absence of E. histolytica. When the sera of 93 macaques were examined by an indirect fluorescent antibody test, only 3 animals proved to be positive for E. histolytica, showing the lowest titer. These results demonstrate that infection with E. dispar, but not E. histolytica, is predominant in macaques.
Using an axenic encystation system in vitro, we examined the effect of wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), which is a signaling molecule responsible for numerous cellular responses, on the encystation of Entamoeba invadens. Wortmannin inhibited both encystation and growth of E. invadens strain IP-1 in a dose-dependent manner, the former being more resistant to the drug than the latter. There was little decrease in the number of trophozoites after 3 days of culture in encystation medium containing wortmannin; and the cells remained motile, suggesting that the inhibitory effect of the drug on encystation was not due to its toxic effect on trophozoites. The addition of wortmannin after the induction of encystation was also inhibitory for encystation. Trophozoites incubated for 1 day in encystation medium with wortmannin did not encyst after removal of the drug, suggesting that the drug effect was not reversible in encystation medium. In contrast, trophozoites cultured in growth medium with wortmannin did encyst after their transfer to encystation medium without the drug. Encystation with wortmannin was more strongly inhibited among trophozoites grown in the presence of the drug than among those grown in the absence of the drug. The process of cyst maturation was slightly affected by wortmannin. These results suggest a possible role for PI 3-kinase in the signaling involved in the encystation of E. invadens.
The effects of calcium antagonists, calcium channel blockers, and calmodulin inhibitors on the growth of Entamoeba histolytica and the growth and encystation of Entamoeba invadens were examined. Calcium chelators ethyleneglycol bis (beta-aminoethyl ether)-N,N'-tetraacetate (EGTA) and ethylene-diaminetetraacetate (EDTA) inhibited the growth of both Entamoeba and also the encystation of E. invadens in a dose-dependent manner, with EDTA being more effective than EGTA. A putative antagonist of intracellular calcium flux, 8-(N,N-diethylamino) octyl-3,4,5-trimethoxybenzoate (TMB-8) also inhibited both growth and encystation, with the E. histolytica being more sensitive than E. invadens, and with the growth of E. invadens being more sensitive than encystation. The slow Na+-Ca2+ channel blockers bepridil and verapamil inhibited both growth and encystation. Bepridil was more effective than verapamil. The calmodulin (CaM) inhibitors, W-7 (N-(6-aminohexyl)-chloro-1-naphtalene sulphonamide) and trifluoperazine (TFP), were also inhibitory for both the growth and encystation; TFP was more effective than W-7, and encystation was more sensitive than growth in E. invadens. These results indicate that extracellular calcium ions, amebic intracellular calcium flux, calcium channels, and a CaM-dependent process contribute to the growth and encystation of Entamoeba.
A 68-year-old woman was diagnosed with gastric lymphoma of the mucosa-associated lymphoid tissue (MALT) type with a high-grade component. Surgical treatment was recommended because of the presence of the high-grade component, but she refused surgery. As an alternative, she received Helicobacter pylori eradication treatment, which successfully induced regression of the lymphoma. She shows no sign of recurrence endoscopically and histologically, as of 29 months after the eradication treatment. Moreover, the B-cell monoclonality and Helicobacter pylori infection demonstrated at diagnosis has disappeared. This is one of the rare cases of gastric lymphoma of the MALT type with a high-grade component cured by Helicobacter pylori eradication alone.
To demonstrate the prognostic value of measuring blood lactate concentrations and to investigate the mechanisms of lactate production in patients with systemic inflammatory response syndrome (SIRS), we conducted a prospective cohort study. Among 22 patients with SIRS, there were 9 survivors and 13 nonsurvivors. Serial arterial lactate concentrations were measured on the day of admission to the intensive care unit (day 0). then on days 1-4. The subjects of this study consisted of 14 patients with SIRS, 6 with severe sepsis, and 2 with septic shock. On admission, the lactate concentrations did not differ between the two groups, but remained high in the nonsurvivors throughout the study period, while they progressively decreased in the survivors. The incidence of disseminated intravascular coagulation (DIC) was significantly higher in the nonsurvivors than in the survivors. The nonsurvivors had persistently higher DIC scores and lower platelet counts than the survivors. The changes in lactate concentration over time were statistically different between the patients with DIC and those without DIC. The findings of this study clearly demonstrated that serial arterial lactate measurements can predict a poor outcome in patients with SIRS, severe sepsis, or septic shock. DIC might play an important role in the pathogenesis of lactate production in these newly defined critically ill patients.
An extremely rare case of metachronous primary hyperparathyroidism (PHP) due to a parathyroid adenoma and subsequent carcinoma with local lymphatic spread is presented herein. A 55-year-old woman was operated on for a parathyroid adenoma in the right inferior gland. Thirteen years after the first operation, she was again hospitalized for hypercalcemia and the presence of a hard mass in the right anterior neck region. Exploratory surgery and a histological examination of the resected tumor provided evidence of a parathyroid neoplasm in the right superior gland but the malignancy was equivocal. Postoperatively, her serum parathyroid hormone (PTH) level remained at 1.5-fold the upper limit of the normal range, and hypercalcemia again gradually developed. The results of higher positive rates by Ki-67 immunohistochemical staining and an aneuploid pattern by a flow cytometric analysis of the second neoplasm were consistent with a histological diagnosis of carcinoma, and she therefore underwent further surgery. A radical neck dissection revealed two lymph node metastases which were both successfully removed. The postoperative serum PTH and calcium levels then returned to within the normal ranges. These findings indicate the usefulness of Ki-67 immunohistochemical staining and a flow cytometric analysis for differentiating malignant lesions from benign parathyroid lesions, and the importance of surgically treating cases limited to local regions without distant metastasis.
Adenomyoepithelioma of the breast is a rare lesion, and has a bicellular pattern of epithelial and myoepithelial cells which are regularly distributed in the tubular structures based on the histologic and ultrastructural features. It is thought to be a benign or a low-grade malignant disease. We herein describe a case of malignant adenomyoepithelioma of the breast with lung metastases in an 86-year-old woman. A primary massive tumor in the left breast grew rapidly within a short period of time. A simple mastectomy with sampling of the axillary lymph nodes was performed. The obtained lymph nodes did not include any metastatic lesions. Malignancy was evidenced by the presence of a high mitotic rate and severe nuclear atypia. Three months after the operation, radiology showed multiple lung metastases, and the patient died 2 weeks thereafter. Reviewing the literature, nine similar cases were reported, and the prognosis of malignant adenomyoepithelioma of the breast with distant metastases was very poor with the time of recurrence varying after initial treatments. Malignant adenomyoepithelioma should be followed up with careful screening for distant metastases.
An alteration of the p53 gene function is a major factor in the development of esophageal cancer. Recently, p53 gene therapy has been applied for clinical studies in lung cancer and head and neck cancer. However, no preclinical studies have yet demonstrated an anticancer effect of adenoviral-mediated wild-type p53 gene therapy on esophageal cancer. We herein evaluated the effect of p53 adenoviral gene therapy on human esophageal squamous cell carcinoma to test the ability of clinical application. A normal esophageal epithelial cell line (EN53F) and two human esophageal cancer cell lines (ECGI-10 and T.Tn) with a p53 alteration were used. The transduction efficiency, p53 protein expression, p21 protein expression, the induction of apoptosis, and growth suppression were assessed by using the recombinant adenoviral vector Ad5CMV-p53. The transduction efficiency was 60%-80% at 100 plaque-forming units (PFU)/cell and 80%-100% at 300PFU/cell. A significant growth suppression following an Ad5CMV-p53 infection was observed in both cancer cell lines. A Western blot analysis confirmed the presence of both exogenous p53 protein expression and p21 protein induction. Apoptotic cell death was observed with TUNEL staining. T.Tn xenografts in nude mice transduced with Ad5CMV-p53 demonstrated significant growth suppression. These data suggest that Ad5CMV-p53 may thus be a potentially effective therapeutic agent for locally advanced esophageal cancer.
We set out to determine the responses of macrophage migration inhibitory factor (MIF) to hepatic resection and investigate its role in predicting short-term postoperative morbidity and outcome. Blood samples from 29 patients undergoing hepatic resection and eight healthy volunteers were obtained serially for 24h and assayed for serum MIF, cortisol, and tumor necrosis factor (TNF)-alpha. The MIF and cortisol levels showed a parallel increase and their peak levels were significantly correlated (r2 = 0.33, P = 0.0011). The TNF-alpha levels also increased during and after hepatic resection, but did not correlate with the MIF levels. The patients were classified into an extended hepatectomy group (n = 9); a lobectomy/segmentectomy group (n = 12); and a subsegmentectomy group (n = 8). There were no differences in the time courses of MIF (P = 0.8699), cortisol (P = 0.7485), and TNF-alpha (P = 0.3819) among the three groups. No patients developed organ dysfunction and all were discharged from the intensive care unit without any complications. Our findings demonstrate that MIF production occurs in patients undergoing hepatic resection. Surgical stress may play a more important role in MIF secretion than inflammatory stimulus by TNF-alpha in these patients. Therefore, MIF minimally affects short-term postoperative morbidity and outcome.
To evaluate the efficiency of measuring telomerase activity levels in clinical diagnosis, we performed a semiquantitative analysis of telomerase activity in breast tumors and compared the results with the histological findings. Breast tissue adjacent to areas of cancer were also serially resected and checked for telomerase activity. The amount of telomerase activity in the breast cancers ranged widely, from 0.36 to 1180 units/microg, with 31 of the 34 (91.2%) showing a value above 1.0unit/microg. None of the normal breast tissues including mastopathy, and only 4 (23.5%) of 17 benign breast masses had values above 1.0unit/microg. Telomerase activity was detectable in serial sections of adjacent tissues as far as 10mm from the macroscopic tumor margin with histologically detectable cancer cells. Furthermore, telomerase activity was detectable in the scrape specimens obtained from the stump of the surgical margins for breast-conserving surgery, and this activity was in accordance with the histological findings. These findings show that conducting a semiquantitative assay of telomerase activity is useful for evaluating the surgical margin in breast-conserving surgery.