[Etiology and treatment of inflammatory bowel diseases. 4. Intestinal Behcet's disease].
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Adolescent↗
Biomedical subjects
M Tada
Publications and source records attributed to M Tada.
Importance of left ventricular minimal pressure as a determinant of transmitral flow velocity pattern in the presence of left ventricular systolic dysfunction.
OBJECTIVES: This study was designed to assess whether the transmitral flow velocity pattern provides an estimation of left atrial pressure irrespective of the presence of left ventricular systolic dysfunction and, if not, to clarify the mechanism. BACKGROUND: The pulsed Doppler transmitral flow velocity pattern, particularly peak early diastolic filling velocity, has been shown to change in parallel with left atrial pressure. However, extremely elevated left atrial pressure in association with heart failure does not necessarily cause an increase in peak early diastolic filling velocity in patients. METHODS: Left atrial pressure was elevated with intravenous saline infusion in 11 dogs (normal left ventricular function group) and hemodynamic, transesophageal Doppler echocardiographic and M-mode echocardiographic variables were recorded at three different loading levels. In another 12 dogs, left atrial pressure was elevated by production of left ventricular systolic dysfunction with the stepwise injection of microspheres into the left coronary artery (left ventricular dysfunction group) and the same set of recordings was obtained at three different levels of dysfunction. RESULTS: Peak early diastolic filling velocity increased with left atrial pressure in the normal left ventricular function group and correlated with mean left atrial pressure (r = 0.61, p < 0.01) and early diastolic left atrial to left ventricular crossover pressure (r = 0.71, p < 0.01). In contrast, peak early diastolic filling velocity did not increase with left atrial pressure in the left ventricular dysfunction group and did not correlate with mean left atrial pressure (r = -0.05) or the crossover pressure (r = 0.06). Peak early diastolic filling velocity correlated well with the difference between the crossover pressure and left ventricular minimal pressure in the left ventricular dysfunction group (r = 0.64, p < 0.01). In contrast to peak early diastolic filling velocity, deceleration time of the early diastolic filling wave correlated with mean left atrial pressure and the crossover pressure irrespective of the primary cause of preload alteration (r = -0.54, r = -0.59, p < 0.01 respectively, n = 69 for all data). CONCLUSIONS: Preload dependency of the Doppler transmitral flow velocity pattern is hampered if an increase in left atrial pressure is due to left ventricular systolic dysfunction. In this setting, the increase in left ventricular minimal pressure due to left ventricular systolic dysfunction cancels the effect of the increase in left atrial pressure on the flow velocity pattern.
Animals↗
Identification of regions in the Ca(2+)-ATPase of sarcoplasmic reticulum that affect functional association with phospholamban.
When the SERCA 2 isoform of the Ca(2+)-ATPase of cardiac and slow-twitch muscle sarcoplasmic reticulum was coexpressed with phospholamban in COS-1 cells, a reduction in Ca2+ affinity (measured as Ca2+ dependence of Ca2+ transport) of 0.2-0.3 pCa units was observed. This inhibitory effect was reversed by phosphorylation of phospholamban with cAMP-dependent protein kinase A. SERCA 1 and SERCA 3, were also expressed in COS-1 cells, alone and together with phospholamban. SERCA 1 had high Ca2+ affinity which was reduced upon coexpression with phospholamban, but SERCA 3 had lower Ca2+ affinity, which was unaltered by coexpression with phospholamban. To identify which regions of the Ca2+ ATPase sequence determine its functional interaction with phospholamban, chimeric Ca(2+)-ATPases between SERCA 2 and SERCA 3 were constructed and coexpressed with phospholamban. Measurement of Ca2+ affinities for a series of chimeras showed that two separate regions of the cytoplasmic domain of SERCA 2 were required for manifestation of a functional interaction between phospholamban and the Ca(2+)-ATPase. The first is a region between amino acids 336 and 412 in the phosphorylation domain, which corresponds to a phospholamban interaction site identified earlier (James, P., Inui, M., Tada, M., Chiesi, M., and Carafoli, E. (1989) Nature 342, 90-92). The second region is the nucleotide binding/hinge domain (amino acids 467-762) which determines high Ca2+ affinity for SERCA type pumps (Toyofuku, T., Kurzydlowski, K., Lytton, J., and MacLennan, D. H. (1992) J. Biol. Chem. 267, 14490-14496).
Amino Acid Sequence↗
Evaluation of the treatment response of lung cancer with positron emission tomography and L-[methyl-11C]methionine: a preliminary study.
We carried out a study to evaluate treatment response and residual mass in lung cancer with positron emission tomography (PET), using L-[methyl-11C]methionine (MET). MET tumour uptake and tumour volume measured by computed tomography (CT) before and within 2 weeks after radiotherapy or chemoradiotherapy were compared in 43 studies of 21 patients. Ten patients with local control (no recurrence) of tumour showed a larger decrease in MET uptake (65.2% +/- 12.2%) than in tumour volume (50.8% +/- 9.6%, P < 0.01). Five patients with early recurrence (from 1 to 4 months) showed smaller decreases in both MET uptake (22.2% +/- 13.5%) and tumour volume (28.6% +/- 20.0%) than those in the no-recurrence group (P < 0.01). Four patients with late recurrence (after 11 months or more) showed a similar decrease to the no-recurrence group in MET uptake (72.8% +/- 14.8%) but little change in tumour volume (18.5% +/- 19.0%), the latter result corresponding to that in the early-recurrence group. Using tumour volume only, the no-recurrence group was differentiated from both the early- and the late-recurrence group (P < 0.01), but the early-recurrence group was not differentiated from the late-recurrence group. Using the MET uptake data, the early-recurrence group was clearly distinguished from the late-recurrence group (P < 0.01), but the late-recurrence group was indistinguishable from the no-recurrence group. CT was useful in distinguishing the no-recurrence group from the groups in which there was ultimate recurrence, whether early or late. When a residual mass is seen on CT, PET seems to be helpful in evaluating tumour viability.
Adenocarcinoma↗
Recent advances in immunobiology of brain tumors.
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Antibody Formation↗
Responses of human glioblastoma cells to human natural tumor necrosis factor-alpha: susceptibility, mechanism of resistance and cytokine production studies.
Responses and susceptibility of 14 human glioblastoma cell lines to human natural tumor necrosis factor-alpha (TNF) were studied in vitro. Susceptibility of glioblastoma cells to TNF varied in experimental conditions applied. Most of glioblastoma cell lines were resistant to cytotoxic activity of TNF in a MTT assay at concentrations below 16 U/ml for 72 h exposure. However, TNF at higher dose, in prolonged exposure and against low density of target cells was antiproliferative for certain glioblastoma cultures. TNF exposure at 10 U/ml for 48 h suppressed DNA synthesis in 9 of 14 glioblastoma cultures, but increased in 3 cultures. In addition, colony forming assay showed anti-clonogenic activity of TNF in 5 of 6 glioblastoma cell lines tested. In spite of their low susceptibility to TNF, glioblastoma cells well responded to TNF stimulation at low dose (10 U/ml) for a short period in the absence of cell damage. Productions of Interleukin-6 (IL-6), IL-8-like activity, granulocyte-macrophage colony stimulating factor (GM-CSF), prostaglandin E2 (PGE2) and manganous superoxide dismutase (Mn-SOD) were enhanced or induced by the low-dose TNF stimulation. Mn-SOD, a protein protective against oxidative cell damage, was well induced in time- and dose-dependent manner, however did not correlate with TNF resistance. Whereas the levels of PGE2 in TNF-susceptible cell lines, H-4 and SF-188, were higher than those of other lines. In conclusion, most of glioblastoma cells are resistant to TNF cytotoxic effects, but highly responsive to TNF stimulation. Its effect on glioblastoma cells appears to modulate cell differentiation rather than to kill the cells.
Cell Division↗
Human glioblastoma cells produce 77 amino acid interleukin-8 (IL-8(77)).
The production of interleukin 8 (IL-8), a neutrophil chemotactic factor, and its amino acid sequence were examined in glioblastoma cell lines in vitro. Neutrophil chemotactic activity was demonstrated in 9 conditioned media of 15 human glioblastoma cell lines. Tumor necrosis factor (TNF)-alpha stimulated secretion of the activity in 7 lines and induced secretion in 4 other lines. ELISA quantification disclosed that the conditioned media contained interleukin 8 (IL-8) in an amount equivalent to the chemotactic activity. The IL-8 secretion increased with the stimulation by TNF-alpha. Northern blot analysis and the RT-PCR method confirmed expression of mRNA in the glioblastoma cells and its augmentation by TNF-alpha and/or IL-beta. Reversed-phase HPLC following ion-exchange chromatography revealed that the chemotactic activity was a single peptide, which was determined to be IL-8 by the retention time and ELISA. Furthermore, amino acid analysis disclosed that a major part of the glioblastoma-cell derived IL-8 peptide was 77 amino acid IL-8 (IL-8(77); with the N-terminal sequence AVLPRSAKELRCQCI-).
Amino Acid Sequence↗
Cellular and cytokine responses of the human central nervous system to intracranial administration of tumor necrosis factor alpha for the treatment of malignant gliomas.
To elucidate the role of tumor necrosis factor alpha (TNF alpha) as a biological response modifier, we studied cellular and cytokine responses of the central nervous system to TNF alpha administered intracranially in a phase I clinical trial for patients with malignant gliomas. Six patients received injections of TNF alpha (1.25 x 10(3)-10 x 10(3) U/injection) into the tumor cavities, and regional fluids (RF) and lumbar cerebrospinal fluids (CF) were serially sampled before and after the injections. Recruitment of neutrophils occurred, mostly peaking 8 h after TNF alpha injection, and fewer numbers of CD4+ T cells and monocytes/macrophages migrated, subsequently peaking at 24 h. The CF leukocytosis persisted for 48 h and was associated with an increased level of neutrophil chemotactic activity in the CF. This neutrophil chemotactic activity was attributed to interleukin-8 (IL-8) by HPLC. The level of IL-6 activity in the CF and RF consistently increased; beginning 2 h after TNF alpha injection and reaching the maximum between 8 h and 12 h. It returned to the basal level within 48 h. IL-1 beta was detected in the CF of three patients, its level peaking at 8 h. Prostaglandin E2 also increased after injection of TNF alpha, peaking between 4 h and 12 h and then gradually decreasing. Transforming growth factor beta was found in all cases tested and one patient showed a significant change after TNF alpha injection. IL-2 activity, interferon alpha (INF alpha) activity, IFN beta, and granulocyte/macrophage-colony-stimulating factor were not detected in the CF or RF. In conclusion, TNF alpha is biologically effective in inducing migration of immune cells and generating multiple cytokine responses in the human central nervous system.
Adult↗
Brief myocardial ischemia affects free radical generating and scavenging systems in dogs.
This study examined whether brief repeated myocardial ischemia altered free radical generating and scavenging activity in a dog model. In dogs preconditioned with four 5-min left anterior descending coronary artery (LAD) occlusions and reperfusions, we examined transcardiac changes in both the function of neutrophils, cells which are major free radical generators, and in myocardial antioxidant enzyme activity, as an indication of free radical scavenging. Neutrophil function was assessed by determining luminol-enhanced whole blood chemiluminescence (CL) induced by zymosan. Blood was taken simultaneously from the carotid artery and the cardiac vein running along the occluded LAD. Preconditioning with sublethal ischemia significantly reduced whole blood CL in the cardiac vein compared with the carotid artery after the first and fourth 5-min reperfusions, while there was no difference in neutrophil count between these sampling sites. Immediately after brief repeated ischemia and reperfusion, manganese-superoxide dismutase (SOD) activity was significantly enhanced, and glutathione reductase activity was markedly reduced in the ischemic, compared with the non-ischemic, myocardium. There were no differences in the myocardial activities of copper, zinc-SOD, glutathione peroxidase, and glutathione S-transferase between the ischemic and non-ischemic regions. Also, no difference was observed between the reduced myocardial glutathione levels in these regions, although the oxidized glutathione level was significantly higher in the ischemic regions of the subepicardial and subendocardial areas. We demonstrated that brief repeated ischemia affects free radical generating and scavenging systems in the ischemic myocardium.
Animals↗
A combination of lipopolysaccharide and B-cell growth factor increases lymphocyte metaphase yields in B-cell chronic leukemia.
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Adjuvants, Immunologic↗
The action of 4-hydroxyaminobiphenyl in Escherichia coli: cytotoxic and mutagenic effects in DNA repair deficient strains.
The cytotoxic and mutagenic effects of 4-hydroxyaminobiphenyl (N-OH-ABP) were studied using Escherichia coli strains with different repair capacities. N-OH-ABP was equally cytotoxic for uvrA and recA mutants as well as in wild-type cells while polA mutant strains proved particularly sensitive to its toxicity. In contrast, the mutation frequency in the uvrA strains tested was elevated to 30-400-fold the wild-type values. We suggest that aminobiphenyl-DNA adducts responsible for mutation are repaired by UVR endonuclease but different pathways exist for removal of DNA lesions responsible for bacterial killing. From the 32P-postlabeling analysis, it was concluded that ABP-DNA adducts can be relatively rapidly repaired in wild-type strains, while persisting in the uvrA strains.
4-Nitroquinoline-1-oxide↗
Effects of high-molecular-weight hyaluronates on the functions of guinea pig polymorphonuclear leukocytes.
The effect of hyaluronate (HA) with a molecular weight of 1,900,000 (HA190) purified from products of Streptococcus equi on various functions of guinea pig peritoneal polymorphonuclear leukocytes (PMNs) was examined. HA190 effectively inhibited both the chemotactic activity of PMNs for a chemotactic peptide, formyl-Met-Leu-Phe, and the phagocytic activity of the cells for serum-opsonized zymosan (SOZ) in a dose-dependent manner. When the inhibitory activity of the HAs of different molecular weights, including HA190, HA of molecular weight 800,000 (HA80), and HA of molecular weight 300,000 (HA30), was assessed, the HA190 showed the strongest inhibitory activity and HA30 the lowest activity. In contrast, significant inhibition of the superoxide generation by PMNs upon stimulation with SOZ was not observed even in the presence of HA190 and HA80 at the highest concentration used (2.5 mg/mL). This finding indicated that the HAs studied did not prevent the interaction of PMNs with stimuli. From these data it is concluded that the binding of high-molecular-weight HAs to the HA receptors on PMNs may produce intracellular signals that are responsible for suppression of phagocytosis and chemotaxis but not for superoxide generation.
Animals↗
Cellular accumulation of 18F-labelled boronophenylalanine depending on DNA synthesis and melanin incorporation: a double-tracer microautoradiographic study of B16 melanomas in vivo.
The cellular distribution of 4-borono-2-[18F]fluoro-L-phenylalanine ([18F]FBPA, an analog of p-boronophenylaline), a potential agent for boron neutron capture therapy (BNCT), and [6-3H]thymidine ([3H]Thd, a DNA precursor) in murine two B16 melanoma sublines and FM3A mammary carcinoma was studied in vivo using double-tracer microautoradiography. Tumour volume, tumour age, cell density in the tissues and the proportion of S phase cells in the cell cycle were the same in the three tumour models. Volume doubling time, which represents tumour growth rate, was fastest in B16F10, followed by B16F1 (P < 0.05), the slowest being in FM3A (P < 0.001). The rate of DNA synthesis in S phase cells corresponded to the volume doubling time. The greatest amount of [18F]FBPA was observed in S phase melanocytes and the lowest amount was found in non-S phase non-melanocytes. The [18F]FBPA accumulation was primarily related to the activity of DNA synthesis and, secondarily, to the degree of pigmentation in melanocytes. The therapeutic efficacy of BNCT with p-boronophenylalanine may be greater in melanoma that exhibits greater DNA synthesis activity and higher melanin content.
Animals↗
Impact of staging on treatment of gastric carcinoma.
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Antineoplastic Agents↗
Endoscopic resection of early gastric cancer.
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Aged↗
Transcardiac alteration of neutrophil function relates to myocardial ischaemia/reperfusion injury.
OBJECTIVE: The aim was to define the relation between transcardiac changes in neutrophil function in myocardial ischaemia and the progression of myocardial necrosis. METHODS: Samples of blood from carotid artery, jugular vein, and cardiac vein streaming from the ischaemic area were taken simultaneously in a canine coronary occlusion-reperfusion model of myocardial infarction. Neutrophil function was evaluated by neutrophil count, whole blood chemiluminescence and leucocyte infiltration into the ischaemic myocardium. Myocardial necrosis was assessed by plasma creatine kinase and dual staining technique using Evans blue dye and triphenyltetrazolium chloride. Effects of a free radical scavenger, N-2-mercaptopropionyl glycine (MPG), initiated 15 min before reperfusion and continued during the reperfusion phase, were also examined. RESULTS: Whole blood chemiluminescence of the cardiac vein was reduced at 90 min after coronary artery occlusion as compared to carotid artery [5.8(SEM 0.5) v 7.5(0.7) count x 10(3) cell neutrophil-1 x 10 min-1, p < 0.05], and then increased abruptly after reperfusion to peak after 10 min of reperfusion [7.1(0.7) count x 10(3) cell neutrophil-1 x 10 min-1]. The neutrophil count in cardiac venous blood was significantly reduced within 5 min of reperfusion. MPG significantly attenuated the reperfusion associated increase in cardiac vein whole blood chemiluminescence and the decrease in the cardiac venous blood neutrophil count. The increase in myocardial free radical generation 1-3 h after reperfusion, as assessed by the electron paramagnetic resonance spin trapping technique, was reduced markedly, as was the extent of leucocyte infiltration into the ischaemic myocardium. Under these conditions, administration of MPG significantly reduced myocardial infarct size [40.3(4.5)% v 21.4(4.2)%, p < 0.05]. A marked increase in transcardiac creatine kinase release after reperfusion observed in control dogs was also reduced significantly. CONCLUSIONS: A transient alteration of neutrophil function occurs in the coronary circulation immediately after reperfusion, which may augment neutrophil infiltration and free radical generation in the ischaemic myocardium, leading to the propagation of myocardial ischaemia/reperfusion injury.
Animals↗
Free radical generation coupled with arachidonate lipoxygenase reaction relates to reoxygenation induced myocardial cell injury.
OBJECTIVE: The role of arachidonate lipoxygenase activity in reoxygenation induced cell injury in adult canine cardiac myocytes was investigated. METHODS: The production of hydroxyeicosatetraenoic acids (HETEs), which are lipoxygenase metabolites, was measured with high pressure liquid chromatography in canine cardiac myocytes cultured under hypoxic conditions and then reoxygenated. Free radical generation was evaluated by electron paramagnetic resonance spectroscopy with a spin trapper, 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and luminol enhanced chemiluminescence emission. Cell injury was estimated in terms of morphological changes and release of intracellular enzymes. Morphological damage to myocytes was quantified in terms of the percentage of hypercontracted "round" cells. The effects of nordihydroguaiaretic acid, AA-861, mepacrine, indomethacin, aspirin, alpha tocopherol, and 2-0-octadecylascorbic acid (CV-3611) on lipoxygenase metabolism, free radical generation and cell injury were also assessed. RESULTS: Cardiac myocytes produced 5-HETE and 12-HETE at less than 0.1 ng.mg-1 protein under normoxic conditions. Production of HETE was greatly increased at five hours of reoxygenation after 45 minutes of hypoxia [5-HETE = 12.0(SEM 0.5), 12-HETE = 23.6(1.1) ng.mg-1 protein]. Both DMPO-OH adduct generation and chemiluminescence emission were considerably increased after one to three hours of reoxygenation, although they increased only slightly after 45 minutes of hypoxia. After five hours of reoxygenation, long rod cells gradually became deformed; 92.0% of the cells were converted to hypercontracted "round" cells. Cell injury and HETE production were significantly suppressed by nordihydroguaiaretic acid (10 microM), AA-861 (2 microM), and mepacrine (10 microM). Indomethacin (10 microM) and aspirin (50 microM) enhanced cell injury and HETE production. alpha Tocopherol and CV-3611 greatly suppressed cell injury and free radical generation, but not HETE production. CONCLUSION: The arachidonate lipoxygenase metabolic pathway may have an important role in reoxygenation induced myocardial cell injury in adult cardiac myocytes, possibly because of the generation of free radicals.
Animals↗
Further studies on guinea pig Z-1 antigen that is involved in phagocytosis of zymosan by macrophages: cell type distribution of the antigen and cross-reactivity of anti-Z-1 with human cR3.
We have previously identified a heterodimer molecule, Z-1, on guinea pig peritoneal macrophages (M phi s) by the newly prepared monoclonal antibody, anti-Z-1, and Z-1 has been assumed to be the complement receptor type three (CR3) in this species. To clarify this assumption, the cell type distribution of the antigen in guinea pig and the cross-reactivity of anti-Z-1 with other species were analyzed. It was demonstrated that Z-1 was expressed on peritoneal M phi s, pulmonary M phi s, peritoneal polymorphonuclear leukocytes (PMN), peripheral neutrophils, and some subpopulations of spleen cells and of bone marrow cells, but not on erythrocytes, circulating lymphocytes, and lymphocytes in both spleen and bone marrow in detectable amounts. Thus the expression of Z-1 seems to be restricted to phagocytes as is CR3 of other species. Furthermore, it was found that anti-Z-1 bound with peripheral neutrophils from human, horse and goat and HL-60 cells differentiated into monocytes. Any cross-reactivity of the antibody was not detected with neutrophils from rabbit, cow, sheep and dog and nondifferentiated HL-60 cells. Human Z-1 was indistinguishable from human CR3, since both were the heterodimer consisting of alpha chain of 170 kDa (pI = 6.6-7.2) noncovalently associated with beta chain of 100 kDa (pI = 5.6-6.7). In addition, human CR3 in detergent-lysate of neutrophils was completely adsorbed with anti-Z-1 F(ab')2- Sepharose. These findings indicate that guinea pig Z-1 shares an antigenic determinant with human CR3. It thus seems to be possible that Z-1 may function as CR3 in guinea pigs.
Animals↗