[Strategy for improvement of operative results of broad aortic replacement for DeBakey-I type aortic dissection].
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Adult↗
Biomedical subjects
M Kitamura
Publications and source records attributed to M Kitamura.
Effect of nitric oxide-releasing aspirin derivative on gastric functional and ulcerogenic responses in rats: comparison with plain aspirin.
The effects of a nitric oxide (NO)-releasing derivative of aspirin, NCX-4016, on gastric functional and ulcerogenic responses in rat stomachs were examined in comparison with those of aspirin. Topical application of aspirin (80 mM) to the stomach markedly decreased transmucosal potential difference and slightly increased luminal pH (acid back-diffusion) with minimal effect on mucosal blood flow, whereas NCX-4016 caused a marked increase in mucosal blood flow with no effect on potential difference and pH. Aspirin itself was ulcerogenic, causing damage in the mucosa when administered p.o., and it markedly potentiated gastric ulcerogenic response to hypothermic stress (28 degrees C-30 degrees C) with no effect on acid secretion when given s.c. NCX-4016, however, was not ulcerogenic by itself, did not modify the ulcerogenic response to stress and even showed a dose-dependent protection against HCl/ethanol-induced gastric lesions. When NCX-4016 was given intragastrically to pylorus-ligated rats, a large amount of NO was detected in both gastric contents and serum. NCX-4016 administered either p.o. or s.c. produced an equipotent inhibition of mucosal PGE2 generation in the stomach, as compared with aspirin. In addition, both aspirin and NCX-4016 suppressed carrageenan-induced rat paw edema. These results suggest that, unlike aspirin, the NO-releasing derivative of aspirin NCX-4016 neither had a topical irritating action on the stomach nor exerted a worsening effect on gastric ulcerogenic response to stress, but rather provided gastric protection against ethanol, despite inhibiting cyclo-oxygenase activity and showing anti-inflammatory action much as aspirin does. NCX-4016, probably by releasing NO, exerted protective effects that counteracted the potential damaging effects of cyclo-oxygenase inhibition.
Animals↗
[Radiobiological considerations for stereotactic irradiation].
Stereotactic radiosurgery (SRS: stereotactic irradiation [STI] delivered in a single high dose) was initially developed by Leksell for non-malignant brain lesions, but there has been increasing interest in using it to treat small primary brain tumors or metastases. In more recent years, stereotactic radiotherapy (SRT: fractionated STI) has been developed, but radiobiological factors have not been sufficiently evaluated in relation to these techniques. Larson classified potential STI targets into four categories according to whether the target tissue is early- or late-responding and whether it is embedded within or only surrounded by normal tissue. We have actually calculated biologically effective doses for these categories to determine the indications for SRS and SRT, and to be able to choose suitable SRT schedules. Based on our calculations, theoretically SRS would be recommended for AVMs and benign tumors having distinct margins separating them from surrounding normal tissue and SRT would be recommended for low or high grade astrocytomas without clearly defined boundaries and metastasis. Recommended SRT schedules would be 49 Gy/7 fractions, 52 Gy/8 fractions or 54.9 Gy/9 fractions completed within 2 weeks. However, clinically, these indications and SRT schedules should be modified according to the many other factors involved in individual cases, such as tumor size, presence of tumor necrosis, the patient's general condition, prognosis, and so on.
Brain↗
[Intrahepatic arterial infusion chemotherapy with angiotensin II for liver metastasis from gastric cancer].
The theoretical purpose of induced hypertensive chemotherapy used together with injection of Angiotensin II is to increase the delivery of anticancer drug to the target tumor tissue by increasing blood flow in the tumor. Angiotensin II (50 micrograms) was dissolved in 50 ml of normal saline, and given through a peripheral vein by a microinfusion pump. When systolic pressure rose to about 140 to 150 mmHg, mitomycin C (10 to 20 mg/body) was given for 10 minutes via implanted port, whose tip was located in hepatic artery, followed by continuous infusion of 5-FU at 250 mg/day for 5 days. Response could be measured in 7 of all 10 cases (70.0%), CR was found in 4 and PR in 3. As for complications, one case of pseudo-aneurysm and one case of bile duct necrosis owing to drug toxicity were observed. Bone metastases or carcinomatous peritonitis occurred after a few months in two CR cases. We concluded that this mode of chemotherapy was a useful measure for the treatment of liver metastases from gastric cancer.
Aged↗
Pseudomonas aeruginosa folliculitis: a sporadic case from use of a contaminated sponge.
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Adult↗
[Schedule of stereotactic radiotherapy: a study considering the factors of repair and cell proliferation].
Stereotactic radiosurgery (SRS: stereotactic irradiation [STI] delivered in a single high dose) was initially developed by Leksell for non-malignant brain lesions, but there has been increasing interest in using it to treat small primary brain tumors or metastases. Recently, stereotactic radiotherapy (SRT: fractionated STI) has been recommended on the basis of radiobiological considerations for tumors in which both normal glial cells and tumor cells reside within the tumor margin. Strangely, the factors 'repair' and 'cell proliferation' have been neglected in the radiobiological evaluations of STI reported so far, mainly because of the complexity of the calculations. 'Half-time repair' which is the key value in the 'repair' factor may be larger for nervous tissue than for many other normal tissues because nerve cells have decreased ability to recover from damage. 'Cell proliferation' should be an important factor when the total radiation period is extended by applying SRT. In this study, we created models based on estimated 'half-time repair' and 'cell doubling time' and attempted to determine optimal SRT schedules. When repair and cell proliferation factors are also taken into consideration, the recommended SRT schedules would be 7 Gy x 7 fractions every other day for malignant tumors and 3.5 Gy x 12 fractions every other day for benign tumors. However, clinically, these schedules should be modified according to factors in individual cases, e. g., tumor size, presence of tumor necrosis, the patient's general condition, prognosis, and so on.
Brain↗
The human beta globin locus introduced by YAC transfer exhibits a specific and reproducible pattern of developmental regulation in transgenic mice.
The human beta globin locus spans an 80-kb chromosomal region encompassing both the five expressed globin genes and the cis-acting elements that direct their stage-specific expression during ontogeny. Sequences proximal to the genes and in the locus control region, 60 kb upstream of the adult beta globin gene, are required for developmental regulation. Transgenic studies have shown that altering the structural organization of the locus disrupts the normal pattern of globin gene regulation. Procedures for introducing yeast artificial chromosomes (YACs) containing large genetic loci now make it possible to define the sequences required for stage-restricted gene expression in constructs that preserve the integrity of the beta globin locus. We demonstrate that independent YAC transgenic lines exhibit remarkably similar patterns of globin gene expression during development. The switch from gamma to beta globin predominant expression occurs between day 11.5 and 12.5 of gestation, with no more than twofold differences in human beta globin mRNA levels between lines. Human beta globin mRNA levels were twofold to fourfold lower than that of mouse betamaj, revealing potentially significant differences in the regulatory sequences of the two loci. These findings provide an important basis for studying regulatory elements within the beta globin locus.
Adult↗
c-Jun/AP-1, but not NF-kappa B, is a mediator for oxidant-initiated apoptosis in glomerular mesangial cells.
Oxidant stress is a trigger of cell death in various cell types. Hydrogen peroxide (H2O2) induced mesangial cell death with nuclear condensation and DNA fragmentation typical of apoptosis. To explore molecular mechanisms involved in this process, redox-sensitive transacting molecules, activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappa B), have been brought into focus. Northern blot analysis and transient transfection assays using reporter plasmids showed that H2O2 activated both AP-1 and NF-kappa B. Downregulation of c-Jun/AP-1 using a transdominant negative mutant of c-jun, an antisense c-jun, or a pharmacologic inhibitor curcumin inhibited the H2O2-initiated apoptosis. In contrast, inhibition of the NF-kappa B activation using a transdominant negative mutant of the p50 NF-kappa B subunit did not affect the H2O2-triggered cellular death. These data elucidated that c-Jun/AP-1, but not NF-kappa B, is involved in the oxidant-initiated cell death program in glomerular mesangial cells.
Animals↗
Cloning and expression of the dog mast cell alpha-chymase gene.
Chymases are chymotrypsin-like serine proteinases secreted by mast cells. Alpha- and beta-chymases differ in structure, function, and mast cell subset- and species-specific expression. Seeking genetic regulatory elements shared by alpha-chymases, we sequenced the dog alpha-gene. Extensive homology was found in intronic and flanking sequences of the dog, human, and mouse alpha-chymase genes, but little in corresponding beta-chymase sequences. Repetitive elements probably derived from retroposons are unique features of the dog flank. DNA blots suggest that the dog alpha-gene, like its human counterpart, may be the genome's sole chymase, unlike in rodents, in which beta-chymases predominate. Nuclear runoff studies predict that transcriptional mechanisms explain differences in steady state chymase and tryptase mRNA levels between mastocytoma and non-mast cells. In dog BR mastocytoma cells incubated with phorbol ester, high steady state levels of alpha-chymase mRNA drop dramatically with little change in tryptase mRNA, whereas dexamethasone decreases expression of both mRNAs. Portions of the dog or human gene 5' flank transfected into BR cells drive expression of a reporter gene and define regions with active promoters. Thus, BR cells express high levels of alpha-chymase mRNA regulated independently of tryptase and support transcription using dog or human promoters. These studies reinforce the alphabeta-chymase dichotomy and suggest the utility of BR cells in probing regulation of alpha-chymase expression.
Animals↗
Cytokines promote glomerular mesangial cell survival in vitro by stimulus-dependent inhibition of apoptosis.
Resolution of glomerular inflammation requires the removal of proliferating resident glomerular mesangial cells, but excessive loss of glomerular cells is a feature of postinflammatory scarring. Because apoptosis regulates mesangial cell number in glomerular inflammation, we have studied the exogenous control of apoptosis triggered in cultured mesangial cells by stimuli likely to be important in vivo. Apoptosis could be induced by serum deprivation to model decreased availability of survival factors, by etoposide as an example of DNA-damaging agents, by ligation of mesangial cell Fas, and by protein synthesis inhibition by cycloheximide. Insulin-like growth factor I (IGF-I), IGF-II, and basic fibroblast growth factor were each able to suppress apoptosis induced by serum deprivation, whereas TGF-beta 1, epidermal growth factor, and platelet-derived growth factor had no effect. IGF-I and IGF-II (but not basic fibroblast growth factor) were also able to protect cells from apoptosis induced by etoposide or cycloheximide. However, Fas-mediated apoptosis was resistant to suppression by all three cytokines. None of the cytokines tested caused a change in the levels of expression of Bcl-2, Bax, Bcl-x, or Bak proteins. The survival-promoting properties of serum-free medium conditioned by mesangial cells was abrogated by neutralizing IGF-I Ab. These experiments are the first to define cytokines that inhibit apoptosis and thereby promote survival of mesangial cells, and the data indicate a paracrine survival signaling role for IGF-I. Finally, the data show that Fas ligation can override cytokine survival signaling, emphasizing a candidate role for this molecule in the undesirable apoptotic loss of mesangial cells during the progression of glomerular scarring.
Animals↗
Creation of an In vivo cytosensor using engineered mesangial cells. Automatic sensing of glomerular inflammation controls transgene activity.
Automatic control over exogenous gene expression in response to the activity of disease is a crucial hurdle for gene transfer-based therapies. Towards achieving this goal, we created a "cytosensor" that perceives local inflammatory states and subsequently regulates foreign gene expression. alpha-Smooth muscle actin is known to be expressed in glomerular mesangial cells exclusively in pathologic situations. CArG box element, the crucial regulatory sequence of the alpha-smooth muscle actin promoter, was used as a sensor for glomerular inflammation. Rat mesangial cells were stably transfected with an expression plasmid that introduces a beta-galactosidase gene under the control of CArG box elements. In vitro, the established cells expressed beta-galactosidase exclusively after stimulation with serum. To examine whether the cells are able to automatically control transgene activity in vivo, serum-stimulated or unstimulated cells were transferred into normal rat glomeruli or glomeruli subjected to anti-Thy 1 glomerulonephritis. When stimulated cells were transferred into the normal glomeruli, beta-galactosidase expression was switched off in vivo within 3 d. In contrast, when unstimulated cells were transferred into the nephritic glomeruli, transgene expression was substantially induced. These data indicate the feasibility of using the CArG box element as a molecular sensor for glomerular injury. In the context of advanced forms of gene therapy, this approach provides a novel concept for automatic regulation of local transgene expression where the transgene is required to be activated during inflammation and deactivated when the inflammation has subsided.
Actins↗
IL-1beta depresses expression of the 70-kilodalton heat shock protein and sensitizes glomerular cells to oxidant-initiated apoptosis.
The 70-kDa heat shock protein (hsp70) is induced by several physical stimuli, whereas little is understood about the regulation and function of this molecule during inflammation. We found that the proinflammatory cytokine IL-1beta depressed hsp70 expression in glomerular mesangial cells and that IL-1-pretreated cells were more susceptible to apoptotic death triggered by oxidant stress. To examine whether the altered expression of hsp70 causes the effect of IL-1beta on apoptosis, rat mesangial cells were stably transfected with a hsp70 cDNA under the control of a constitutively active regulatory element. Compared with mock-transfected cells, the established cells overexpressing hsp70 showed resistance to the effect of IL-1beta. The effects of IL-1beta on hsp70 expression and apoptosis were also examined in isolated rat glomeruli. Consistent with the results from mesangial cells, IL-1beta repressed the expression of hsp70 and enhanced the oxidant-initiated apoptosis in the glomerulus. The relationship between glomerular hsp70 and apoptosis was further investigated using an experimental model of anti-glomerular basement membrane glomerulonephritis in which IL-1 and oxidants play crucial roles. Compared with normal expression, the expression of hsp70 was significantly reduced in the inflamed glomeruli. Furthermore, the nephritic glomeruli exhibited oligonucleosomal DNA fragmentation typical of apoptosis. These findings suggested a novel mechanism by which IL-1 may induce glomerular injury. IL-1beta has the potency to affect intrinsic cytoprotective machinery and thereby sensitizes glomerular cells to oxidant-initiated apoptosis. We identified hsp70 as a potential molecular target in this process.
Animals↗
In vivo transfer of engineered macrophages into the glomerulus: endogenous TGF-beta-mediated defense against macrophage-induced glomerular cell activation.
Communication between resident glomerular cells and infiltrating macrophages plays a crucial role in the pathogenesis of glomerular disease. Using matrix metalloproteinase-9 (MMP-9) as an indicator molecule, we examined the interaction between mesangial cells and macrophages. Mesangial cells cocultured with activated macrophages or exposed to macrophage-conditioned media produced abundant MMP-9. We identified the stimulator secreted by macrophages as IL-1 because mesangial cells overexpressing IL-1 receptor antagonist protein showed a blunted expression of MMP-9 in response to the macrophage-conditioned medium. In contrast, culture supernatants of mesangial cells inhibited MMP-9 production by macrophages in a dose-dependent fashion. This inhibitor was identified to be TGF-beta1, since neutralization of TGF-beta1 abrogated the inhibitory effect of the mesangial cell-conditioned medium. To investigate whether activated macrophages induce glomerular MMP-9 expression, and if so, how endogenous TGF-beta1 modulates the induction, stimulated reporter macrophages were transferred into normal rat glomeruli or glomeruli in the regeneration phase of acute anti-Thy-1 glomerulonephritis. In the normal glomeruli, MMP-9 expression was up-regulated in resident cells after the transfer of activated macrophages. This induction was substantially repressed in the regenerating glomeruli that produced active TGF-beta1. These results point to potential mechanisms involved in glomerular control of MMP-9. Based upon the in vitro evidence, TGF-beta1 was identified as an endogenous "defender" that attenuates certain actions of infiltrating macrophages in the glomerulus.
Animals↗
Identification of an inhibitor targeting macrophage production of monocyte chemoattractant protein-1 as TGF-beta 1.
Monocyte chemoattractant protein-1 (MCP-1) is expressed in a diverse range of cells in response to various pathologic stimuli, whereas little is known about endogenous inhibitors of MCP-1 expression. I sought negative regulators of MCP-1 in culture medium conditioned by several cell lines and found that glomerular mesangial cells exclusively secrete a factor that inhibits expression of MCP-1 by activated macrophages. Treatment of J774.2 macrophages with conditioned medium from mesangial cells blunted the induction of MCP-1 by LPS. Even after the induction, subsequent treatment of macrophages with the conditioned medium down-regulated the MCP-1 expression. Medium conditioned by normal rat glomeruli contained a similar inhibitory activity that was enhanced in regenerating glomeruli, where mesangial cells are activated. The activity of the conditioned medium was not diminished, but enhanced by heat treatment, which was consistent with the unique property of TGF-beta family of molecules. Indeed, the mesangial cell-derived medium contained active TGF-beta 1. An anti-TGF-beta 1 neutralizing Ab abolished the inhibitory effect exerted by the mesangial cell medium, and externally added TGF-beta 1 suppressed the MCP-1 expression by macrophages at both mRNA and protein levels. The inhibitory effect of TGF-beta 1 on MCP-1 was observed in other macrophage cell lines, RAW264.7 and NR8383, and peritoneal macrophages, but not in fibroblastic cell line NRK49F. Treatment of J774.2 macrophages with TGF-beta 1 inhibited LPS induction of c-jun that was found to be crucial for the MCP-1 expression. These data demonstrate that TGF-beta 1 functions as an inhibitor of MCP-1 expression in macrophages possibly via down-regulation of c-Jun/activator protein-1.
Animals↗
Cloning and expression of the rubredoxin gene from Desulfovibrio vulgaris (Miyazaki F)--comparison of the primary structure of desulfoferrodoxin.
A gene encoding rubredoxin from Desulfovibrio vulgaris (Miyazaki F) was cloned and overexpressed in Escherichia coli. A 1.1-kilobase pair DNA fragment, isolated from D. vulgaris (Miyazaki F) by double digestion with SmaI and SalI, contained two genes, the rubredoxin gene (rub) and the desulfoferrodoxin gene (rbo) which was situated upstream of rub. The deduced amino acid sequence of desulfoferrodoxin was homologous to those from other strains and Cys residues that are responsible to bind irons were also conserved. The expression system for rub was constructed under the control of the T7 promoter in E. coli. The purified protein was soluble and had a characteristic visible absorption spectrum. Inductively coupled plasma-atomic emission analysis and electron paramagnetic resonance analysis of the recombinant rubredoxin revealed the presence of an iron ion in a distorted tetrahedral geometry that was the same as native D. vulgaris rubredoxin. In vitro NADH reduction analysis indicated that recombinant rubredoxin was active, and its redox potential was determined as -5 mV.
Amino Acid Sequence↗
Direct measurement of doxorubicin concentration in the intact, living single cancer cell during hyperthermia.
BACKGROUND: It is well known that the effect of doxorubicin on cancer cells is enhanced by hyperthermia. The mechanism of this phenomenon is not fully understood. METHODS: Two esophageal squamous cell carcinoma cell lines, TE-2 and TE-6, were used; these cell lines have different sensitivities for doxorubicin. The cells were exposed to 1 microgram/mL of doxorubicin for 30 minutes. With a confocal laser scanning microscope and a transparent warming plate, doxorubicin concentration was measured continuously in the intact, living single cancer cells, and the two-dimensional distribution of the drug during hyperthermia (43 degrees C) was analyzed. RESULTS: A doxorubicin sensitivity difference was confirmed between TE-2 and TE-6 cells by colonogenic assay (P < 0.05). Hyperthermia increased the sensitivity of both cell lines to the drug (P < 0.05) and eliminated the sensitivity difference. Doxorubicin accumulated in the nuclei in both cell lines 30 minutes after exposure to the drug in a time-dependent manner (P < 0.05). Without hyperthermia, the doxorubicin concentration in the nuclei of the TE-2 cells (4.8 +/- 0.3 micrograms/mL) was higher than in the nuclei of the TE-6 cells (2.3 +/- 0.5 micrograms/mL) (P < 0.05). With hyperthermia, there was no significant difference in doxorubicin concentration between the nuclei of the TE-2 cells (20.8 +/- 1.3 micrograms/mL) and the nuclei of the TE-6 cells (16.5 +/- 3.9 micrograms/mL). CONCLUSIONS: Hyperthermia increased the uptake of doxorubicin in the nuclei of cancer cells. Thus, the authors concluded that hyperthermia increases the cells' sensitivity to the drug.
Antibiotics, Antineoplastic↗
Membrane-bound cytochromes in a sulfate-reducing strict anaerobe Desulfovibrio vulgaris Miyazaki F.
Cytoplasmic membranes were isolated from the cells of a sulfate-reducing strict anaerobe Desulfovibrio vulgaris Miyazaki F and membrane-bound cytochromes were characterized. Redox difference spectra at 77 K revealed the presence of cytochromes with the alpha peaks at 552 and 556 nm while CO-binding difference spectra showed the presence of o-type cytochrome(s). Partial purification of the cytochromes demonstrated that the membranes contain cytochromes c550, c551, c556 and possibly d1 besides high molecular mass cytochrome c and cytochrome c3. It turned out that two kinds of novel CO-binding c-type cytochromes are present in the membrane. The membranes and a partially purified fraction showed weak ubiquinol-1 oxidase activity but no cytochrome c oxidase activity. Results suggest that D. vulgaris does not express the heme-copper terminal oxidase under our growth conditions in spite of the presence of the col gene, which is homologous to the gene of subunit I of the aa3-type oxidase.
Journal Article↗
Laparoscopic repair of a paraesophageal hiatus hernia without fundoplication.
We treated a case of paraesophageal hiatus hernia by laparoscopic repair. The procedure included a reduction of the gastric fundus and duodenal bulbus, closure of the diaphragmatic defect, mesh wrapping of the closure, gastropexy to the diaphragm, and a gastrostomy. Preoperative monitoring of the pH for 24 h showed no reflux. Intraoperative intraluminal manometry of the esophagus after hernia reduction showed the pressure of the lower esophageal sphincter to be normal, and thus an antireflux procedure was not deemed to be necessary. The patient was put on a soft diet from postoperative day 2. A postoperative upper gastrointestinal series showed no gastroesophageal reflux. No complications or recurrence of the hiatus hernia have been observed in the 12 months since the operation. Laparoscopic repair of a paraesophageal hiatus hernia with normal pressure of the lower esophageal sphincter, so that fundoplication is not needed, is thus considered to be possible.
Aged↗