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Biomedical subjects

Y Nitta

Publications and source records attributed to Y Nitta.

At least 19 recordsLinked to original sources
PubMed1998

Systemic delivery of interleukin 10 by intramuscular injection of expression plasmid DNA prevents autoimmune diabetes in nonobese diabetic mice.

We previously demonstrated that intramuscular plasmid injection serves as a useful method of long-term systemic delivery of cytokines. In the present study, we assess intramuscular DNA injection as a means of systemically delivering interleukin 10 (IL-10), a cytokine with immunosuppressive properties, and preventing the progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse, an excellent model for human insulin-dependent diabetes mellitus (IDDM). We injected IL-10 expression plasmid (pCAGGS-IL10) or a control pCAGGS plasmid into the muscles of NOD mice twice at 3 and 5 weeks of age. IL-10 was detectable by ELISA in the sera of mice injected with pCAGGS-IL10 for more than 2 weeks after the injection. Although the severity of insulitis at 13 weeks of age was not improved by the intramuscular injection of pCAGGS-IL10, the incidence of diabetes was markedly reduced in NOD mice injected with pCAGGS-IL10 as compared with those injected with pCAGGS or as compared with nontreated NOD mice. These results show that the progression of autoimmune diseases in mice can effectively be suppressed by intramuscular DNA injection, and suggest that this method is potentially applicable to the treatment of human autoimmune diseases.

Animals↗
PubMed1998

Displacement of platelets from blood to spleen following intravenous injection of liposomes encapsulating dichloromethylene bisphosphonate.

Liposomes encapsulating dichloromethylene bisphosphonate (Cl2MBP-liposomes) have been shown to cause selective depletion of phagocytic macrophages. We have shown that intravenous injection of Cl2MBP-liposomes into mice induces an almost complete depletion of F4/80-positive cells (mature macrophages) in the liver and in the splenic red pulp, but not in the lung. Platelets in the mouse contain a large amount of 5-hydroxytryptamine (5HT; serotonin) and so, by measuring 5HT, it is possible to assess the translocation of platelets to tissues. The injection of Cl2MBP-liposomes was found to induce a prolonged and marked increase in 5HT that occurred selectively in the spleen. On the other hand, 5HT in the blood decreased by as much as 50%. These changes in 5HT corresponded well with each other in terms of both time course and dose-response relationship. To judge from measurements made at the peak of the response, the 5HT increase in the spleen corresponded to about 80% of the 5HT lost from the blood. Electron microscopic analysis revealed a great accumulation of platelets in the splenic cords. We have shown that aggregation and degranulation of platelets in the lung is involved in rapid anaphylactoid shock induced within 10 min of intravenous injection into mice of a lipopolysaccharide [Shibazaki, M., Nakamura, M., Endo, Y., 1996. Biphasic, organ-specific, and strain-specific accumulation of platelets induced in mice by a lipopolysaccharide from Escherichia coli and its possible involvement in shock. Infect. Immun. 64, 5290-5294; Endo, Y., Shibazaki, M., Nakamura, M., Takada, H., 1997. Contrasting effects of lipopolysaccharides (endotoxins) from oral black-pigmented bacteria and Enterobacteriaceae on platelets, a major source of serotonin, and on histamine-forming enzyme in mice. J. Infect. Dis. 175, 1404-1412]. In the present study, it was found that such shock was almost completely prevented in those mice in which platelets were displaced from the blood by Cl2MBP-liposomes. These results suggest that in the spleen the depletion of phagocytic macrophages may impair the function or structure of this organ. This may lead to the entry of platelets into the spleen in such large numbers as to reduce their level in the blood and result in their prolonged accumulation in the spleen. The Cl2MBP-liposome may be an excellent tool for the in vivo investigation of the role of platelets, as well as that of macrophages.

Analgesics, Non-Narcotic↗
PubMed1998

Translocation of platelets into Disse spaces and their entry into hepatocytes in response to lipopolysaccharides, interleukin-1 and tumour necrosis factor: the role of Kupffer cells.

BACKGROUND/AIMS: Injection into mice of a small dose of either a lipopolysaccharide or interleukin-1 induces a slowly developing accumulation of 5-hydroxytryptamine, predominantly in the liver. We have established that this 5-hydroxytryptamine accumulation is the result of the translocation of platelets to hepatic sinusoidal spaces and, further, into Disse spaces, and that the platelets make direct contact with hepatocytes. In the present study, we report our recent findings on this phenomenon. METHODS: Platelets contain a large amount of 5-hydroxytryptamine, but the 5-hydroxytryptamine content of the liver is normally very small. Therefore, the translocation of platelets to the liver was assessed by measuring 5-hydroxytryptamine as in previous studies, and it was also analysed by electron microscopy. RESULTS: Anti-platelet agents, such as heparin and inhibitors of prostaglandin synthesis, were ineffective in preventing the lipopolysaccharide-induced accumulation of 5-hydroxytryptamine in the liver. Of the various cytokines tested, only interleukin-1 and tumour necrosis factor induced such an accumulation of 5-hydroxytryptamine. Intravenous injection of liposomes encapsulating dichloromethylene bisphosphonate resulted in an almost complete depletion of macrophages from the liver. The lipopolysaccharide- and cytokine-induced hepatic accumulations of 5-hydroxytryptamine were abolished almost completely in such macrophage-depleted mice. Electron microscopy revealed no accumulation of platelets in the liver after injection of lipopolysaccharide into the macrophage-depleted mice. Surprisingly, in normal mice injected with lipopolysaccharide, several platelets were found inside some hepatocytes, even though there was no visible damage to these hepatocytes. In fact, there were many polysomes around the degranulated platelets within the hepatocytes, suggesting an enhanced protein synthesis. CONCLUSION: These results suggest that, in response to lipopolysaccharide, interleukin-1 or tumour necrosis factor, platelets translocate into the liver in a way that is different from aggregation, and that some, at least, enter hepatocytes. During these processes, hepatic macrophages play an essential role.

Animals↗
PubMed1998

Mobilization of primitive haemopoietic progenitor cells and stem cells with long-term repopulating ability into peripheral blood in mice by pegylated recombinant human megakaryocyte growth and development factor.

We investigated in detail the effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on peripheral blood progenitor cell (PBPC) mobilization in male BDF1 mice. Treatment with PEG-rHuMGDF for 5 d stimulated a striking expansion of the circulating levels of multiple types of colony-forming units in culture (CFU-c), including CFU-granulocyte-macrophage, CFU-megakaryocyte, burst-forming units-erythroid, and multipotent CFU-c, and primitive day-12 CFU-spleen. All of these progenitors were mobilized into the peripheral blood (PB) with similar kinetics; their numbers peaked after the cessation of treatment and then declined earlier than platelet numbers peaked. The maximal increase in any of the four CFU-c in the PB was attained with at least 300 microg/kg/d of PEG-rHuMGDF, whereas peripheral platelet counts plateaued at 30 microg/kg/d. Adoptive transfer with PB from PEG-rHuMGDF-treated donor mice resulted in greater survival of lethally irradiated recipients. The majority of the recipients that survived at 187 d after transplantation with PEG-rHuMGDF-mobilized PB showed significant donor engraftment at the progenitor cell level. The combined administration of appropriate doses of PEG-rHuMGDF and recombinant human granulocyte colony-stimulating factor induced a synergistic increase in the circulating levels of the four CFU-c compared to either factor alone. These results indicate that PEG-rHuMGDF as a single agent can mobilize a full spectrum of PBPCs in mice.

Animals↗
PubMed1998

Estimation of dose absorbed fraction for 131I-beta rays in rat thyroid.

The dose absorbed fraction of rat thyroid by internal deposit of 131I has been calculated as a function of effective diameter of thyroid. The calculations were done using two types of Monte Carlo simulations: one was by a simple energy-loss calculation in spherical volume according to the electron stopping power, and another by a more realistic simulation using Monte Carlo N-Particle Transport code system Version 4A (MCNP). These two calculations were consistent with each other within a deviation of 5%. The absorbed fractions in spherical thyroid were drastically changed up to 5 mm diameter, and then almost all energy was deposited within 10 mm diameter. For the practical application to the animal experiment, the absorbed fractions of ellipsoid-shaped thyroids were also calculated for 1-, 4- and 9-week-old rats, where the fractions were estimated to be 0.61, 0.67 and 0.68, respectively. It was also found that the absorbed fraction of the ellipsoid with various dimensions can be simulated by a calculation for spherical volume with a comparable effective diameter.

Animals↗
PubMed1998

Intrahypothalamic perfusion of KP102 stimulates growth hormone release in goats.

The hypothalamic actions of KP102 (also called GHRP-2) on the release of GH were studied in female goats. KP102 (10(-5) M) was perfused into the goat hypothalamus through a microdialysis probe (CMA/10 probe with a 4 mm membrane length) at a rate of 4 microl/min for 90 min, and plasma GH concentrations before and after perfusion were measured. The intrahypothalamic perfusion of 10(-5) M KP102 significantly stimulated GH release in goats (P<0.05). The GH levels began to rise after commencement of perfusion, and reached a maximum mean value at 180 min. The concentrations of GH at 165, 180, 195, 210, 225 and 240 min after commencement of perfusion of KP102 were significantly higher than the corresponding values for control animals (P<0.05). KP102 had no effect on GH pulse frequency, but it significantly increased the GH pulse amplitude after the perfusion (P<0.05). In contrast to KP102, intrahypothalamic perfusion of 10(-5) M GHRH had no effect on the stimulation of GH release in goats even if intravenous injection of 10(-5) M GHRH significantly stimulated GH release (P<0.05). These results suggest that KP102 may act partly on the hypothalamus to stimulate GH release in goats.

Animals↗
PubMed1997

Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel.

ATP-sensitive K+ (KATP) channels are known to play important roles in various cellular functions, but the direct consequences of disruption of KATP channel function are largely unknown. We have generated transgenic mice expressing a dominant-negative form of the KATP channel subunit Kir6.2 (Kir6.2G132S, substitution of glycine with serine at position 132) in pancreatic beta cells. Kir6.2G132S transgenic mice develop hypoglycemia with hyperinsulinemia in neonates and hyperglycemia with hypoinsulinemia and decreased beta cell population in adults. KATP channel function is found to be impaired in the beta cells of transgenic mice with hyperglycemia. In addition, both resting membrane potential and basal calcium concentrations are shown to be significantly elevated in the beta cells of transgenic mice. We also found a high frequency of apoptotic beta cells before the appearance of hyperglycemia in the transgenic mice, suggesting that the KATP channel might play a significant role in beta cell survival in addition to its role in the regulation of insulin secretion.

Adenosine Triphosphate↗
PubMed1997

Enhancement of cell-mediated immunity against HIV-1 induced by coinnoculation of plasmid-encoded HIV-1 antigen with plasmid expressing IL-12.

Previous investigations have demonstrated that CTL may play an important role in suppressing the disease progression of HIV infection. In this study, we inoculated mice with IL-12 expression plasmid together with plasmid-encoding HIV-1 envelope to enhance CTL activity by activating a Th1-type response. The results of delayed-type hypersensitivity using the footpad swelling response and of CTL activity clearly showed that HIV-1-specific cell-mediated immunity was enhanced by inoculation of the IL-12 expression plasmid. Quantitation of cytokine in the sera of IL-12-inoculated mice revealed that IFN-gamma significantly increased. The enhanced cell-mediated immunity responses were abrogated by combined administration of the IL-12 expression plasmid and neutralizing anti-IFN-gamma Ab. Together, these results suggest that enhanced virus-specific cell-mediated immunity occurred via an endogenously produced IFN-gamma by inoculation of IL-12 expression plasmid.

AIDS Vaccines↗
PubMed1997

Pitted keratolysis: clinical manifestations in 53 cases.

Pitted keratolysis (PK) has been reported to be more common among bare-footed people living in tropical regions. It is now known that the disease is not limited to the tropics but has a world-wide distribution. However, no study has previously been performed analysing the clinical manifestations of the disease in temperate countries. A survey of 53 patients revealed several distinctive clinical features. Hyperhidrosis is the most frequently observed symptom of this condition. Malodour and sliminess of the skin are also distinctive features, evident in 88.7% and 69.8% of the cases, respectively. The most common sites of onset of PK are the pressure-bearing areas, such as the ventral aspect of the toe, the ball of the foot and the heel. The next most common site is a friction area, the interface of the toes. Lesions are rarely seen on the non-pressure-bearing locations. Some of the primary lesions originate as a small defect along the plantar furrow, which gradually grows into the characteristics crateriform pit. Several clinical features are helpful in diagnosing PK.

Adolescent↗
PubMed1997

Case of malignant lymphoma associated with primary systemic plasmacytosis with polyclonal hypergammaglobulinemia.

Systemic plasmacytosis (SP), which has a histologic appearance similar to that of multicentric Castleman's disease (MCD), is also known as benign plasma cell proliferation with polyclonal hypergammaglobulinemia, cutaneous plasmacytosis, and/or generalized plasmacytic lymphadenopathy. The prognosis of SP reportedly has been good. A 59-year-old Japanese man was treated for multiple cutaneous lesions of his trunk as well as polyclonal hypergammaglobulinemia. A skin biopsy showed infiltration of lymphocytes and polyclonal plasma cells in the dermis. The patient developed enlarged superficial lymph nodes 5 years later, and T-cell lymphoma, diffuse mixed type, was diagnosed. At that time, his cutaneous plasmacytosis remained but the polyclonal hypergammaglobulinemia had resolved. Ours is the first reported case of SP to be complicated by the development of T-cell lymphoma.

Humans↗
PubMed1997

Attenuation of heat shock protein expression by coronary occlusion in hypertrophied hearts.

Hearts hypertrophied by pressure-overload are more susceptible to ischemia than nonhypertrophied hearts, which may result from the attenuation of self-protective responses. Because heat shock proteins (HSPs) are reported to protect against ischemic injuries, we hypothesized that HSP expression by coronary occlusion may be attenuated in hypertrophied hearts. We banded the ascending aorta to develop ventricular hypertrophy and put a snare around the left coronary artery in rats. After 4 wk, coronary occlusion was applied by tightening the snare for 5 or 10 min in rats with and without aortic banding. The hearts were excised 0, 0.5, 1, 2, 4, 8, 12, and 24 h after coronary occlusion. Ischemic and nonischemic myocardial tissues were obtained after the snare was tightly tied, and dye was infused from the aorta. The mRNAs and protein of 72-kDa HSP (HSP 72) and/or 73-kDa HSP (HSP 73) were detected by Northern and Western blot analyses. Protein and mRNA levels of HSPs expressed by 5-min coronary occlusion in hypertrophied hearts (left ventricular weight, 577 +/- 16 mg) were lower compared with those in control hearts (462 +/- 9 mg). A longer period of coronary occlusion (10 min) elevated the attenuated expression to a level similar to that in control hearts. Treatment with an angiotensin-converting enzyme (ACE) inhibitor (cilazapril, 10-15 mg.kg(-1).day(-1)) for 4 wk preserved HSP mRNA expression even in hearts with ascending aortic banding. In hypertrophied hearts, HSP 72 and 73 expression by coronary occlusion was attenuated and was modulated by the duration of coronary occlusion and by ACE inhibitor treatment.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Eosinophils as a source of matrix metalloproteinase-9 in asthmatic airway inflammation.

Bronchial asthma is characterized by eosinophil infiltration and tissue remodeling. Matrix metalloproteinases (MMPs) are thought to play critical roles by degradating interstitial matrices in a wide range of lung diseases associated with reorganization of the airway architecture. To investigate whether MMPs are involved in the pathologic processes of bronchial asthma, we examined MMP expression in asthmatic subjects. In situ hybridization revealed abundant expression of MMP-9 (gelatinase B) mRNA in biopsy specimens from asthmatic subjects (n = 5), with an average positive cell distribution of 117.8 +/- 41.1 (mean +/- SEM)/mm2. In contrast, sparse expression of the mRNA (10.8 +/- 4.8 /mm2) was observed in specimens from normal subjects (n = 4). The vast majority of cells expressing the mRNA were eosinophils in asthmatic tissues (92.2 +/- 1.2%). MMP-9 protein, which was confined to the submucosal cells in the normal subjects, was not abundantly expressed in inflammatory cells, but there was positive reactivity for MMP-9 protein in the extracellular matrix. Immunoelectron microscopic analysis showed sparse immunolocalization of MMP-9 in the perinuclear spaces of eosinophils, but not in the granules. These findings suggest the overexpression of MMP-9 by eosinophils in bronchial tissues of asthmatic individuals, and the participation of MMPs in the pathologic changes in asthmatic airways.

Adult↗
PubMed1997

[Effects of pre-operative administration of steroids on the serum interleukin (IL)-6, IL-8 and organ injuries in replacement of thoracic aorta].

To investigate whether pre-operative steroids administration decreases the post-operative serum IL-6, IL-8 and prevents organ injuries, we prospectively studied patients undergoing elective replacement of thoracic aorta using an extracorporeal circulation. Six of 10 patients (group S) were pretreated with methylprednisolone 500 mg 2 hours before operation while the other 4 patients (group C) were not. Though post-operative serum IL-6, IL-8, C-reactive protein and amylase elevated in group C, the elevations were significantly decreased in group S (p < 0.05). These findings show that in replacement of thoracic aorta, pre-operative steroid administration decreases the post-operative elevations of serum inflammatory cytokines (IL-6 and IL-8) and may prevent organ injuries.

Aged↗
PubMed1997

[Study on coagulation fibrinolytic systems in predialysis patients with chronic renal failure--comparison between patients with chronic glomerulonephritis and patients with diabetic nephropathy].

To clarify the abnormalities of coagulation and fibrinolytic systems on predialysis patients with chronic renal failure, we measured indices of coagulation and fibrinolytic systems in 33 predialysis patients whose creatinine (Cr) levels were over 3.0 mg/dl. We termed twenty-four patients with chronic glomerulonephritis the "CGN group". We also termed nine patients wit diabetes mellitus the "DM group". We measured thrombin.antithrombin III complex (TAT), alpha 2-plasmin inhibitor plasmin complex (PIC), D-dimer, protein C, protein S, thrombomodulin (TM), vitronectin, tissue plasminogen activator.plasminogen activator inhibitor-1 complex (tPAI-C) in theses two groups. Furthermore, we measured the same indices after 6 months in the CGN group. As a result, the plasma levels of both TAT, PIC, TM/Cr ration in the DM group were significantly higher that those in the CGN group, changes in both protein S activities and plasma levels of tPAI-C were reduced significantly after 6 months. In conclusion, the abnormalities of coagulation and fibrinolytic systems in predialysis diabetic patients were stronger than those in predialysis patients with CGN. Furthermore, these abnormalities were worsened after 6 months in predialysis patients with chronic renal failure.

Adult↗
PubMed1996

In vivo effects of pegylated recombinant human megakaryocyte growth and development factor on hematopoiesis in normal mice.

The in vivo effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a truncated molecule of recombinant human thrombopoietin modified with polyethylene glycol, were investigated in normal Balb/c mice. PEG-rHuMGDF was more potent in producing platelets and the dose-response curve was steeper compared with the case of the nonpegylated form of this molecule. Five consecutive injections with PEG-rHuMGDF caused a dose-dependent increase in peripheral platelet counts with a peak on day 8. There was a dose-dependent rise in platelet counts on day 8 at daily doses from 0.333 to 30 micrograms/kg. Intermediate doses of PEG-rHuMGDF (1.111 to 10 micrograms/kg/day) caused a significant decrease in mean platelet volume, and conversely, higher doses of PEG-rHuMGDF (30 to 270 micrograms/kg/day) induced a dose-dependent increase in mean platelet volume. There was a dose-dependent decrease in hemoglobin concentration with a minimum on day 8 but no significant reduction in reticulocyte counts following PEG-rHuMGDF administration. White blood cell counts were unchanged by PEG-rHuMGDF treatment. Marrow megakaryocyte size enlarged to 1.5-fold and the number of marrow megakaryocytes increased to sixfold by consecutive administration of PEG-rHuMGDF at 30 micrograms/kg/day. A twofold increase in the number of marrow megakaryocytic progenitor cells (colony-forming units-megakaryocyte) was also observed. Marrow erythroid progenitor (colony-forming units-erythroid) counts decreased but splenic colony-forming units-erythroid, marrow and splenic erythro/myeloid progenitor cell counts, and splenic granulocyte/macrophage progenitor cell counts increased with PEG-rHuMGDF treatment. Marrow and splenic erythroid burst-forming cells were unchanged. These results indicate that PEG-rHuMGDF, a truncated molecule of thrombopoietin, is a potent stimulator for megakaryopoiesis and thrombopoiesis, and also affects the development of other hematopoietic cells in normal mice.

Animals↗