Effects of FK506 on rat thymic microenvironment in thymocyte maturation, proliferation, and mobilization.
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Animals↗
Biomedical subjects
K Naito
Publications and source records attributed to K Naito.
A long term follow-up of a randomized trial comparing interferon-alpha with busulfan for chronic myelogenous leukemia. The Kouseisho Leukemia Study Group.
To evaluate the long-term effectiveness of interferon-alpha (IFN-alpha) therapy in patients with chronic myelogenous leukemia (CML) in chronic phase, we examined the updated outcomes of 159 patients who had been enrolled between 1988 and 1991 into a randomized trial comparing IFN-alpha with busulfan. At a median follow-up of 73 months, the median survival was 71 months in the IFN-alpha group and 55 months in the busulfan group (P=0.0563), and the median time of remaining in chronic phase was 58 months in the IFN-alpha group and 39 months in the busulfan group (P=0.4676). Landmark analysis showed a significant advantage in survival (P=0.009) and duration of chronic phase (P=0.0001) in patients with any cytogenetic response among the IFN-alpha group. About half patients were discontinued IFN-alpha administration in spite of cytogenetic response in this study. It appears that continuation of IFN-alpha might possibly confer a survival advantage. Pretreatment factors associated with cytogenetic response included high hemoglobin level, low percentage of peripheral basophils and low leukocyte counts. Multivariate analysis identified lower percentage of bone marrow basophilia (P=0.007) for survival advantage. If a group with a very good prognosis is predicted by a new prognostic model, it might be an option to wait for bone marrow transplantation.
Adult↗
Evidence that cyclosporin A and dexamethasone inhibit allergic airway eosinophilic inflammation via suppression of interleukin-5 synthesis by T cells.
1. We have recently demonstrated that airway eosinophilic inflammation can be transferred to unprimed mice by infusing interleukin (IL)-5-producing T cell clones. Using that murine model, we performed this study to delineate the mechanism of cyclosporin A and dexamethasone to inhibit allergic airway eosinophilic inflammation. 2. The ovalbumin-reactive murine T cell clones, FJ17, produced IL-2, IL-4 and IL-5 upon stimulation with relevant antigen. In FJ17-transferred mice, messenger RNA (mRNA) of IL-2 and IL-5 expressed in the lungs, the number of eosinophils in bronchoalveolar lavage fluid (BALF) was increased and the bronchial responsiveness to acetylcholine was enhanced after antigen provocation. 3. Cyclosporin A (10, 100 ng ml(-1)) and dexamethasone (10, 100 ng ml(-1) suppressed the production of IL-5 as well as IL-2 and IL-4 by FJ17 in vitro. 4. Subcutaneously administered cyclosporin A (30 mg kg(-1)) and dexamethasone (10 mg kg(-1)) inhibited antigen-induced mRNA expression of IL-2 and IL-5, increase of BALF eosinophils and bronchial hyperresponsiveness of FJ17-transferred mice in vivo. The number of BALF eosinophils was correlated with the bronchial responsiveness to acetylcholine (r=0.672). 5. The results clearly indicated that the suppression of IL-5 synthesis by T cells is involved in the effects of cyclosporin A and dexamethasone to inhibit allergic airway eosinophilic inflammation.
Animals↗
Reconstitution of peripheral blood lymphocyte subsets in the long-term disease-free survivors of patients with acute myeloblastic leukemia.
The number of long-term survivors of patients with acute myeloblastic leukemia (AML) has increased as a result of the progress of chemotherapy. We examined the recovery of peripheral blood lymphocytes (PBL) subset after chemotherapy to clarify the reconstitution of the immune system in AML. Thirty patients with AML in complete remission (CR) were entered into the study. There were 12 males and 18 females; one M0, six M1, 14 M2, three M3, two M4 and four M5 according to FAB classification. The age ranged from 21 to 78 years (median age, 46 years) and the duration of disease-free survival after completion of chemotherapy ranged from 5 to 122 months (median, 35 months). The chemotherapy was performed according to the protocol designed by the Japan Adult Leukemia Study Group (JALSG). PBL subsets were analyzed by flow cytometry with the use of monoclonal antibodies against CD2, CD3, CD4, CD5, CD8, CD16, CD20, CD45RA, CD56, CD57 and HLA-DR. There was a significant positive relationship between the absolute number of CD4+, CD45RA+ CD4+ cells and the duration of time post-therapy and a significant negative relationship between %CD5+ B, CD56+ cells and the duration of time post-therapy. The appearance of autoantibodies (rheumatoid factor and anti-DNA antibody) tended to increase after 2 years, however, there was no relationship between CD5+ B cells and the frequency of rheumatoid factor. These findings demonstrate that patients in CR have a low number of CD4+ and CD45RA+ CD4+ T cells at an early period after chemotherapy and that each subset recovered to a normal level in 2 years. %CD5+ B and CD56+ cells gradually decreased and returned to their normal level after 4 years. There were high numbers of DR+ T cells and NK cells for a long time, suggesting that activated T cells and NK cells may play a role in the immune surveillance system after chemotherapy.
Adult↗
Characterization of the immunoglobulin light chain variable region gene expressed in multiple myeloma.
We studied the organization, diversification and clinical significance of the immunoglobulin light chain (IgL) variable region genes expressed in 17 kappa-chain and 16 lambda-chain producing multiple myeloma (MM) samples. The V genes from 31 MM samples had over 84.9% homology to the known germline Vkappa/lambda genes, whereas one Vkappa and one Vlambda gene had only 75.5% and 65.9% homology, respectively. While all five Jkappa segments were equally used, only Jlambda-1 or Jlambda-2/3 was used among seven Jlambda segments. N nucleotide addition was found at two Vkappa-Jkappa and five Vlambda-Jlambda junctions. The lambda-chain complementarity determining region (CDR)-3 was longer and more variable than the kappa-chain CDR-3 mainly due to junctional flexibility of Vlambda and Jlambda segments. Somatic mutations were more frequent in the Jlambda than the Jkappa segments, and were distributed in the CDR-3 as well as the frame work region (FWR)-4. Those of the Jkappa segments, however, were limited to FWR-4. In FWR-4, replacement mutations were clustered at codon 106 of kappa-chain and 103 of lambda-chain. Thus nucleotide mutation or conservation was dependent on position, indicating a structural necessity of IgL for the development of myeloma cells in addition to a non-random distribution of mutations. There was no characteristic IgL sequence according to the isotype of M-protein, clinical stage or renal complication.
Adult↗
The induction of apoptosis and cell cycle arrest by arsenic trioxide in lymphoid neoplasms.
Arsenic trioxide (As2O3) has recently been shown to induce complete remission in acute promyelocytic leukemia (APL). As2O3 reportedly has dose-dependent dual effects on APL cells, triggering apoptosis at relatively high concentrations and inducing differentiation at lower concentrations. However, its effect is still controversial for other AML cells and hematological neoplasms. We studied the in vitro effect of As2O3 on lymphoid lineage cells: lymphoma cell lines, NOL-3, Raji and Daudi, a myeloma cell line, NOP-1, normal peripheral blood lymphocytes (PBL), non-Hodgkin's lymphoma (NHL) cells and chronic lymphocytic leukemia (CLL) cells, and compared it with the effect on APL cell line, NB4, as well as other myeloid cell lines, HL-60 and NKM-1. As2O3 at a concentration of 1 micromol/l markedly inhibited both proliferation and viability of NB4, NOP-1, NOL-3 and NKM-1 cells, but it reduced only viability in normal PBL, CLL cells and NHL cells. As2O3 induced apoptosis and down-regulated bcl-2 expression in NB4, NOP-1 and NKM-1 cells. On the other hand, in HL-60, Raji and Daudi cells, 1 micromol/l As2O3 inhibited only the proliferation weakly, and neither induced apoptosis nor down-regulated bcl-2 expression, but arrested only cell cycle at G1 phase. As2O3 at a low concentration of 0.1 micromol/l had no effect on proliferation and viability of these cells except for NB4. These results showed that As2O3 exerted variable and definite effects on lymphoid cells and indicated that As2O3 might be clinically useful in lymphoid neoplasms such as malignant lymphoma and CLL.
Antineoplastic Agents↗
Quantitative expression of thrombopoietin receptor on leukaemia cells from patients with acute myeloid leukaemia and acute lymphoblastic leukaemia.
Using a non-isotopic ligand binding assay, we quantitatively examined the amount of human thrombopoietin (TPO) receptor (TPO-R) on leukaemia cells from 128 patients with acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL). The TPO-R was expressed in 53 (47%) of 114 AML cases, and an in vitro treatment with TPO led to proliferation (stimulation index >1 5) of leukaemia cells in 13 (20%) of 66 AML cases examined. The TPO levels had no relation to the FAB classification except for FAB-M7 AML. All five FAB-M7 cases expressed TPO-R, and one of three FAB-M7 examined showed in vitro proliferative response to TPO. Although there was no significant correlation (r = 0.3125) between the amount of TPO-R and the proliferative response, all of the AML cases which showed the in vitro response had TPO-R expression. There was no relationship between TPO-R amount and CD phenotypes, or the amount of granulocyte-colony stimulating factor (G-CSF) receptor. TPO-R was also expressed in two (14%) of 14 cases of ALL, and only these two cases had in vitro proliferative response to TPO. One had only lymphoid antigens, and the other had both lymphoid and myeloid antigens. Our results suggest that some leukaemia cells express functionally active TPO-R.
Acute Disease↗
Mitogen-activated protein kinase translocates into the germinal vesicle and induces germinal vesicle breakdown in porcine oocytes.
The role of mitogen-activated protein kinase (MAPK) in the meiotic resumption of porcine oocytes was examined. First, using indirect immunofluorescence staining with a specific antibody against rat MAPK, we monitored the dynamics of the subcellular distribution of MAPK during meiosis initiation. We found that the inactive MAPK was already present in immature oocytes arrested at the G2 stage and that this inactive kinase was localized exclusively in the cytoplasm. At the G2/M transition stage, part of the MAPK moved into the germinal vesicle (GV) before germinal vesicle breakdown (GVBD). In addition, immunoblot analysis showed that the nuclear MAPK existed in an active form. To determine whether this active MAPK could induce GVBD, we microinjected active MAPK into immature porcine oocytes. The active MAPK injected into the cytoplasm was quickly inactivated and could not accelerate GVBD. In contrast, MAPK injection into the GV markedly accelerated GVBD. These results show that in porcine oocytes, 1) inactive MAPK localizes in the cytosol of immature GV oocytes, 2) part of the activated MAPK translocates into the GV just before GVBD, and 3) exogenous MAPK maintains its activity level in the GV and induces GVBD, indicating that MAPK mediates the maturation-inducing signal from the cytoplasm into the nucleus and induces meiosis reinitiation.
Animals↗
Blunted natriuretic response to endogenous atrial natriuretic peptide during rapid cardiac pacing in anaesthetized dogs.
1. We investigated whether diuresis and natriuresis induced by endogenous atrial natriuretic peptide (ANP) were blunted during rapid cardiac pacing. 2. Changes in plasma ANP, renal function and haemodynamics during rapid cardiac pacing were studied in anaesthetized closed-chest dogs. Dogs were paced via the right ventricle at a rate of 200 b.p.m. (moderate pacing) or 250 b.p.m. (severe pacing) for 180 min. 3. The maximal increases in plasma ANP and urinary excretion of cGMP during severe pacing were four- and three-fold higher, respectively, than those during moderate pacing. Despite the higher concentration of plasma ANP, the maximal increases in urine volume, urinary excretion of sodium and fractional excretion of sodium during severe pacing were similar to those during moderate pacing. Mean arterial pressure and renal vascular resistance were decreased only by severe pacing. The increase in total peripheral resistance during severe pacing was significantly smaller than that during moderate pacing. However, the glomerular filtration rate was kept at basal levels by both moderate and severe pacing. 4. These results suggest that there are certain mechanisms that counteract renal tubular sodium reabsorption induced by endogenous ANP under conditions of severe pacing. The suppression occurs at tubular sites but at glomerular sites. One of the possibilities for the suppression is the decrease in renal perfusion pressure accompanied by decreases in peritubular capillary hydrostatic pressure.
Animals↗
Inhibition of pulmonary eosinophilia does not necessarily prevent the airway hyperresponsiveness induced by Sephadex beads.
BACKGROUND: The Lewis rat among highly inbred strains exhibits significant airway hyperresponsiveness (AHR) following intravenous administration of Sephadex G-200 (Sephadex). The aim of this study was to investigate the association of Sephadex-induced AHR with changes in airway inflammation in Lewis rats. METHODS: A suspension (0.5 mg/ml/rat) of Sephadex was intravenously administered to male Lewis rats on days 0, 2 and 5. Measurement of airway responsiveness to serotonin, bronchoalveolar lavage (BAL) and histological study were performed on day 2-11. RESULTS: Significant AHR induced by Sephadex was recognized on day2 (p < 0.05), and AHR reached a maximum on day 7 (p < 0.001). In the BAL study, eosinophils increased on day2 (p < 0.01) with a peak on day 5 (p < 0.05). In the histological study, we found Sephadex beads trapped in small arteries of the lung and granulomatous arteritis on day 2 or later. Pulmonary granulomas, horseshoe-shaped multinuclear giant cells, eosinophils and goblet cell hyperplasia were observed on day 2, and the degree became intense on day 5-7. GCC-AP0341 (10 mg/kg, i.p. x 3) inhibited the recruitment of eosinophils in BAL fluid and in lung tissue, but it did not inhibit AHR. The compound also inhibited pulmonary granulomas and goblet cell hyperplasia. CONCLUSION: The mechanism of Sephadex-induced AHR may not be directly associated with inflammatory changes such as recruitment of eosinophils, pulmonary granulomas and hyperplasia of goblet cells in rats.
Animals↗
Augmentation of sinecomitant immunity in mice by gamma-(9H-purine-6-yl)thiomethyl L-glutamate (6-MPG), a water-soluble derivative of 6-mercaptopurine.
Effects of the administration of gamma-(9H-purine-6-yl)thiomethyl L-glutamate (6-MPG), a water-soluble derivative of 6-mercaptopurine, on concomitant and sinecomitant immunity against the implanted MethA tumor were studied in BALB/c mice. In the concomitant immunity experiments, mice were intradermally inoculated with 1x10(5) MethA cells at the right inguinal region on day 0. In sinecomitant immunity experiments, mice were similarly inoculated on day -21, and the grown tumor was excised on day -11. Both the tumor-bearing and tumor-ectomized animals were re-inoculated with 3x10(6) MethA cells intradermally at the left inguinal region on day 10. Administration of 6-MPG (100 mg/kg, i.p.) on days 3 through 7 significantly inhibited growth of the re-inoculated tumor in both series of experiments. Cyclophosphamide, adriamycin, mitomycin C and cis-diamminedichloroplatinum (II) had no significant effect on the growth of the re-inoculated tumor in the tumor-ectomized mice. Spleen cells harvested from the 6-MPG-treated tumor-ectomized mice showed a strong tumor-neutralizing activity (Winn assay).
Animals↗
A novel anti-allergic drug, betotastine besilate, suppresses interleukin-5 production by human peripheral blood mononuclear cells.
The effect of a novel anti-allergic drug, betotastine besilate (betotastine) on interleukin (IL)-5 production by human peripheral blood mononuclear cells (PBMC) was investigated. PBMC of Dermatophagoides farinae extract (Df)-sensitive donors produced IL-5 and showed a proliferative response upon stimulation with relevant antigen (10 microg/ml). Df-induced IL-5 production by PBMC was significantly inhibited by betotastine at 10 and 100 microM. Betotastine also suppressed proliferation of PBMC with less potency. The effect of betotastine on IL-5 production was enhanced and significant even at 0.1 microM when the drug was added 120 min before antigen stimulation. Ketotifen and cetirizine also inhibited IL-5 production, but the effects of these drugs were significant only at 100 microM. These findings indicate that the suppression of IL-5 production may be involved in the anti-allergic effect of betotastine.
Adult↗
Nephrotoxic serum-induced nephritis in Wistar-Kyoto rats: a model to evaluate antinephritic agents.
We investigated nephrotoxic serum (NTS)-induced glomerulonephritis in Wistar-Kyoto (WKY) rats as a model to evaluate antinephritic agents. WKY rats required only a small amount of NTS to induce crescentic glomerulonephritis and the rats progressively lost their renal function in a few weeks. In a comparative study with WKY and Sprague-Dawley (SD) rats, WKY rats showed a normal distribution pattern in the severity of proteinuria with a small variance. While SD rats needed a much higher amount of NTS to exhibit a comparable proteinuria which was not normal and had a large variance. The effects of clinically available antinephritic drugs, methylprednisolone, cyclophosphamide and cyclosporin A, were studied in both strains. In WKY rats, these drugs significantly inhibited the proteinuria, glomerular histological changes and decrease in creatinine clearance. On the other hand, such significant inhibitory effects on proteinuria were not observed with any of these drugs in SD rats. In conclusion, NTS nephritis in WKY rats may prove to be a useful model for studying antinephritic agents.
Animals↗
Difference in inhibitory effects of dexamethasone and cyclosporin A on Sephadex bead-induced airway hyperresponsiveness and inflammation in rats.
We investigated the effects of dexamethasone and cyclosporin A on Sephadex bead (Sephadex G-200, Sephadex)-induced airway hyperresponsiveness (AHR) and inflammation in rats. Sephadex (0.5 mg/animal) was intravenously administered on days 0, 2 and 5. Bronchoalveolar lavage, histological study and measurement of AHR were performed on day 7. Dexamethasone (0.1, 1 and 10 mg/kg, p.o. x 3) and cyclosporin A (0.1, 1 and 10 mg/kg, s.c. x 3) clearly inhibited the increase in eosinophils in bronchoalveolar lavage fluid after Sephadex injection. On histological study, pulmonary eosinophilia, granulomatous arteritis with horseshoe-shaped multinuclear giant cell formation and goblet hyperplasia were observed after Sephadex injection. Both dexamethasone (10 mg/kg x 3) and cyclosporin A (10 mg/kg x 3) inhibited these findings and an increase in eosinophil peroxidase in the lung. Dexamethasone dose-dependently inhibited AHR induced by Sephadex, and completely suppressed it at a dose of 1 mg/kg (x 3). Cyclosporin A, however, did not inhibit AHR even at a dose of 10 mg/kg ( x 3). These results show that there is a difference between dexamethasone and cyclosporin A in the inhibitory effect on Sephadex-induced AHR, and they suggest that eosinophils are not directly associated with the development of AHR after Sephadex injection.
Animals↗
Comparison of calculated nasal resistance from Röhrer's equation with measured resistance at delta P150Pa.
Values of nasal resistance at delta P150Pa have been recommended by the International Standardization Committee for clinical use. However, this point seems somewhat high for quiet nasal breathing. To determine the usefulness of calculated nasal resistance at delta P150Pa from Röhrer's equation when transnasal pressure fails to reach the point, the values at delta P150Pa calculated from the method have been compared with actually measured nasal resistances at delta P150Pa by active anterior rhinomanometry with a nasal nozzle. The mean value of measured unilateral nasal resistance in 75 patients is 0.513 +/- 0.511 Pa/cm3/s on expiration and 0.335 +/- 0.193Pa/cm3/s on inspiration. The mean value of calculated nasal resistance from Röhrer's equation is 0.511 +/- 0.515Pa/cm3/s on expiration and 0.337 +/- 0.207Pa/cm3/s on inspiration. Correlations between measured and calculated nasal resistances have been assessed and are almost identical in both expiration and inspiration. Calculated nasal resistance at delta P150Pa from Röhrer's equation seems to be suitable for evaluation when transnasal pressure fails to attain the point.
Adolescent↗
[Influence of acute aortic dissection on long-term results of aortic root reconstruction in patients with Marfan's syndrome].
Objective of this study is to evaluate influence of acute aortic dissection on long-term results of aortic root reconstruction in patients with Marfan's syndrome. 19 patients who underwent consecutive aortic root reconstruction between 1985 May to 1998 February were retrospectively reviewed. Patients who associated acute aortic dissection at the time of operation (group D, n = 7) were compared long-term results with those who did not (group non-D, n = 12). Mean follow-up period was 5.1 +/- 3.2 years and longest follow-up term was 12.5 years. In each group early postoperative death was found in one patient. In-hospital mortality in each group were respectively; 14.2% and 8.3%. Late deaths were found in four patients who all belonged to group D, respectively caused by; rupture of thoracoabdominal aneurysm, DIC after subsequent thoracoabdominal surgery, sepsis due to prosthetic valve endocarditis, and sudden death. Actuarial overall survival rate including operative death in D and non-D group were respectively; 0.0 +/- 0% at 6.6 years and 91.1 +/- 8.0% at 12 years. Overall cumulative survival rate was 56.6 +/- 14.0%. Freedom from cardiovascular events, in D and non-D group were respectively; 0.0 +/- 0% at 6.6 years and 60.0 +/- 25.3%, and freedom free form dilatation of residual aorta were respectively; 0.0 +/- 0% at 6.6 years and 100.0 +/- 0% at 12 years. Freedom from subsequent cardiovascular surgery in group D, group non-D and over-all patients were respectively; 0.0 +/- 0% at 6.6 years, 60.0 +/- 25.3% at 12 years and 42.6 +/- 20.2%. In this study, acute aortic dissection in Marfan's syndrome significantly increased late cardiovascular events including dilatation of residual aorta, subsequent aortic surgery and late mortality. On the other hand, excellent long-term results after aortic root reconstruction were found in non-dissection Marfan's syndrome. Considering high incidence of late dilatation of residual aorta, simultaneous total arch replacement with aortic root reconstruction is recommended in acute dissecting Marfan's syndrome. Whereas, preventive simultaneous arch replacement is not required in non-dissecting Marfan's syndrome because of less postoperative vascular events.
Acute Disease↗
[Evaluation of effectiveness of community mental health system in Kawasaki City--a comparison with national statistics].
UNLABELLED: The pioneering community mental health system of Kawasaki was evaluated by comparison with national statistics using the data from a citywide survey of patients with schizophrenia. METHOD: Subjects were citizens of Kawasaki who were receiving medical treatment for schizophrenia (ICD-9) in the city. All inpatients (565 cases) and a random sample of outpatients (685 cases; extraction rate was 1/3) who met the criteria were asked to complete the questionnaires by themselves. The responsible medical staffs of the subjects were also asked to complete the questionnaires. In order to calculate the total prevalence rate in the city, the number of patients who received medical treatment outside the city was estimated by extrapolation. RESULTS: Higher outpatient rate and lower inpatient rate of Kawasaki were indicated despite the almost equal prevalence (i.e. 32.7 per 10,000 population) compared to the national rate. The outpatient rate was 70.6% in Kawasaki, which was 16% higher than the national average. And the rate of outpatients with schizophrenia living alone in Kawasaki was three times higher. While national outpatient rates declined significantly when patients became 40 years old, such a decline was not evident in Kawasaki. On the other hand, as patients with schizophrenia got older, the rate of outpatients living alone or living with spouse increased in Kawasaki due to the change of caregivers' generation. CONCLUSION: The higher outpatient rate especially of people over 40 years old and the higher rate of patients who lived alone may be explained by the effective community care system in Kawasaki. However, more an intensive support system which provides' daily services such as home-help and group home services should be developed, as the living conditions of outpatients who lived alone were very difficult.
Adult↗
[Urolithiasis associated with Crohn's disease: a case report].
We report a case of urolithiasis caused by surgical treatment for Crohn's disease. A 28-year-old woman was referred to our department for further examination of renal stones from the medical department in September, 1995. She suffered from Crohn's disease and had a history of jejuno-ileal resection because of perforation of the ileum in 1988. Radiographs revealed multiple bilateral renal stones, and the urine oxalate concentration was elevated. She was treated with extracorporeal shock wave lithotripsy and the administration of sodium bicarbonate and citrate, but these treatments did not prevent recurrence and enlargement of stones. Renal function was gradually worsened and we performed transurethral lithotomy and percutaneous nephrolithotripsy. The stones were mainly composed of oxalate calcium monohydrate. A renal biopsy was performed at the operation, showing deposition of crystals in almost all renal tubules. Diet therapy (low oxalate and low fat) and the administration of sodium bicarbonate and citrate were performed strictly and recurrence was not recognized 10 months after complete removal of the stones.
Adult↗