Familial polycythemia vera in father and daughter.
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Adult↗
Biomedical subjects
T Inaba
Publications and source records attributed to T Inaba.
Effects of three inhibitors of nitric oxide synthase on host resistance to bacterial infection.
OBJECTIVE: To examine the effects of three nitric oxide synthase inhibitors on survival in a murine sepsis model. DESIGN: Prospective randomized experimental trials. SETTING: Laboratory. SUBJECTS: Female Balb/c mice. INTERVENTIONS: Escherichia coli (10(8) colony-forming-units/body) were injected into the peritoneal cavities of Balb/c mice. NG-nitro-L-arginine-methyl-ester, NG-monomethyl-L-arginine, or N-iminoethyl-L-ornithine was given at various concentrations, intraperitoneally, one hour before bacterial challenge. MEASUREMENTS: One hundred and fifteen animals were observed for survival. RESULTS: These inhibitors provided the mice no protection from the bacterial challenge. Notably, pretreatment with NG-nitro-L-arginine-methyl-ester (100 mg/kg i.p.) actually reduced survival time after E. coli challenge. CONCLUSIONS: Inhibition of nitric oxide production improved neither the survival time nor rate in this murine sepsis model.
Animals↗
Hyperinsulinaemia accelerates accumulation of cholesterol ester in aorta of rats with transplanted pancreas.
Hyperinsulinaemia may play a role in the development of atherosclerosis; however, the direct effect of endogenous insulin on the atherosclerotic process is not well understood. To clarify this situation we performed pancreas transplantation with systemic venous drainage in Wistar Shionogi (WS) and Spontaneous Hypertensive (SHR) rats. Both rats received syngeneic pancreaticoduodenal transplants from donor rats. SHR rats were used to observe the additive effects of both hypertension and hyperinsulinaemia on the atherosclerotic process. Peak blood insulin levels after a glucose load were approximately two times higher in transplanted rats than in non-transplanted WS and SHR rats. By contrast, there was no difference in plasma glucose responses between transplanted and non-transplanted rats. Hyperinsulinaemia was not related to dyslipidaemia and hypertension in transplanted rats. Nine months after transplantation, the cholesterol ester contents of the aortas of both WS and SHR transplanted rats were significantly higher than in the control rats (WS: 1.9 +/- 1.0 vs 3.8 +/- 2.1 mg/g dry tissue, p < 0.01; SHR: 1.7 +/- 1.3 vs 3.7 +/- 1.4 mg/g dry tissue, p < 0.05). No differences were demonstrated in the thickness of the intima or in the histology of the aortas of transplanted and control rats. To study the mechanism for cholesterol ester accumulation in the arterial wall, we measured neutral cholesterol ester hydrolase activities in vascular medial smooth muscle cells. Insulin significantly suppressed neutral cholesterol ester hydrolase activities in medial smooth muscle cells. Our results indicate that endogenous hyperinsulinaemia contributes to the development of atherosclerosis by accelerating cholesterol ester accumulation in the arterial wall.
Animals↗
Reversible suppression of pituitary-testicular function by a sustained-release formulation of a GnRH agonist (leuprolide acetate) in dogs.
Pituitary-testicular function was studied in 15 dogs following treatment with a sustained-release formulation of a GnRH agonist, leuprolide acetate (LA). Adult male dogs were treated with a single subcutaneous injection of microencapsulated LA (0.1 or 1 mg/kg). Treatment with LA at a dose of 1 mg/kg resulted in decreased (P<0.001) ejaculatory volume and disappearance of morphologically normal spermatozoa within 8 wk and the effect persisted for 6 wk, while the 0.1 mg/kg dose was not adequate to effect suppression of spermatogenesis. The larger dose treatment (1 mg/kg) caused a transient rise in plasma levels of LH and testosterone followed by a marked decline to below the normal level by 2 wk, the low levels being maintained for at least 5 wk, indicating a prolonged effect of LA treatment on pituitary-gonadal axis. Twenty weeks after treatment with LA, a complete return to normal spermatogenesis was observed. The full reversibility of spermatogenesis in the dog after LA treatment suggests that this peptide could be used as a reversible method of male contraception.
Journal Article↗
t(7;11) and trilineage myelodysplasia in acute myelomonocytic leukemia.
A 48-year-old Japanese man was admitted to our hospital because of general fatigue, nasal bleeding, and petechiae on his extremities. He was diagnosed with acute myelomonocytic leukemia with trilineage myelodysplasia (T-MDS). Chromosomal analysis of bone marrow cells revealed t(7;11)(p15;p15), which has been rarely reported but known to be characteristic of Japanese patients. Although t(7;11)(p15;p15) has been reported mainly in acute myelogenous leukemia (AML), it can be occasionally found in so-called stem cell diseases such as chronic myelogenous leukemia or chronic myeloproliferative disorders. Therefore, t(7;11)(p15;p15) might affect trilineage progenitors or stem cells as well as myeloid lineage cells, subsequently resulting in AML with T-MDS, as in our case reported here.
Antineoplastic Combined Chemotherapy Protocols↗
Effects of growth hormone and insulin-like growth factor 1 (IGF-1 ) on hepatic IGF-1-mRNA, plasma IGF-1 and nitrogen excretion in gastrectomized rats with liver cirrhosis.
The growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis is impaired in liver cirrhosis. We determined the effects of GH and IGF-1 treatments in gastrectomized rats with thioacetamide-induced cirrhosis. GH did not increase hepatic IGF-1-mRNA, plasma IGF-1 or the tissue, i.e. gastrocnemius muscle IGF-1 level. IGF-1 administration increased plasma IGF-1 without increasing hepatic IGF-1-mRNA. GH and IGF-1 independently decreased postoperative urinary nitrogen excretion. We conclude that both GH and IGF-1 improve postoperative nitrogen metabolism. Furthermore, GH may exert its anabolic effects directly and/or via actions mediated by IGF-1 production, other than in the liver and in the skeletal muscle, in the setting of cirrhosis.
Journal Article↗
Distribution of activated complement, C3b, and its degraded fragments, iC3b/C3dg, in the colonic mucosa of ulcerative colitis (UC).
The third component of complement (C3) is central to both the classical and alternative pathways in complement activation. In this study, involvement of C3 activation in the mucosal injury of UC was investigated. We examined the distribution of activated (C3b) and degraded fragments (iC3b/C3dg) of C3, terminal complement complex (TCC), and complement regulatory proteins in normal and diseased colonic mucosa including UC and other types of colitis using immunohistochemical techniques at the level of light and electron microscopy. While C3b and iC3b/C3dg staining was negligible in the normal mucosa, iC3b/C3dg and, to a lesser extent, C3b were deposited in UC mucosa along the epithelial basement membrane. The deposition was enhanced in relation to the severity of mucosal inflammation (C3b, P less than 0.05; iC3b/C3dg, P less than 0.01). Epithelial deposition of TCC was not observed in most UC mucosa. Immunoelectron microscopy showed that C3b and iC3b/C3dg were distributed mainly along the epithelial basement membrane and the underlying connective tissue in a granular, studded manner, and weakly present along the basolateral surface of epithelial cells. These C3 fragments were also deposited in inflammatory control mucosa such as ischaemic and infectious colitis. Our findings suggest that deposition of the C3 fragments occurs in inflamed colonic mucosa of diverse etiologies, including UC, but to define a role of the deposition in the development of mucosal injury in UC awaits direct study.
Adult↗
Route of nutritional supply influences local, systemic, and remote organ responses to intraperitoneal bacterial challenge.
OBJECTIVE: The authors' aim was to investigate whether antecedent nutritional routes influence immune responses after surgical insult. SUMMARY BACKGROUND DATA: Total parenteral nutrition (TPN) may influence host responses to infection. To the best of the authors' knowledge, however, no study has focused on the mechanisms underlying the influence of nutritional route on local, systemic, and remote organ (lung) responses after surgical insult. METHODS: Sixty-eight rats were divided into TPN and total enteral nutrition (TEN) groups. The two groups received identical nutrients for 7 days and were then challenged intraperitoneally with 3 x 10(8) Escherichia coli. In the first experiment, the rats were observed for survival. In the second experiment, the rats were killed before (0 hours) challenge or 2 or 6 hours after challenge. Peritoneal exudative cells (PEC) and bronchoalveolar cells (BALC) were harvested and cultured in vitro. Colony-forming units of bacteria in the peritoneal lavage fluid (PLF) were determined. Tumor necrosis factor (TNF), interleukin-1 alpha (IL-1 alpha), interferon-gamma (IFN-gamma) levels in serum, PLF, bronchoalveolar lavage fluid (BALF), and cell culture supernatants were measured. RESULTS: The 48-hour survival rate was higher in TEN than in TPN rats. Local immunity was depressed in the TPN group. Bacterial colony counts in PLF were significantly higher in the TPN group than in the TEN group after challenge. The number of PECs was significantly lower, and at 2 hours, local cytokine (TNF and IL-1 alpha) responses were diminished in the TPN group compared with the TEN group at 2 hours. The number of PECs showed a significant positive correlation with levels of local cytokines in the TEN group but not in the TPN group. Elevation of local IFN-gamma was significant from 0 to 6 hours in the TEN group but not in the TPN group. In vitro production of TNF by PEC was impaired in the TPN rats before challenge. Remote organ (lung) responses were suppressed in the TPN group. The number of BALCs and the TNF levels in BALF declined significantly between 0 and 2 hours in the TEN group but not in the TPN group. Interferon-gamma levels in BALF were higher in the TEN group than in the TPN group at 2 hours. Systemic cytokine responses were disturbed in the TPN group. Production of systemic TNF was greater, but the IFN-gamma response was diminished in the TPN group compared with the TEN group after intraperitoneal bacterial challenge. CONCLUSION: Local, systemic, and remote organ (lung) immune responses to intraperitoneal bacterial challenge are suppressed in TPN-treated animals, leading to poor survival after challenge. Enteral nutrition before surgical insult may enhance host immune responses after the insult as compared to parenteral nutrition.
Animals↗
Growth hormone and insulin-like growth factor I augment Escherichia coli-killing activity of murine peritoneal exudative cells.
Effects of growth hormone (GH) and insulin-like growth factor (IGF)-I on Escherichia coli-killing activity of murine peritoneal exudative cells (PECs) were investigated. Plasma from the mice, injected subcutaneously with saline, GH (4.8 mg/kg/day), or IGF-I(24 mg/kg/day) for 6 days, was mixed with E. coli and pooled murine PECs. Plasma from GH- and IGF-I-treated mice modestly but significantly augmented the E. coli-killing activity of PECs, as compared with that from saline controls. Plasma from IGF-I-treated mice also enhanced PEC interleukin 1 production. In the next experiment, PECs preincubated with medium, GH (10-1000 ng/mL), or IGF-I (50-5000 ng/mL) for 3 h were investigated for E. coli-killing activity. Preincubation of PECs with all concentrations of GH and IGF-I significantly enhanced the E. coli-killing activity of PECs, as compared with the medium control. These results indicate that GH and IGF-I enhance phagocytosis and the E. coli-killing activity of PECs, via a modestly increased plasma capacity to support these activities, as well as by a strong direct action.
Animals↗
Expression of adhesion molecules on myeloma cells.
We investigated the expression of adhesion molecules including LFA-1 alpha (CD11a), Mac-1 (CD11b), LFA-1 beta (CD18), VLA-beta 1 (CD29), H-CAM (CD44), VLA-4 (CD49d), VLA-5 (CD49e), ICAM-1 (CD54), N-CAM (CD56), LFA-3 (CD58), VNR-beta (CD61), and LECAM-1 (CD62L) on fresh myeloma cells and human myeloma cell lines. By two-color flow cytometric analysis with anti-CD38 antibody, we demonstrated that myeloma cells were located in the strongly CD38-positive (CD38++) fractions. Fresh myeloma cells were obtained from 28 patients with multiple myeloma (MM) and 3 patients with plasma cell leukemia (PCL). All myeloma cells expressed VLA-4 on their surface. Most of the myeloma cells also expressed VLA-5, ICAM-1, and LFA-3, H-CAM was strongly expressed in 3 cases of PCL and 2 cases of aggressive myeloma, and moderately expressed in other MMs. N-CAM was expressed in 68% of MMs, but none of the 3 PCLs. LFA-1 was expressed in two cases of aggressive myeloma, but not expressed in other non-aggressive myelomas. Most of the myeloma cells did not express Mac-1, VNR-beta, or LECAM-1. These results suggest that VLA-4, VLA-5, ICAM-1, LFA-3, and H-CAM are involved in cellular interaction and migration in MM, and that the expression of N-CAM and LFA-1 varies with disease activity in MM.
ADP-ribosyl Cyclase↗
Venlafaxine oxidation in vitro is catalysed by CYP2D6.
1. Several selective 5-HT reuptake inhibitors (SSRIs) are inhibitors of the genetically polymorphic drug metabolizing enzyme, CYP2D6. We studied the interaction of venlafaxine, a new SSRI, with CYP2D6 in human liver microsomes. 2. Venlafaxine was a less potent inhibitor of this enzyme activity in vitro than other SSRIs tested. The average apparent Ki values determined using CYP2D6-dependent dextromethorphan O-demethylation were: 33, 52 and 22 microM for rac-venlafaxine, R(+)-venlafaxine and S(-)-venlafaxine, respectively, vs 0.065 to 1.8 microM for paroxetine, fluoxetine, norfluoxetine, fluvoxamine and sertraline. 3. Microsomes from human livers (n = 3) and from yeast transformed with an expression plasmid containing human CYP2D6 cDNA catalyzed the O-demethylation of venlafaxine, which is the major metabolic pathway in vivo. Intrinsic metabolic clearance values (Vmax/Km) indicated that S(-)-venlafaxine was cleared preferentially via this pathway. 4. In microsomes from CYP2D6-deficient livers (n = 2), Vmax/Km of O-demethylation of venlafaxine was one to two orders of magnitude lower and was similar to the rate of N-demethylation. 5. Studies with chemical probes which preferentially inhibit P450 isoforms suggested that CYP3A3/4 is involved in venlafaxine N-demethylation. 6. These in vitro findings predict phenotypic differences in the kinetics of venlafaxine in vivo, although the clinical importance of this is unclear as O-demethylvenlafaxine is pharmacologically similar to the parent drug. The findings also predict relatively limited pharmacokinetic interaction between venlafaxine and other CYP2D6 substrates.
Catalysis↗
Transcription factor PU.1 mediates induction of c-fms in vascular smooth muscle cells: a mechanism for phenotypic change to phagocytic cells.
The macrophage colony-stimulating factor receptor encoded by the c-fms gene is expressed in vascular intimal smooth muscle cells isolated from atherosclerotic lesions. A combination of platelet-derived growth factor-BB and epidermal growth factor induces stable expression of c-fms in normal vascular medial smooth muscle cells. The mechanism by which these growth factors induce c-fms expression has now been investigated in an attempt to gain insight into the events that underlie the phenotypic conversion of vascular smooth muscle cells in atherosclerosis. Deletion analysis of the c-fms promoter revealed that the region including a binding site for transcription factor PU.1 was required for transcriptional activity in human aortic medial smooth muscle cells. Mutation in the PU.1 binding site markedly reduced promoter activity. Northern (RNA) blot analysis demonstrated that growth factors induced the expression of PU.1 mRNA in vascular medial smooth muscle cells and that PU.1 mRNA was expressed in vascular intimal smooth muscle cells. PU.1 antisense oligonucleotides inhibited growth factor-induced c-fms expression and foam cell formation. These results suggest that transcription factor PU.1 plays an essential role in the phenotypic conversion of vascular smooth muscle cells to macrophagelike cells by mediating the induction of c-fms.
Aorta↗
Growth hormone and the immune response to bacterial infection.
Growth hormone (GH) and insulin-like growth factor 1 (IGF-1), especially the former, have immunoregulatory effects in addition to anabolic effects. The hormones may act to protect the host from lethal bacterial infection by promoting the maturation of myeloid cells, stimulating phagocyte migration, priming phagocytes for the production of superoxide anions and cytokines, and enhancing opsonic activity. GH administration may be beneficial for the prevention, as well as treatment, of severe sepsis in critical illness.
Animals↗
Changes in plasma concentrations of gonadotropins and steroid hormones during the formation of bovine follicular cysts induced by the administration of ACTH.
Bovine follicular cysts were induced by treatments with ACTH (3 mg, im) daily for 14 days beginning in the late luteal phase. Cortisol concentrations in plasma significantly increased after ACTH treatments. During the formation of follicular cysts induced by the injections of ACTH, mean plasma concentrations of progesterone were significantly higher than those in the untreated preovulatory period, while mean plasma concentrations of estradiol-17 beta were significantly lower. During the treatment period, mean plasma concentrations of LH and FSH remained low, and the preovulatory surges of LH and FSH did not occur. Suppressed concentrations of LH and FSH might be caused by the increases in secretions of cortisol and progesterone, and by the decrease in secretion of estradiol-17 beta.
Adrenocorticotropic Hormone↗
Enhanced expression of platelet-derived growth factor-beta receptor by high glucose. Involvement of platelet-derived growth factor in diabetic angiopathy.
Coronary heart disease is a major complication of diabetic subjects, and platelet-derived growth factor (PDGF) has been implicated in the development of atherosclerosis. We investigated the effects of high glucose on expression of PDGF-beta receptor. In a binding assay with 125I-labeled PDGF-BB homodimer, high concentrations of glucose increased high-affinity binding of PDGF-BB on human monocyte-derived macrophages and rabbit aortic medial smooth muscle cells. Northern blot analysis confirmed the enhanced effect of glucose on expression of PDGF-beta receptor mRNA in human monocyte-derived macrophages. The protein kinase C inhibitor, staurosporin, completely suppressed an increase in PDGF-BB binding by high glucose, and high glucose significantly activated protein kinase C. These results indicated that PDGF-beta receptor expression was enhanced by high glucose through the activation of protein kinase C. Furthermore, we observed similar effects of high glucose on both PDGF-beta receptor expression and protein kinase C activation in rat mesangial cells and human capillary endothelial cells. Our results suggest that stimulation of the PDGF system is significantly involved in the development not only of diabetic atherosclerosis but also of microangiopathy.
Alkaloids↗
[Natural killer cell lymphoma having a nodular shadow in the lung as an initial finding, developed to leukemia complicated with hemophagocytic syndrome at the time of relapse].
A 57-year-old female was admitted to Uji hospital for the further evaluation of nodular shadow on her right lung. During the period of admission, she developed cervical lymph node swelling. She was diagnosed as having malignant lymphoma (diffuse, small cleaved cell) by lymph node biopsy. She received combined chemotherapy and obtained partial remission for seven months until she developed fever and pancytopenia. Laboratory data showed increased number of large granular lymphocytes (LGLs) in blood. Bone marrow revealed increased number of LGLs with hemophagocytosis by macrophage. Surface marker analysis revealed LGLs were positive for CD2 CD16, and CD56 and negative for CD3, CD4, CD8, and CD20. T-cell receptor genes beta and gamma were in germ line configuration. Analysis of Epstein-Barr virus genome using termini probe indicated a monoclonal proliferation of LGLs. Reexamination of the biopsy specimen of lymph node revealed LGLs which was negative for CD3 and CD20. The patient was diagnosed as a leukemic phase of natural killer (NK) cell lymphoma complicated with hemophagocytic syndrome (HPS). Serum levels of interferon-gamma, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and interleukin-6 increased, which might be related to HPS.
Antigens, CD↗
The greater omentum is the primary site of neutrophil exudation in peritonitis.
BACKGROUND: Peritonitis remains a major infectious problem. Neutrophil influx into the peritoneal cavity is one of the most important host defense mechanisms. However, no studies have focused on the site of neutrophil exudation. This study examined the primary anatomic site of neutrophil exudation in bacterial peritonitis. STUDY DESIGN: Fifty-five rats were injected intraperitoneally with saline solution (control group) or 10(7) Escherichia coli (peritonitis group). In experiment 1, 1 x 10(6) fluorescein-labeled neutrophils were infused 3 hours after the challenge. Then, peritoneal-lavaged fluids and peritoneal tissues (the greater omentum, mesentery, parietal peritoneum, colon, and ileum) were obtained. Subpopulations of peritoneal exudative cells and numbers of labeled neutrophils in tissues were counted. In experiment 2, labeled neutrophils were infused at 10 minutes and at 1 and 5 hours after the challenge. Peritoneal tissues were also harvested. The number of labeled neutrophils in each tissue was determined. RESULTS: In experiment 1, numbers of labeled peritoneal neutrophils and exudative neutrophils were higher in the peritonitis group than in the control group. Numbers of exudative neutrophils showed a positive correlation with numbers of labeled peritoneal neutrophil. In experiment 2, at 1 and 5 hours after the challenge, the number of labeled neutrophils was higher in the peritonitis group than in the control group. The number of neutrophils in the omentum was higher than the number in other peritoneal tissues. CONCLUSIONS: Our fluorescence microscopic method is useful for detecting neutrophil adhesion. Neutrophil exudation into the peritoneal cavity was most marked in the omentum. The greater omentum may play an important role in host defense as a source of exudative neutrophils.
Animals↗
[Three cases of secondary acute myeloid leukemia after long-term treatment with oral etoposide].
Three cases of secondary acute myeloid leukemia (AML) that developed after long term treatment with oral etoposide were reported. Case 1 was a 72-year-old male in whom small cell lung cancer was diagnosed in January 1987. He developed AML (M4) in February 1993 after long-term treatment with oral etoposide (total dose 14,650 mg) t(9; 11) (p21; q23) with rearrangement of MLL genes was recognized. Case 2 was a 68-year-old female non-Hodgkin's lymphoma (NHL) was diagnosed in February 1989. AML (M4Eo) with inv(16) (p13q22) developed in March 1994 after long-term treatment with oral etoposide (total dose 5,100 mg). Case 3 was a 39-year-old male in whom NHL was diagnosed in January 1991. He developed AML(M2) with t(11; 19) (q23; p13) in May 1994 after long-term treatment with oral etoposide (total dose 20,450 mg). These three cases suggest that long-term treatment with oral etoposide may be associated with a risk of developing a secondary AML in patient with malignancies.
Administration, Oral↗