Biomedical subjects
Publications and source records attributed to H Ninomiya.
Adrenalectomy of 17-, 18- and 19-day-old male and female rats did not cause any changes in the weight of thymus 4 days later. Adrenalectomy on day 20 of age induced a significant hypertrophy of the thymus 4 days later. These results indicate that on day 20 of age, just before weaning, the thymus is under some inhibitory regulation by the adrenal gland.
The paramesonephric (Müllerian) duct was first observed in the vicinity of the mesonephric (Wolffian) duct in 30-day-old swine fetuses of both sexes at the level close to the gonad. The paramesonephric duct extended caudally in parallel with the mesonephric duct on day 35 of gestation. By day 40 the paramesonephric duct reached the urogenital sinus. At this stage, the paramesonephric duct began to degenerate in the male, while it continued to develop in the female. This suggests that an anti-Müllerian duct hormone (AMH) is produced before day 40 of gestation. By day 45 of gestation, the mesonephric duct began to decrease in diameter and was accompanied with the involution of the mesonephros in both sexes. By day 60, the male and female mesonephric ducts reduced in their diameter by 70%. Thereafter, the female mesonephric ducts disappeared, while the male ducts developed again. The sex differences was first observed on day 35 in the differentiation of the external genitalia when a small circular urogenital orifice and the anogenital raphe appeared at the sites caudal to the genital tubercle in the male. Such structures were not present in the female. These results suggest that the fetal pig testis is activated to secrete androgen before day 35 of gestation.
By using nuclear magnetic resonance (NMR), the aged testis of Chinese hamster was studied by measuring relaxation times of tissue water protons. Spin-spin relaxation time (T2) was significantly prolonged compared to young testis when edema was apparent in the interstitial space of the aged testis. When edema was experimentally induced in the young testis by ligation of a subcapsular vein, T2 was prolonged to the similar extent as in the aged testis. Spin-lattice relaxation time (T1) and water content of the tissue were essentially the same in the testes of the young and aged animals. It is concluded that T2 can serve as a sensitive parameter for assessing the age-dependent histological changes in the testis of Chinese hamster.
On day 13 of gestation in Mongolian gerbil fetuses, the mesonephric (Wolffian) duct was already visible. On day 14, the anlage of the paramesonephric (Müllerian) duct was first observed close to the mesonephric duct in both sexes at the cranial part of the mesonephros. Thereafter, the paramesonephric duct grew caudally in parallel with the mesonephric duct. On day 19, the duct reached the urogenital sinus. At this stage, the anogenital distance was significantly longer in male than in female. Also in male, the mesonephric duct was increased and the paramesonephric duct was decreased in diameter compared with those in female. These suggest that both testosterone and anti-Müllerian hormone are produced in fetal Mongolian gerbils at least before day 19 of gestation.
A detailed knowledge of the vascular system of tumors is requisite to a clear understanding of tumor physiology and pathology. Accordingly, in this study, examination was made of the vascular architecture of rat fibrosarcomas induced by 3-methyl choranthrene by scanning electron microscopy of resin casts to observe the three-dimensional vascular pattern of the sarcoma. The results were compared with those of corresponding serial sections of India ink-injected tissue. The major arteries in and around tumors appeared devoid of intra-arterial cushions which regulate blood flow. The arterial lining of resin casts was smooth just at the site where it entered the tumor. This may possibly be indication of degeneration and loss of the smooth muscle layer in the vascular wall. Casts of capillaries were very thin from 4 to 6 microns in diameter and very few sprouts could be seen. Capillaries, frequently present in superficial regions of the tumor, formed a rich irregular fine polygonal network. In fibrous tissue in deeper regions of the tumor, this network was coarse. The absence of intra-arterial cushions and degeneration of muscle cells may thus possibly be the reason for the characteristic haemodynamics of tumors.
Hemosiderinuria caused by intravascular hemolysis is a characteristic clinical feature of an acquired hemolytic disorder, paroxysmal nocturnal hemoglobinuria (PNH). We examined the deposition of hemosiderin (iron) in the kidneys of 6 patients with PNH using magnetic resonance imaging (MRI). Three patients with autoimmune hemolytic anemia (AIHA), a hemolytic disorder showing extravascular hemolysis, served as controls. In five of the six patients with PNH, a characteristic T2-weighted MRI of the kidneys, suggesting the deposition of iron (hemosiderin) predominantly in the renal cortex, was obtained. Hemosiderin-deposition was not revealed in the kidneys of any of the patients with AIHA. We conclude that MRI is a sensitive means of detecting hemosiderin deposited in the renal cortex of patients with PNH and that this feature is considerably specific for diseases showing intravascular hemolysis, as represented by PNH.
Bronchiolitis obliterans organizing pneumonia (BOOP) is a pathologic entity characterized by intraluminal fibrosis of distal air spaces. Corticosteroids have been widely used for the treatment of this condition, and most patients showed a dramatic response to it. However, long-term treatment with corticosteroids, which often increases the risk of several undesirable side-effects, is usually required because a relapse tends to occur soon after termination of treatment. We administered erythromycin (EM) at low-dose (600 mg daily) for 3-4 months to 6 patients with BOOP, and obtained a good clinical, radiological, and physiological improvement. This suggests that EM can be successfully used, instead of corticosteroids, in the treatment of BOOP.
Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder characterized by the deficiency of glycosyl phosphatidylinositol (GPI)-anchored proteins in blood cell membranes. We experienced a patient with PNH whose grade of hemolysis was reduced during the course of the disease. An analysis of the expression of GPI-anchored proteins on blood cells revealed typical PNH defects in polymorphonuclear leukocytes (PMN), but not in red blood cells (RBC). Accordingly, we investigated the expression of CD59 on RBC and of CD59 and CD16 on PMN in PNH patients, using immunofluorocytometry. We examined the cells of 8 PNH patients with different grades of hemolysis. PNH-affected PMN deficient in CD16 and CD59 were clearly demonstrated in every patient, including those with low-grade hemolysis. We conclude that demonstration of PNH-affected PMN deficient in GPI-anchored proteins has diagnostic values even in PNH patients with low-grade hemolysis.
Endothelins (ETs) are a family of peptides with potent constrictive activity in vascular and treacheal smooth muscle. The lung tissues are abundant in these peptides and their receptors; the peptides are produced by endothelial cells and airway epithelial cells, while its receptor is mainly located on smooth muscle. Therefore, it has been proposed that endothelins act in a paracrine fashion on nearby smooth muscle, thus regulating its tone. However, little is known about its physiological and pathological roles in pulmonary functions. We hypothesized that ET plays an important role in bronchoconstriction elicited by antigen challenge. In order to test this hypothesis, we investigated tracheal contractile activities and ET-receptors by employing an animal model in guinea pigs. Here, we report that guinea pigs who were sensitized followed by multiple challenges with the antigens had alterations of ET receptor(s) with respect to number and affinity.
To distinguish hypoplastic myelodysplastic syndrome (MDS) from aplastic anemia (AA), morphological abnormalities of bone marrow hematopoietic cells in 8 patients with MDS and 39 patients with AA were studied. All the patients with MDS and AA showed prolonged plasma iron disappearance time, (PIDT1/2) > 120 min. Five hundred erythroid and myeloid cells, as well as 20 megakaryocytes were counted. Dysplastic changes were defined if morphological changes were present in more than 1.0% cells with only one lineage, or in more than 0.6% cells with more than two lineages. Twenty six of 39 patients with AA showed morphological abnormalities. In MDS cases, morphological abnormalities were prominent in trilineage cells in some cases, in bilineage (erythroid and megakaryocytic or myeloid and megakaryocytic cells), in others, or solely in myeloid cells or in megakaryocytic cells in other cases. Morphological abnormalities seen solely in erythroid cells, especially those with segmented nuclei were considered to be less significant for the diagnosis of MDS. The findings were considered to be useful to distinguish hypoplastic MDS from AA.
Between April 1990 and June 1992, a multicenter clinical trial of chemotherapy regimens was performed with patients, aged 65 years or more, suffering from malignant lymphoma. The total number of patients was 38 included 30 initial cases (median age: 72) and 8 relapsed cases (79). The chemotherapy regimen, administered every 3 weeks, included pirarubicin (30 mg/m2; day 1), cyclophosphamide (500 mg/m2; day 1), vindesine (1.5 mg/m2; day 1), and prednisolone (40 mg/m2; days 1-5) for the initial cases, and etoposide (100 mg/m2; days 1-5) in addition for relapse cases. The complete response and partial response rates were 50.0% and 40.0% in initial cases, respectively, and 50.0% and 0% in relapsed cases, respectively. The 50% survival period was 25.9 months in initial cases and 18.0 months in relapse cases. There were no serious side effects related to the regimens. Performance status deteriorated in only one case after chemotherapy. We concluded that the chemotherapy regimens were useful and safe for elderly patients with malignant lymphoma.
Enkephalinase exists in airway epithelial cells, smooth muscle, and submucosa near glands, and cleaves tachykinins to inactive metabolites, thereby reducing there effects. To study the role of enkephalinase in asthmatic response, we measured its activity in guinea pig model of asthma. When compared with the control values, the enkephalinase activity was reduced during in immediate asthmatic response (IAR) and late asthmatic response (LAR). Compared with the control values (100%), each value was 79.7%, 73.4% in the trachea and 74.3%, 55.7% in the lung respectively. Tracheal muscle preparation taken from the control, IAR, and LAR groups were made and mounted in oxygenated modified Krebs-Ringer solution. The response was monitored by isometric transducer. Concentration response curves to NKA with or without phosphoramidon were obtained. The contractile responses of the LAR groups were enhanced in potency and efficiency. Phosphoramidon potentiated the NKA induced contraction of control and the IAR groups but was less potent in enhancing the contractile response in the LAR group, showing less enkephalinase activity in the LAR. These results suggest that the enkephalinase plays an important role in LAR. In LAR, the enkephalinase activity may be inhibited and the responsiveness of the smooth muscle to some bronchoconstrictor, such as tachykinins, may be increased.
We report a therapeutic protocol for elderly patients with chronic idiopathic thrombocytopenic purpura (ITP) and related conditions. Twelve chronic ITP patients over 60 years of age (elderly group), and 40, 59 years old or less (young group) were evaluated in this study. The therapeutic protocol for ITP, proposed by the Japanese Idiopathic Disease of Hematopoietic Organ Research Committee, was modified for the elderly (group) as follows: the initial dosage of prednisolone was reduced by half and danazol therapy was selected in cases in which splenectomy was impossible. Platelet counts and PAIgG showed no significant difference between the two groups. All 12 elderly patients were initially treated with prednisolone, and five patients responded to it. Among the seven non-responders, four patients underwent splenectomy, and the three three others (non splenectomized patients) were treated with danazol. Platelet counts were maintained over 150 x 10(3)/microliters in eleven patients except one splenectomized patient. The outcome in the elderly ITP group was better than in the young group.
An elderly man with an intestinal hemorrhage from bowel diverticulosis developed human parvovirus B19-induced aplastic crisis. A 71-year-old man noticed occasional tarry stools and at the same time showed fever, arthralgia and severe anemia. Blood counts revealed Hgb 5.3g/dl, reticulocytes 0%, and WBC 1,900/microliters. Bone marrow examination showed hypocellular marrow with rare erythroid precursors (4.8%). A few giant proerythroblasts were found in the bone marrow smears. A diagnosis of parvovirus B19 infection was made because of detection of B19-specific IgM and IgG antibodies. Parvovirus B19 infection should be carefully checked for in patients with hemorrhage as well as those with hemolysis.
One-staged operation was successfully performed in a 23-year-old female with funnel chest, mitral regurgitation and annulo aortic ectasia secondary to Marfan's syndrome. A midline skin incision was made and the sternum and costal cartilages were mobilized for sternal turnover with rectus muscles pedicle. This procedure offered an excellent operative field, even though the heart and aneurysmal ascending aorta were displaced into the left hemithorax. The combined superior-transseptal approach to the left atrium was used to perform mitral valve replacement. This approach also provided an excellent exposure of the mitral valve. Cabrol's operation was done for annulo aortic ectasia. Our concepts for the operation of open heart surgery complicated with severe funnel chest were discussed.
Endothelin(ET)-1 triggered histamine release of mast cells from pulmonary tissue but not from the peritoneal cavity of guinea pigs. The observed difference in response to ET-1 was attributable to a quantitative difference in ET-1 binding sites between both cells. The concentrations of ET-1 required for half maximal release of histamine and half maximal binding of [125I]ET-1 were approximately 0.05 and 0.08 nM, respectively. The release of histamine by ET-1 was a Ca(2+)-dependent but not a cytotoxic process. These observations, taken together, suggest that ET-1 induces histamine release from mast cells in a receptor-dependent fashion.
The erythrocyte membrane inhibitor of the human terminal complement proteins, surface antigen CD59, has previously been shown to enter into a detergent-resistant complex with either the membrane-bound complex of C5b-8 or C5b-9 (Meri, S., Morgan, B. P., Davies, A., Daniels, R. H., Olavesen, M. G., Waldmann, H. and Lachmann, P. J. (1990) Immunology 71, 1-9; Rollins, S. A., Zhao, J., Ninomiya, H., and Sims, P. J. (1991) J. Immunol, 146, 2345-2351). In order to further define the interactions that underlie the complement-inhibitory function of CD59, we have examined the binding interactions between 125I-CD59 and the isolated components of human complement membrane attack complex, C5b6, C7, C8, and C9. By density gradient analysis, we were unable to detect interaction of 125I-CD59 with any of these isolated complement components in solution. Specific binding of 125I-CD59 to C8 and C9 was detected when these human complement proteins were adsorbed to either plastic or to nitrocellulose, suggesting that a conformational change that accompanies surface adsorption exposes a CD59-binding site that is normally buried in these serum proteins. The binding of 125I-CD59 to plastic-adsorbed C8 and C9 was saturable and competed by excess unlabeled CD59, with half-maximal binding observed at 125I-CD59 concentrations of 80 and 36 nM, respectively. No specific binding of 125I-CD59 was detected for surface-adsorbed human C5b6 or C7 nor was such binding observed for C8 or C9 isolated from rabbit serum. Binding of CD59 to human C8 and C9 was not mediated by the phospholipid moiety of CD59, implying association by protein-protein interaction. In order to further define the binding sites for CD59, ligand blotting with 125I-CD59 was performed after separation of C8 into its noncovalently associated subunits (C8 alpha-gamma and C8 beta) and after alpha-thrombin digestion of C9. These experiments revealed specific and saturable binding of 125I-CD59 to C8 alpha-gamma subunit (half-maximal binding at 75 nM), but not to C8 beta, and specific and saturable binding to the 37-kDa fragment (C9b) of thrombin-cleaved C9 (half-maximal binding at 35 nM), but not to the 25-kDa C9a fragment. Partial reduction of C8 alpha-gamma revealed that only C8 alpha polypeptide exhibited affinity for CD59, and no specific binding to the C8 gamma chain was detected.(ABSTRACT TRUNCATED AT 400 WORDS)
The contribution of N-linked carbohydrate to the complement-inhibitory function of the human erythrocyte membrane glycoprotein, CD59, was investigated. Amino acid sequence analysis of tryptic peptides labeled with [3H]borohydride revealed an N-linked carbohydrate moiety at the Asn18 residue. No O-linked carbohydrate was detected, as judged by the failure of asialo-CD59 to bind peanut agglutinin and by its resistance to digestion by O-glycanase. The apparent molecular mass of CD59 was reduced from 18-20 to 14 kDa upon complete digestion with N-glycanase, with no detectable proteolysis. N-glycanase digestion of CD59 was associated with an 88 +/- 4% loss of the complement-inhibitory activity of the protein, as assessed by its capacity to protect chicken erythrocytes from lysis by the human C5b-9 proteins. By contrast, no change in function was observed after digestion of CD59 with neuraminidase, under conditions that removed greater than 60% of [3H]sialic acid residues. Despite loss of functional activity after N-glycanase digestion, we detected no change in the capacity of the deglycosylated CD59 to incorporate into erythrocyte membranes or to bind specifically and with species selectivity to the C8 and C9 components of the membrane attack complex. In order to alter the branched-chain structure of the N-linked carbohydrate of CD59 without enzymatic digestion, Chinese hamster ovary (CHO) cells transfected with cDNA for human CD59 were grown in the alpha-mannosidase inhibitor, 1-deoxymannojirimycin, resulting in conversion of approximately 70% of the membrane glycoprotein to a high mannose. When grown in the presence of 1-deoxymannojirimycin, the C5b-9-inhibitory activity of CD59 expressed on the surface of the transfected CHO cells was reduced by an amount comparable to that observed for the N-glycanase digested protein. Taken together, these data suggest that normal glycosylation of Asn18 in CD59 is required for the normal expression of its complement-inhibitory activity on membrane surfaces, although these N-linked sugar residues do not contribute to CD59's affinity for the C8 and C9 components of the C5b-9 complex.