Biomedical subjects

M Ninomiya

Publications and source records attributed to M Ninomiya.

At least 19 recordsLinked to original sources

PubMed2006

Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice.

The cellular components of the hematopoietic stem cell niche have been gradually identified. However, the niche for malignant hematopoiesis remains to be elucidated. Here, using human leukemia cells, which could be transplanted to immunodeficient mice, we studied the in vivo homing, proliferation and survival sites by immunohistopathology, compared with the corresponding sites for cord blood CD34(+) (CBCD34(+)) cells. The human leukemia cells initially localized on the surface of osteoblasts in the epiphysial region, and expanded to the inner vascular and diaphysial regions within 4 weeks. The percentage of CD34(+) leukemia cells in the bone marrow was transiently increased up to 50%. In vivo 5-bromo-2'-deoxyuridine labeling revealed that the epiphysis was the most active site for leukemia cell proliferation. CBCD34(+) cells showed the similar pattern of homing and proliferation to leukemia cells. After high-dose administration of cytosine-1-beta-D-arabinofuranoside, residual leukemia cells were localized in the perivascular endothelium as well as in contact with the trabecular endosteum. These findings suggest that xenotransplantation into immunodeficient mice provides a useful model to study the leukemia niche.

Animals↗

PubMed2005

Living donor liver transplantation for hepatocellular carcinoma: a special reference to a preoperative des-gamma-carboxy prothrombin value.

BACKGROUND: Des-gamma-carboxy prothrombin (DCP) is a sensitive marker related to vascular invasion of hepatocellular carcinoma (HCC). The aim of this study was to clarify the risk factors of HCC recurrence in living donor liver transplantation (LDLT) with special reference to preoperative DCP values. METHODS: Forty consecutive adult HCC patients who underwent LDLT were examined for a correlation between the DCP value and vascular invasion. Risk factors for recurrence were also investigated using clinicopathological variables including preoperative DCP levels. RESULTS: The incidence of positive histological vascular invasion in patients with DCP values above 300 mAU/mL was higher than that with those with DCP value below 300 mAU/mL. Other significant risk factors for recurrence were over 5 cm tumor diameter, not meeting the Milan criteria, AFP value >400 ng/mL, histological vascular invasion, poorly differentiated histology, and male gender. Among the patients who did not meet the Milan criteria, those with both no more than 5 cm of tumor diameter and no more than 300 mAU/mL DCP exhibited a good prognosis. CONCLUSIONS: A high DCP value, namely >300 mAU/mL correlated with histological vascular invasion and was one of the strongest prognostic variables. Therefore, special attention should be paid to HCC patients with high DCP values. No correlation between the number of tumor nodules and recurrence was found; therefore, the Milan criteria may require revision regarding the number of tumor nodules.

Adult↗

PubMed2004

Is graft size a major risk factor in living-donor adult liver transplantation?

Graft size is known to be a major risk factor in living donor adult liver transplantation (LDALT). The aim of this study is to reassess whether graft size is a critical factor in LDALT or not. A series of 75 LDALTs excluding auxiliary transplantation and ABO blood-type incompatible transplantation were analyzed. The patients were divided into two groups, according to graft volume (GV) and standard liver volume (SLV): group 1 (small-size group) (GV/SLV: <40%), and group 2 (non-small-size group) (> or =40%). Perioperative clinical data were compared between the two groups, including graft survival and postoperative complications. These parameters were also compared under the conditions of cirrhotic recipients. No difference in graft survival was found between the two groups. No difference was found in incidence of postoperative complications, such as intractable ascites and persistent hyperbilirubinemia. Even in cirrhotic patients with Child-Pugh's class C, there was no difference in graft survival between the two groups. Risk factors related to graft loss were a preoperative urgent status due to chronic liver disease, pre-operative hyperbilirubinemia of over 10 mg/dl, and ABO blood type of not identical but compatible combination between donor and recipient. Graft size is not always considered to be a major risk factor in LDALT, although the number of patients was small in this study. Therefore, a left-lobe graft, even a "small-for-size" graft for adult recipients, remains a feasible option in LDALT.

Adolescent↗

PubMed2004

The hydroxyl radical scavenger MCI-186 protects the liver from experimental cold ischaemia-reperfusion injury.

BACKGROUND: Oxidative stress contributes to hepatic ischaemia-reperfusion (IR) injury in a biphasic pattern. In addition to direct cytotoxic effects, oxidative stress also initiates the signal transduction processes that promote second-phase liver injury. The present study investigated the effects of the hydroxyl radical scavenger MCI-186 on the biphasic process of hepatic cold IR injury. METHODS: After cold preservation for 16 h, rat livers were reperfused on an isolated liver perfusion system for 120 min with oxygenated Krebs-Henseleit bicarbonate buffer. Perfusate samples were obtained serially, and portal flow rates were also recorded. To determine whether MCI-186 affected cytokine levels that control the second-phase injury, levels of interleukin (IL) 10 and tumour necrosis factor (TNF) alpha were measured in the perfusate. RESULTS: Addition of MCI-186 1 mg/l into the perfusate significantly improved portal flow (P<0.050), hepatic enzyme release into the perfusate (P=0.038), total bile production (P=0.029) and malondialdehyde concentration (P=0.038). Furthermore, treatment with MCI-186 led to a substantial increase in IL-10 release (P=0.032). TNF-alpha levels were not affected. CONCLUSIONS: MCI-186, an agent ready for clinical use, appears to have direct and indirect protective effects against hepatic cold IR injury.

Animals↗

PubMed2004

Retinoic acid syndrome in NOD/scid mice induced by injecting an acute promyelocytic leukemia cell line.

All-trans retinoic acid (ATRA) induces complete remission in patients with acute promyelocytic leukemia (APL). However, ATRA sometimes causes retinoic acid syndrome (RAS) characterized by respiratory distress, pleural effusions, fever and weight gain. To investigate the pathophysiology of RAS, we generated an animal model by injecting an APL cell line, NB4, into immunodeficient mice. When NOD/scid mice were injected intravenously with fully differentiated NB4 cells (1 x 10(7)) and then given a daily administration of ATRA, three of 12 mice died of pulmonary edema within 14 days. Pathologically, dilated lung capillary vessels and alveolar effusions were observed. After the injection, NB4 cells were detected in the lung within 2 days and in the pleural effusion later on. The gene expression levels of CXC chemokines (MIP-2 and KC) and ICAM-1 were increased in the lung and heart by the ATRA administration. In immunohistochemical analyses, MIP-2 was clearly detected in alveolar macrophages of the lung in mice with RAS. Dexamethasone treatment prevented the development of RAS and decreased the CXC chemokine mRNA expression in the lung. These findings suggested that the activation of adhesion molecules for leukocytes and expression of CXC chemokines in the lung are closely involved in triggering RAS.

Animals↗

PubMed2003

Ex vivo gene transfer of basic fibroblast growth factor improves cardiac function and blood flow in a swine chronic myocardial ischemia model.

We previously reported adenovirus-mediated ex vivo gene transfer of basic fibroblast growth factor (bFGF) as a new treatment for leg ischemia. This time, we tested this method on a swine myocardial ischemia model, seeking the possibility of its application for ischemic heart disease. An ameroid constrictor was placed around the proximal left circumflex branch of pigs to induce myocardial ischemia. Simultaneously, a skin section was harvested and fibroblasts were cultured. Fibroblasts were then infected with adenovirus vector containing a bFGF cDNA with a secretory signal sequence (bFGF group, n=8) or a LacZ cDNA (control group, n=8). At 28 days after constrictor implantation, 2.5 x 10(6) fibroblasts were administered into each of the right and left coronary arteries. The injected fibroblasts accumulated in the myocardium without causing myocardial ischemia. Echocardiography, electromechanical mapping and coronary arteriography were conducted just before and 28 days after fibroblast injection, and regional left ventricular myocardial blood flow was measured 28 days after fibroblast injection. These evaluations revealed that the bFGF group exhibited significant development of collateral vessels and improvement of myocardial contraction in the ischemic area compared with the control group. We believe that this method is a promising treatment strategy for ischemic heart disease.

Adenoviridae↗

PubMed2002

Mediastinitis after percutaneous dilatational tracheostomy.

In our experience, PDT after total arch replacement, especially after dissection of neck vessels, should be approached with caution. A long skin incision that allows discharge to drain from the wound and a sufficiently long postoperative tracheostomy period to allow tissue healing in the neck are necessary for prevention of mediastinitis.

Aged↗

PubMed2001

Effects of lung metastasectomy on respiratory function.

OBJECTIVE: The effects of lung metastasectomy on respiration were evaluated. SUBJECTS: From 1961 to 1999, 203 patients underwent lung metastasectomy. Of these, 102 patients who had undergone only partial lung resection, had undergone sufficient respiratory function testing, and had not suffered from other lung disease were included. RESULTS: Unilateral thoracoscopic surgery caused less decrease in percent vital capacity than surgery through a posterolateral thoracotomy, in both the early (rate of decrease: 16.2 +/- 9.1 vs. 33.0 +/- 12.0%, p < 0.01), and the late postoperative period (2.0 +/- 4.5 vs. 17.8 +/- 6.0%, p < 0.0001). Two thoracoscopic operations caused less decrease in percent vital capacity than 2 operations through a posterolateral thoracotomy (21.3 +/- 13.8 vs. 61.1 +/- 8.1%, p = 0.02). Bilateral metastasectomy through a median sternotomy caused less decrease in percent vital capacity than that through posterolateral thoracotomies (45.5 +/- 13.7 vs. 60.8 +/- 8.8%, p < 0.05). Four (36%) of 11 patients who had undergone 3 or more metastasectomies exhibited dyspnea of degree 3 or higher on the Hugh-Jones classification. CONCLUSIONS: Thoracoscopic metastasectomy and metastasectomy through a median sternotomy caused less restrictive respiratory dysfunction than metastasectomy through a posterolateral thoracotomy. Since metastatic lung disease often necessitates repeated metastasectomy, and repeated metastasectomy often causes severe restrictive respiratory dysfunction, metastasectomy should be performed with a less invasive procedure.

Adult↗

PubMed2001

Indication and perioperative management for cardiac surgery in patients with liver cirrhosis. Our experience with 3 patients.

Three patients with noncardiac Child A cirrhosis underwent cardiac surgery. All survived surgery, but 2 died during follow-up periods. A 61-year-old woman who underwent successful double valve replacement died of diabetic coma and severe acidosis due to intestinal necrosis 18 months later. A 57-year-old woman who underwent successful mitral valve replacement died of liver failure induced by heart failure 9 years later. A 45-year-old man who underwent coronary artery bypass grafting is doing well 18 months after discharge. Proper perioperative management, including high-flow cardiopulmonary bypass, pharmacological and mechanical circulatory support, and mechanical respiratory support prevented further, potentially lethal, hepatic dysfunction, leading to good early surgical results. We concluded that patients with Child A cirrhosis could tolerate cardiac surgery. Subsequent surgical results, however, were unsatisfactory, and more careful follow-up is necessary to obtain better late results.

Cardiac Surgical Procedures↗

PubMed2001

Midterm results after aortic valve-sparing operation.

OBJECTIVES: We have conducted aortic valve-sparing operation for patients having aortic root dilatation and almost normal aortic valve leaflets since August 1998, and here report midterm results. METHODS: Patients with dilated aortic annulus or Marfan's syndrome were treated with reimplantation, and the remaining patients with remodeling. Either 24 or 26 mm graft was selected based on aortic annular diameter and leaflet size. Aortic valve competence was assessed regularly with echocardiography. RESULTS: Five patients (age: 29 +/- 13 yr), including 4 with Marfan's syndrome, had undergone reimplantation, and 3 (age: 46 +/- 18 yr) remodeling by December 2000. Mean follow-up was 18 (range: 10-32) months, and no postoperative death has occurred and no reintervention has been required thus far. All the patients in the remodeling group showed only a small pressure gradient through the aortic valve and decreased left ventricular diameter. Two in the reimplantation group showed a pressure gradient exceeding 20 mmHg. Two Marfan's syndrome patients in the reimplantation group showed slightly increased diastolic left ventricular diameter and 3 slightly increased systolic left ventricular diameter. Although aortic regurgitation had diminished in all patients by discharge, moderate aortic regurgitation recurred in 1 non-Marfan's syndrome patient in the reimplantation group because of degenerated aortic valve. CONCLUSION: Although postoperative aortic valve function was not perfect in all patients undergoing reimplantation, midterm results after aortic valve-sparing operation were generally satisfactory. Proper selection of patients, procedures, and graft size was thought to be important to ensure a favorable surgical outcome.

Adolescent↗

PubMed2001

Hemolysis after mitral valve replacement with mechanical valve prostheses.

OBJECTIVE: We evaluated effects of type, size, and orientation of mechanical mitral valve prostheses on hemolysis. METHODS: Subjects were 84 patients who had undergone mitral valve replacement. Lactate dehydrogenase was mainly used as a marker of hemolysis and was measured before surgery, 1 month after surgery, and in the late postoperative period. RESULTS: Valves used included 16 Medtronic-Hall, 32 St. Jude Medical, and 36 CarboMedics valves. Medtronic-Hall valves caused less hemolysis than St. Jude Medical or CarboMedics valves in the late postoperative period. This resulted because hemolysis due to Medtronic-Hall valves was more severe 1 month after surgery than in the late postoperative period and because hemolysis due to St. Jude Medical or CarboMedics valves was more severe in the late postoperative period than 1 month after surgery. One reason for this finding is that cardiac output was greater in the late postoperative period than 1 month after surgery, making regurgitation through the pivots of bileaflet valves more severe. The orifice area and the orientation of prostheses did not affect hemolysis. CONCLUSION: St. Jude Medical or CarboMedics valves caused more severe hemolysis than Medtronic-Hall valves in the late postoperative period.

Aged↗

PubMed2001

Synthesis and structure-activity relationships of potent and orally active sulfonamide ETB selective antagonists.

The synthesis and structure activity relationships of a series of N-pyrimidinyl benzenesulfonamides as ETB selective antagonists are described. N-Isoxazolyl benzenesulfonamide 1a, previously reported, (1) was selected as a lead compound, and isosteric replacement of the isoxazole ring of 1a with a pyrimidine ring led to the discovery of the highly potent ETB selective antagonist 6e with oral bioavailability. Modification of the terminal aldehyde group at the 6-position of the pyrimidine ring was investigated, and malonate 15b and acylhydrazone 16f were found to be equipotent to aldehyde 6e. Compound 6e showed ETB antagonistic activity on in vivo evaluation.

Aldehydes↗

PubMed2001

Ischemic heart disease associated with protein C deficiency.

Three patients of ischemic heart disease associated with protein C deficiency are reported. Although delayed diagnosis of protein C deficiency resulted in the failure of repeated interventions, coronary artery bypass grafting performed after making the correct diagnosis has led to satisfactory mid-term results under strict anticoagulation therapy. The level of protein C should be measured more frequently in the field of ischemic heart disease and earlier diagnosis of its deficiency should be made, because measurement of protein C does not cost much.

Aged↗

PubMed2001

Stent-graft implantation through partial sternotomy.

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Adult↗

PubMed2001

Immunohistochemical localization of osteopontin in human pulp stones.

The organic matrix component of human pulp stones was investigated by immunohistochemistry. Two pulp stones were extracted from the upper molar teeth of two patients suffering from irreversible pulpitis. Both were formed in the center of the pulp cavity and located apart from the dentin walls. After demineralization, serial sections of the stones were prepared and subjected to immunohistochemical procedures using specific antibodies to type I collagen and noncollagenous proteins (osteopontin, osteonectin, and osteocalcin), which are reported to be involved in calcified matrix formation. Type I collagen was localized evenly in the stones, indicating that it is a major matrix component of pulp stones. Strong immunostaining of osteopontin appeared in the peripheral area of the stones, whereas osteonectin and osteocalcin were not detected. We previously reported that dental pulp cells produced osteopontin in vitro. Osteopontin has been commonly found in other pathological calcification, such as urinary stones, atherosclerotic plaques, and dental calculus. Taken together, the present findings suggest that osteopontin produced by dental pulp cells is possibly associated with calcification of the pulp stone matrix.

Antibodies↗

PubMed2001

Pharmacologic characterization of S-1255, a highly potent and orally active endothelin A receptor antagonist.

The pharmacologic properties of a novel nonpeptide endothelin (ET) receptor antagonist, S-1255 ([R]-[+]-2-[benzo(1,3)dioxol-5-yl]-6-isopropyl-4-[4-methoxyphenyl]-2H-chromene-3-carboxylic acid), was studied. [3H]S-1255 specifically bound to porcine aortic smooth muscle membranes expressing only ET(A) receptors with a Kd value of 0.39 nM. [3H]S-1255 binding was potently inhibited by ET-1 and selective ET(A) or ET(A)/ET(B) receptor antagonists, such as L-749329, SB209670, bosentan, and BQ-123, but the inhibitory effect of ET-3 and the selective ET(B) receptor antagonist, BQ-788, on the binding was weak. These inhibitory effects on [3H]S-1255 binding correlated well with those on [125I]ET-1 binding. S-1255 inhibited ET(A) receptor- and ET(B) receptor-mediated contractions in isolated rabbit femoral and pulmonary arteries with pA2 values of 8.8 and 6.3, respectively. The pA2 value of S-1255 for ET(B) receptor-mediated relaxation in isolated rabbit mesenteric artery was 7.4. Oral administration of S-1255 (0.3-10 mg/kg) caused dose-dependent inhibition of the pressor response to exogenous ET-1 (0.1 nmol/kg) in conscious normotensive rats, which was similar to that produced by intravenous administration (1 and 3 mg/kg). S-1255 (10 and 30 mg/kg, p.o.) significantly reduced blood pressure in deoxycorticosterone acetate-salt hypertensive rats from 6 h after administration, and the hypotensive effects were sustained up to 24-48 h. These results suggest that S-1255 is a highly potent and orally active ET(A) receptor antagonist.

Animals↗

PubMed2001

Nonselective endothelin receptor antagonist initiated soon after the onset of myocardial infarction may deteriorate 24-hour survival.

To investigate the effects of endothelin blockade initiated immediately after the onset of myocardial infarction on survival and left ventricular remodeling, treatment with the nonselective receptor antagonist TAK-044 (n = 22) or saline (n = 19) for 3 weeks was initiated immediately after coronary ligation in rats. The 24-h survival rate was significantly lower in the TAK-044 group than in the saline group. The systolic blood pressure 24 h after the onset of myocardial infarction was similar in the saline and TAK-044 groups, although it was significantly lower in the TAK-044 group during the 3-week protocol. Heart weight/tibial length was significantly increased in the TAK-044 group compared with the saline group. As all deaths in the TAK-044 group occurred within 24 h after myocardial infarction, we performed additional experiments using a separate group of rats 12-16 h after myocardial infarction. Plasma and myocardial endothelin-1 levels were significantly increased, and a bolus injection of TAK-044 significantly reduced left ventricular dP/dtmax in these rats that had had a myocardial infarction compared with sham-operated rats. Endothelin receptor blockade initiated immediately after the onset of myocardial infarction may deteriorate acute-phase survival and left ventricular remodeling. Inhibition of the positive inotropic action of endothlin-1 may partially explain the increased 24-h mortality.

Animals↗

PubMed2001

Protective effect of endothelin type A receptor antagonist on brain edema and injury after transient middle cerebral artery occlusion in rats.

BACKGROUND AND PURPOSE: Recent evidence strongly suggests that endothelins (ETs) play an important role in the regulation of blood-brain barrier (BBB) functions. The aim of the present study was to evaluate the role of ETs on edema formation and BBB permeability change after cerebral ischemia/reperfusion. METHODS: We examined the brain tissue ET-1 content and evaluated the time and dose response of the therapeutic effects of the specific ET type A receptor (ET(A)) antagonist, S-0139, on brain edema formation, development of infarction, and disruption of BBB after 1 hour of middle cerebral artery occlusion (MCAO) in rats. RESULTS: After 1-hour MCAO and reperfusion, the brain ET-1 content did not change during the first 3 hours, increased at 6 hours, and rose almost continuously over 48 hours in the ischemic region as well as in the ischemic rim. Rats infused with S-0139 (0.03 to 1.0 mg/kg per hour) during reperfusion showed dose-dependent and significant attenuation of the increase in brain water content 24 hours after reperfusion. When the infusion of S-0139 was begun after 10 minutes and 1 hour of reperfusion, the brain edema formation and infarct size were significantly attenuated. Furthermore, posttreatment with S-0139 significantly attenuated the increased Evans blue dye-quantified albumin extravasation and improved the mortality of animals after cerebral ischemia/reperfusion. CONCLUSIONS: Our data demonstrate that infusion with S-0139, an ET(A) antagonist, results in significant reduction of brain injury and plasma extravasation after transient MCAO. Thus, ETs may contribute to cerebral ischemia/reperfusion injury at least partly by increasing the BBB permeability via ET(A)s.

Animals↗