Biomedical subjects

Kimikazu Hamano

Publications and source records attributed to Kimikazu Hamano.

At least 19 recordsLinked to original sources

PubMed2007

Analysis of the origin and population dynamics of cardiac progenitor cells in a donor heart model.

Cardiac progenitor (stem) cells have recently been detected in and isolated from the myocardium of neonatal and adult mice, rats, and humans; however, the precise origin and characterization of these cells remain unclear. Using a heterotopic mouse heart transplantation model, we investigated the origin and population dynamics of cardiac progenitor cells. Donor hearts from wild-type C57/BL6 female mice were transplanted into green fluorescent protein (GFP)-transgenic C57/BL6 male mice. The donor hearts were collected 0, 2, 4, 8, and 12 weeks after transplantation. We used quantitative flow cytometry to analyze the number and origin of stem cells in the donor hearts and immunostaining to evaluate the time-related changes in their characteristics. Extracardiac GFP-positive stem cells immigrated into the donor hearts soon after transplantation. Immunostaining revealed that these GFP-positive stem cells in the donor hearts gradually lost expression of the hematopoietic markers of CD45 and CD34 and shifted to express the cardiac-specific transcription factors GATA-4 and NKx2.5. A few of the GFP-positive cells in the donor hearts finally acquired the mature cardiac phenotype in the absence of cell fusion with donor cardiomyocytes. Our discovery provides the first evidence that extracardiac stem cells may be of bone marrow origin, from which they can transform into cardiac progenitor cells in response to myocardial environment cues.

Animals↗

PubMed2006

Computed tomography-diagnosed emphysema, not airway obstruction, is associated with the prognostic outcome of early-stage lung cancer.

PURPOSE: Because both emphysema and lung cancer can arise from biological damage caused by cigarette smoking, we investigated if the development of emphysema is associated with the clinical features of smoker's lung cancer. EXPERIMENTAL DESIGN: The subjects were a consecutive series of 100 smokers who underwent lobectomy with hilar and mediastinal dissection for clinical stage I non-small cell lung cancer. We studied the relationship between the presence or absence of emphysema at the onset of the lung cancer and clinicopathologic features. Emphysema was diagnosed by measuring the low-attenuation area using computed tomography densitometry. RESULTS: There were no differences in clinicopathologic variables, including the degree of smoking exposure between the patients with (n=58) and those without (n=42) emphysema, although male gender and airflow limitation were predominant in the patients with emphysema. The presence of emphysema, but neither male gender nor airflow limitation, adversely affected both overall and disease-specific survival. According to Cox regression analysis, emphysema was an independent prognosticator among age, gender, degree of smoking exposure, tumor size, nodal status, histologic subtype, histologic grade, and microvessel invasion. These results were stabilized by a bootstrap sampling model. CONCLUSIONS: Computed tomography-diagnosed emphysema, but not airway obstruction, is associated with poor prognosis in smokers with early-stage lung cancer. Thus, routine computed tomography densitometry in smokers with lung cancer should be mandatory.

Aged↗

PubMed2006

Long-term survival of xenogeneic heart grafts achieved by costimulatory blockade and transient mixed chimerism.

BACKGROUND: Xenotransplantation holds great promise in clinical medicine, but is limited by the vigorous rejection response elicited against solid organs transplanted across species barriers. In this study, we investigated the role of anti-CD40L monoclonal antibody (mAb) in inducing xenogeneic mixed chimerism and donor-specific heart transplantation tolerance. METHODS: One day before heart transplantation, mice were injected intraperitoneally with anti-mouse CD8/NK1.1/Thy1.2 mAbs. On day 0, the mice received 3 Gy total body irradiation (TBI), an intravenous injection of unseparated bone marrow (BM) harvested from F344 rats, and an intraperitoneal injection of hamster antimouse CD40L mAb, MR1. Heart grafts from F344 rats were heterotopically transplanted into the abdomen of B6 mouse recipients. Using flow cytometric analysis of peripheral white blood cells, we assessed donor hematopoiesis at various times after bone marrow transplantation (BMT). RESULTS: Chimerism subsided gradually and disappeared completely 18 weeks after BMT. The cardiac graft survived permanently, even after the mixed chimerism disappeared. To determine if the mice acquired donor-specific tolerance, second rat heart grafts were transplanted 120 days after the first heart transplantation. The second transplanted hearts were also accepted over 60 days. Histological analysis revealed no remarkable vasculopathy in the coronary vessels at any stage. CONCLUSIONS: These findings clearly show that costimulatory blockade plays an important role in inducing xenochimerism, and that transient mixed chimerism can induce permanent acceptance of rat to mouse cardiac xenografts. Transplantation of xenogeneic bone marrow cells under costimulatory blockade at the time of heart transplantation may induce transplantation tolerance.

Animals↗

PubMed2006

Physiological rehabilitation after video-assisted lung lobectomy for cancer: a prospective study of measuring daily exercise and oxygenation capacity.

OBJECTIVE: Video-assisted thoracic surgery followed by fast-track rehabilitation has been claimed to accelerate physiological recovery after lung lobectomy for cancer; however, we are still uncertain when the exercise and oxygenation capacity recover and how to determine the rehabilitation time required by each patient. The aim of this study was to evaluate the rehabilitation time after this type of surgery and determine the best predictors of rehabilitation time. METHODS: We measured exercise and oxygenation capacity daily during the perioperative period on a prospective series of 40 patients who had scheduled to undergo video-assisted lung lobectomy for cancer. Postoperative rehabilitation was confirmed when patients had regained more than 80% of their baseline exercise capacity and more than 98% of their baseline oxygenation capacity without the use of routine tubes for oxygen supplementation, fluid transfusion, bladder catheterization, chest drainage, and epidural catheterization. The hypoxemia index, which we found to have correlated with early-postoperative oxygenation capacity, was calculated preoperatively using baseline arterial oxygen saturations and the severity of emphysema on computed tomography. RESULTS: The median rehabilitation time was 3 days. Stepwise Cox regression analysis revealed that the postoperative predicted forced expiratory volume in 1s (relative ratio 1.043, p < 0.01) and the hypoxemia index (relative ratio 1.343, p = 0.02) were the best independent determinants of the postoperative rehabilitation time. CONCLUSIONS: By conducting daily physiological assessments, we identified the rehabilitation time and its determinants in patients who underwent video-assisted lung lobectomy for cancer. Our results are valuable for planning patient-specific fast-track surgery in the hospital setting.

Aged↗

PubMed2006

Cholesterol primes vascular smooth muscle to induce Ca2 sensitization mediated by a sphingosylphosphorylcholine-Rho-kinase pathway: possible role for membrane raft.

Hypercholesterolemia is a major risk factor involved in abnormal cardiovascular events. Rho-kinase-mediated Ca(2+) sensitization of vascular smooth muscle (VSM) plays a critical role in vasospasm and hypertension. We recently identified sphingosylphosphorylcholine (SPC) and Src family tyrosine kinase (Src-TK) as upstream mediators for the Rho-kinase-mediated Ca(2+) sensitization. Here we report the strong linkage between cholesterol and the Ca(2+) sensitization of VSM mediated by a novel SPC/Src-TK/Rho-kinase pathway in both humans and rabbits. The extent of the sensitization correlated well with the total cholesterol or low-density lipoprotein cholesterol levels in serum. However, an inverse correlation with the serum level of high-density lipoprotein cholesterol was observed, and a correlation with other cardiovascular risk factors was nil. When cholesterol-lowering therapy was given to patients and rabbits with hypercholesterolemia, the SPC-induced contractions diminished. Depletion of VSM cholesterol by beta-cyclodextrin resulted in a loss of membrane caveolin-1, a marker of cholesterol-enriched lipid raft, and inhibited the SPC-induced Ca(2+) sensitization and translocation of Rho-kinase from cytosol to the cell membrane. Vasocontractions induced by membrane depolarization and by an adrenergic agonist were cholesterol-independent. Our data support the previously unreported concept that cholesterol potentiates the Ca(2+) sensitization of VSM mediated by a SPC/Src-TK/Rho-kinase pathway, and are also compatible with a role for cholesterol-enriched membrane microdomain, a lipid raft. This process may play an important role in the development of abnormal vascular contractions in patients with hypercholesterolemia.

Animals↗

PubMed2006

Impact of collagen subtype proportions in peritoneal tissues on inguinal hernia formation in adults and infants.

Impaired collagen subtype proportions in the matrices results in the alteration of tissue tensile strength, and is an underlying cause of adult inguinal hernia formation; however, it remains unclear if this alteration is also responsible for infantile inguinal hernia formation. We correlated the ratios of collagen type I to type III between adults and infants with and those without an inguinal hernia, in an attempt to clarify the pathogenesis of this disorder. We extracted collagen from the hernial sacs of patients with an inguinal hernia, and from the normal peritoneum of patients without an inguinal hernia. After separation by electrophoresis, the collagen bands were quantified and we compared the ratios of collagen type I to type III between the patients with and those without an inguinal hernia. The ratio of collagen type I to type III was significantly lower in the adults with an inguinal hernia (n=8, 6.17+/-2.69) than in those without an inguinal hernia (n=8, 9.38+/-2.99, P=0.041), whereas the ratios were similar in infants with (n=10, 5.72+/-2.66) and those without an inguinal hernia (n=6, 5.60+/-1.88, P=0.925). Our results showed that tissue weakness was not involved in the pathogenesis of infantile inguinal hernia formation, confirming that simple herniotomy is adequate treatment.

Adult↗

PubMed2006

Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury.

It is well known that the implantation of bone marrow mononuclear cells (BM-MNCs) into ischemic hearts can induce angiogenesis and improve cardiac function after myocardial infarction, but the precise mechanisms of these actions are unclear. We hypothesize that the cytokines produced by BM-MNCs play a key role in this cell-based therapy. BM-MNCs from rats were cultured under normoxic or hypoxic (1% O2) conditions for 24 h, and then supernatants were collected for study. ELISA and Western blotting analysis showed that various cytokines, including VEGF, IL-1 beta, PDGF, and IGF-1, were produced from BM-MNCs, some of which were enhanced significantly under hypoxia stimulation. When compared with a control blank medium, the supernatants of BM-MNCs cultured under normoxic or hypoxic conditions inhibited apoptosis significantly and preserved the contractile capacity of isolated adult rat cardiomyocytes in vitro (P < 0.05). Using a rat model of acute myocardial infarction, we injected the supernatants of BM-MNCs or control medium intramyocardially on day 0 and then intraperitoneally on days 2, 4, and 6 after infarction. When compared with the control medium, the supernatants of BM-MNCs cultured under both normoxic or hypoxic conditions increased the microvessel density and decreased the fibrotic area in the infarcted myocardium significantly, contributing to remarkable improvement in cardiac function. Various cytokines were produced by BM-MNCs, and these cytokines contributed to functional improvement of the infarcted heart by directly preserving the contractile capacity of the myocardium, inhibiting apoptosis of cardiomyocytes, and inducing therapeutic angiogenesis of the infarcted heart.

Acute Disease↗

PubMed2006

Pravastatin improves remodeling and cardiac function after myocardial infarction by an antiinflammatory mechanism rather than by the induction of angiogenesis.

BACKGROUND: Recent studies have reported that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or statins) can improve angiogenesis. Using an acute infarction model, we examined the therapeutic merit of statins on angiogenesis, alone and in combination with cell-based therapy. METHODS: Zucker fatty rats, a strain characterized by obesity, hyperglycemia, and hyperlipidemia, were used for this study. After ligating the left anterior descending artery, rats were given oral pravastatin 5 or 50 mg/kg per day, or an intramyocardial injection of a total 2 x 10(7) autologous bone marrow mononuclear cells, or a combination of both. Cardiac function was assessed by echocardiography before treatment, then 7, 14, and 28 days after treatment. Histologic estimation of microvessel density, lymphocyte infiltration, and collagen fiber accumulation in the infarcted myocardium was performed 28 days after treatment. RESULTS: Cardiac function was improved, and collagen deposition was decreased significantly after either cell implantation or pravastatin administration alone, but no synergistic effect was seen by their combination. However, microvessel density in the infarcted myocardium was increased only by implantation of bone marrow mononuclear cells, and not by administration of pravastatin. Pravastatin resulted in significant decreases in the serum levels of interleukin 1beta and tumor necrosis factor-alpha, and also in the infiltration of CD45-positive cells, but not CD117-positive stem cells, in infarcted myocardium. Neither the number of circulating CD34-positive cells nor their endothelial differentiation potency was increased significantly 14 days after oral administration of pravastatin. CONCLUSIONS: Pravastatin can improve cardiac function after myocardial infarction, but through an antiinflammatory mechanism, rather than by induction of therapeutic angiogenesis. No synergistic effect for inducing angiogenesis was found by the combination of pravastatin and implantation of bone marrow mononuclear cells.

Angiogenesis Inducing Agents↗

PubMed2006

Breath-hold single-photon emission tomography and computed tomography for predicting residual pulmonary function in patients with lung cancer.

OBJECTIVE: We sought to evaluate the utility of integrated breath-hold single-photon emission tomography and computed tomography imaging compared with that of simple calculation with the lung segment-counting technique for predicting residual pulmonary function in patients undergoing surgical intervention for lung cancer. METHODS: A prospective series of 22 patients undergoing anatomic lung resection for cancer were enrolled in this study. Postoperative residual forced expiratory volume in 1 second was predicted by measuring the radioactivity counts of the affected lobes or segments to be resected within the entire lungs by placement of regions of interest on single-photon emission tomography and computed tomography images. Residual forced expiratory volume in 1 second was also estimated by using the segment-counting technique. RESULTS: Both predicted values agreed well with postoperative forced expiratory volume in 1 second. Although the residual forced expiratory volume in 1 second predicted by means of single-photon emission tomography and computed tomography correlated well with that predicted by using segment counting, the values were significantly underestimated by the segment-counting technique in 4 outliers with severe emphysema. There were 2 patients with borderline pulmonary functional reserve whose residual forced expiratory volume in 1 second values were predicted more accurately by means of single-photon emission tomography and computed tomography than by using segment counting. CONCLUSION: Integrated breath-hold single-photon emission tomography and computed tomography images allow the accurate prediction of postoperative pulmonary function but without statistical superiority over the simple segment-counting technique. Further study of the usefulness of single-photon emission tomography and computed tomography in patients with severe emphysema and borderline lung function should prove valuable because the segment-counting technique underestimates pulmonary functional reserve in these patients.

Aged↗

PubMed2006

Chronic stage left ventricular aneurysm and thrombus after myocardial infarction.

A 60-year-old man had acute myocardial infarction 13 years ago. After percutaneous coronary intervention, the follow-up left ventriculography (8 years ago) showed dyskinesia in the anterolateral and apical segments of the wall. Following this, there was no change in the clinical symptom. After 6 years the patient discontinued aspirin without seeking medical advice. In this year, a thrombus was found in the left ventricle, and thrombectomy was performed. Left ventricular aneurysm has always been a risk for thrombogenesis in any stage, and a periodic follow-up including an echocardiogram and anticoagulation therapy is necessary.

Echocardiography↗

PubMed2006

Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase in mice.

Abdominal aortic aneurysm (AAA) is a common disease that, when surgical treatment is inapplicable, results in rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is eagerly awaited, the destruction of the aortic walls in AAA has been considered an irreversible process. We found that c-Jun N-terminal kinase (JNK) is highly activated in human AAA walls. We also found that JNK activity is essential for the expression of matrix metalloproteinase (MMP)-9 and, concurrently, suppression of the extracellular matrix (ECM) biosynthesis. We therefore investigated the role of JNK in the pathogenesis of AAA in vivo. We created a mouse AAA model by periaortic application of CaCl(2), which was accompanied by activation of JNK and MMPs, and suppression of lysyl oxidase (LOX), which is an essential biosynthetic enzyme for collagen and elastin fibers. Our data indicate that, in addition to MMP activities, suppression of ECM biosynthesis may contribute to the AAA pathogenesis because local LOX gene delivery prevented AAA formation. Treatment of mice with SP600125, a specific JNK inhibitor, completely abrogated the formation of CaCl(2)-induced AAA. Furthermore, SP600125 treatment after the establishment of AAA caused a reduction in the aortic diameters with normalized tissue architecture. SP600125 treatment also caused significant regression of angiotensin II-induced AAA in ApoE-null mice after its establishment, as demonstrated by serial ultrasonographic studies in live animals. These data demonstrate that JNK dictates the abnormal ECM metabolism in AAA pathogenesis by enhancing tissue degradation and suppressing tissue repair. Therefore, inhibition of JNK may provide a novel therapeutic option for AAA.

Animals↗

PubMed2006

Identification of c-Jun N-terminal kinase as a therapeutic target for abdominal aortic aneurysm.

Despite the advances in molecular cell biology, identification of a therapeutic target in a given disease still poses a significant challenge. Here we report a strategy for identification of the therapeutic target in abdominal aortic aneurysm (AAA). We screened for various signaling molecules in human AAA samples and identified c-Jun N-terminal kinase (JNK) as a prominently activated molecule. The JNK pathway-oriented transcriptome analyses revealed that activation of JNK leads to enhancement of the activity of matrix metalloproteinases and, concurrently, suppression of the extracellular matrix biosynthesis, suggesting that JNK may represent a novel therapeutic target in AAA.

Aortic Aneurysm, Abdominal↗

PubMed2006

In vitro assessment of the effect of interleukin-1beta on angiogenic potential of bone marrow cells.

BACKGROUND: Therapeutic angiogenesis for ischemic diseases has been successfully induced by the implantation of autologous bone marrow cells (BMCs). It is understood that interleukin (IL)-1beta increases remarkably in ischemic tissue and has particular effects on angiogenesis. Thus, it is important to clarify how IL-1beta would effect BMCs survival and angiogenic potential. METHODS AND RESULTS: The effect of IL-1beta on BMCs survival, adhesion, and endothelial differentiation, as well as the production of angiogenic growth factors, was investigated using an in vitro assessment approach. BMCs were harvested from Zucker obese rats and cultured at a density of 3x10(6) cells/ml with 5 ng/ml IL-1 beta (IL-1beta group) or without IL-1 beta (control group). Survival and adhesion of BMCs were significantly increased in the IL-1beta group than in the control group after 1, 3, and 7 days of culture (p<0.01). The release of vascular endothelial growth factor in supernatant was also significantly higher in the IL-1beta group than in the control group after 3 and 7 days of culture (p<0.01). Furthermore, the number of differentiated endothelial cells derived from BMCs was significantly higher in the IL-1beta group than in the control group after 7 days of culture (p<0.01). CONCLUSIONS: These results suggest that IL-1beta has a positive effect on the angiogenic potential of BMCs in vitro.

Animals↗

PubMed2006

Pseudo-Meigs' syndrome caused by breast cancer metastasis to both ovaries.

We report a rare case of pseudo-Meigs' syndrome due to metastasis of breast cancer to both ovaries. A 34-year-old woman with exertional dyspnea was admitted to our hospital. Before entry the patient had undergone radical mastectomy for left breast cancer in June 1998. Resection and reconstruction of the chest wall for recurrence of the breast cancer had been performed in April 2001. Right pleural effusion was found on admission to our hospital in October 2002. Continuous thoracic drainage obtained 500-2000 ml of fluid per day. Cytologic results were both normal and benign, and cultures for bacteria and acid-fast bacilli were negative. During treatment of the pleural effusion, which proved to be cryptogenic and intractable, a huge pelvic tumor was found. The primary site was unknown. Surgery was performed in November 2002, and tumors were removed from both ovaries. The right pleural effusion vanished after surgery. Pseudo-Meigs' syndrome with metastasis of breast cancer to both ovaries was diagnosed. The patient died of cachexia related to the carcinoma in January 2005.

Adult↗

PubMed2006

Right atrial separation effect for chronic atrial fibrillation with atrial septal defect: report of four cases.

We operated on 56 adults diagnosed with atrial septal defect (ASD) between 1990 and 2004. Of these, eight had complications of atrial fibrillation (AF) in the preoperative period. After 1998, right atrial separation was performed in four cases. Marked improvement was noted in three out of the four cases. The right atrial separation procedure was a simple, easy, and effective method for the treatment of chronic AF associated with ASD.

Aged↗

PubMed2006

A sewing needle completely buried in the myocardium removed under extracorporeal circulation.

A 14-year-old boy had a needle accidentally inserted through his chest wall. Chest X-ray showed a needle-shaped metallic density localized in the cardiac silhouette. An echocardiography indicated the needle had passed through the interventricular septum, and its eye and point had reached the right and left ventricle, respectively. Surgical removal of the needle was performed. The needle could not be observed from the heart surface, and was recognized in a dent 5 mm on the right side from the left anterior descending branch (LAD). The needle was easily removed under extracorporeal circulation, and he was discharged ten days after the operation.

Adolescent↗

PubMed2006

Successful aortic valve replacement for infective endocarditis in a patient with severe liver cirrhosis.

Patients with liver cirrhosis are prone to the development of severe complications associated with high mortality rates after major surgery, especially cardiac surgery using cardiopulmonary bypass (CPB). We report the case of a 65-year-old man with acute infective endocarditis and aortic valve perforation, complicated by non-cardiac liver cirrhosis (Child-Pugh class B). After careful preoperative anti-inflammatory and systemic support treatment, we successfully treated infective endocarditis-induced aortic valve perforation by performing aortic valve replacement (AVR).

Aged↗

PubMed2005

Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase.

Abdominal aortic aneurysm (AAA) is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is much awaited, few options are available because its molecular pathogenesis remains elusive. Here, we identify JNK as a proximal signaling molecule in the pathogenesis of AAA. Human AAA tissue showed a high level of phosphorylated JNK. We show that JNK programs a gene expression pattern in different cell types that cooperatively enhances the degradation of the extracellular matrix while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in two mouse models. Thus, JNK promotes abnormal extracellular matrix metabolism in the tissue of AAA and may represent a therapeutic target.

Adenoviridae↗