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Biomedical subjects

S Fukuyama

Publications and source records attributed to S Fukuyama.

At least 19 recordsLinked to original sources
PubMed2006

Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region.

An adenovirus (Adv) retaining normal E1A but lacking the 55 kDa E1B protein replicates preferentially in TP53-deficient cancer cells including pancreatic cancer cell lines, resulting in the oncolysis of the tumor. When tumor cells are exposed to hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha) is stabilized and activated to promote the transcription of several genes such as vascular endothelial growth factor (VEGF), but in the presence of E1A hypoxia-induced VEGF m-RNA synthesis is inhibited by E1A binding to p300. In this study, we demonstrated that the cancer cells infected with a mutant Adv in which the p300 binding site in E1A was partially deleted induced a higher expression level of VEGF as compared to those of Adv with normal E1A. An immunoprecipitation study for E1A confirmed that mutant E1A had a reduced binding capacity for p300. Although the expressions of HIF-1alpha m-RNA were almost the same in both cancer cells infected with the mutant Adv and those with the wild Adv, the amount of HIF-1alpha protein in cancer cells infected with the wild E1A Adv was lower than in those infected with the mutant E1A type Adv. In vivo, in contrast to the angiogenesis treated with mutant E1A, wild-E1A inhibited tumor angiogenesis significantly. These results suggested that E1A suppressed the production of VEGF and inhibited tumor angiogenesis by binding with p300, resulting in the inhibition of the HIF-1alpha-mediated transcription of genes through binding to HRE. This study demonstrates, for the first time, the effect of an oncolytic replication-competent Adv in inhibiting tumor angiogenesis.

Adenoviridae↗
PubMed2005

New strategy for acute necrotizing pancreatitis: Continuous Regional Arterial Infusion (CRAI) therapy.

Acute pancreatitis is an autodigestive disease, of which protease inhibition has been the focus of experimental and clinical research. Different from Europe and the United States, protease inhibitors are often applied in the treatment of acute pancreatitis in Japan. However, in clinical settings, the effect of protease inhibitors on acute pancreatitis is still controversial. Continuous Regional Arterial Infusion (CRAI) of protease inhibitors and antibiotics therapy were developed in Japan and it has been demonstrated that CRAI therapy has beneficial effects on severe acute necrotizing pancreatitis. In the Japanese clinical guidelines for the treatment of acute pancreatitis, published in 2003, CRAI therapy is still classified as a special therapy. However, a Randomized Controlled Trial for CRAI therapy has started and CRAI therapy is expected to become a new standard therapy for severe acute pancreatitis. CRAI therapy is aimed at preventing the progression of pancreatic inflammation and pancreatic infection. CRAI therapy can decrease the mortality rate and the frequency of pancreatic infection in severe acute pancreatitis, but it should be started as soon as possible after the onset of acute pancreatitis.

Anti-Bacterial Agents↗
PubMed2004

Allelic variation at the VRN-1 promoter region in polyploid wheat.

Vernalization, the requirement of a long exposure to low temperatures to induce flowering, is an essential adaptation of plants to cold winters. We have shown recently that the vernalization gene VRN-1 from diploid wheat Triticum monococcum is the meristem identity gene APETALA1, and that deletions in its promoter were associated with spring growth habit. In this study, we characterized the allelic variation at the VRN-1 promoter region in polyploid wheat. The Vrn-A1a allele has a duplication including the promoter region. Each copy has similar foldback elements inserted at the same location and is flanked by identical host direct duplications (HDD). This allele was found in more than half of the hexaploid varieties but not among the tetraploid lines analyzed here. The Vrn-A1b allele has two mutations in the HDD region and a 20-bp deletion in the 5' UTR compared with the winter allele. The Vrn-A1b allele was found in both tetraploid and hexaploid accessions but at a relatively low frequency. Among the tetraploid wheat accessions, we found two additional alleles with 32 bp and 54 bp deletions that included the HDD region. We found no size polymorphisms in the promoter region among the winter wheat varieties. The dominant Vrn-A1 allele from two spring varieties from Afghanistan and Egypt ( Vrn-A1c allele) and all the dominant Vrn-B1 and Vrn-D1 alleles included in this study showed no differences from their respective recessive alleles in promoter sequences. Based on these results, we concluded that the VRN-1 genes should have additional regulatory sites outside the promoter region studied here.

Alleles↗
PubMed2004

Dual endoscopic-assisted endoluminal colostomy reversal: a feasibility study.

BACKGROUND: Emergent colostomies are associated with increased morbidity related to second closure operations. The purpose of this canine pilot study was to create a minimally invasive procedure that would reduce the time interval and morbidity involved with colostomy reversals after left colon end colostomies. METHODS: Six mongrel dogs underwent modified laparoscopic Hartmann's procedures in which the stapled end of the rectal stump was approximated to the left colon proximal to the stoma. After 1 week, they underwent an endoluminal colostomy reversal with a computer-mediated, circular stapling device and varying anvil insertion methods. Variables recorded included anvil insertion technique and feasibility, OR time, complications, and number of days to first meal and bowel movement. A contrast enema performed 1 week post colostomy reversal ruled out anastomosis leaks and stenosis. The dogs were euthanized and subjected to necropsy. RESULTS: Of four anvil insertion techniques tested, the most feasible employed a large-bore needle to perforate through the stapled end of the Hartmann pouch into the lumen of the left colon. Simultaneous endoluminal views of the rectal stump with a sigmoidoscope and the left colon lumen with an endoscope permitted a controlled and safe needle puncture. Through the needle, a guide wire was inserted to withdraw the anvil via the colostomy into place. A transanally inserted stapler was then married to the anvil under fluoroscopic guidance, thus completing the anastomosis. The colostomy was then taken down and transected at the level of the colocolostomy. Average operating time was 126 min (range 90-180), diet was tolerated within 1.5 days, and average number of days to first bowel movement was 2.5. The absence of stenosis, leaks, and inadvertent visceral injuries confirmed feasibility. CONCLUSIONS: In this canine model, a dual endoscopic-assisted colostomy reversal with a computer-mediated, circular stapling device is feasible. Using this technique, colostomy reversals can possibly be performed 1 week post-colostomy without entering the peritoneal cavity, thus reducing the number of invasive operations and subsequent morbidity required to manage emergent colon perforations.

Anastomosis, Surgical↗
PubMed2002

Laparoscopic harvesting of small bowel graft for small bowel transplantation.

BACKGROUND: Small bowel transplantation represents a valid therapeutic option for patients with intestinal failure, obviating the need for long-term total parenteral nutrition. Recently, reports have shown the feasibility of performing living related intestinal transplantation using segmental small bowel grafts. The limitations of this technique include inadequate harvested small bowel lengths, as compared with the lengths obtained in cadaveric small bowel harvests, and large incisions for the donor. In this pilot study, we evaluated the feasibility of laparoscopically harvesting long segments of proximal jejunum for small bowel transplantation using a porcine model. The results can be used to evaluate the potential for applying this technique in human cases. METHODS: For this study 10 yorkshire pigs were used. Under general anesthesia, each pig underwent laparoscopic segmental resection of 200 cm of proximal jejunum on a vascular pedicle. The harvested graft then was autoreimplanted using an open technique by anastomosing the vascular pedicle to the superior mesenteric vessels. Success was determined 2 hours after anastomosis by visually identifying a pink graft with viable-appearing mucosa, an artery with a strong thrill, and palpable venous flow. The animals were then sacrificed. RESULTS: The mean operation time required to laparoscopically harvest the small bowel graft was 80 min (range, 35-120 min), and the mean length of harvested graft was 220 cm (range, 200-260 cm). The mean length of the graft's vascular pedicle was 4.5 cm (range, 4-5 cm). All 10 grafts were successfully harvested laparoscopically and then reimplanted using an open technique. All the grafts maintained good vascular flow, and showed no evidence of mucosal necrosis at necropsy. Obviously, further studies would be required to examine the long-term results of reimplanting a laparoscopically harvested small bowel graft, but proposals for such studies is beyond the scope of this report. CONCLUSION: Minimally invasive techniques can be used to harvest proximal small bowel grafts for living related small bowel transplantation.

Animals↗
PubMed2002

Ozone exposure may enhance airway smooth muscle contraction by increasing Ca(2+) refilling of sarcoplasmic reticulum in guinea pig.

Ozone induces airway hyperresponsiveness, but there is controversy about effects of ozone on smooth muscle per se. We therefore investigated effects of in vivo ozone exposure on intracellular calcium mobilization in relation to tracheal smooth muscle contractility in the guinea pig in vitro. Guinea pigs underwent ozone exposure or sham exposure (3 ppm, 2 h). Then, a tracheal smooth muscle strip was mounted in an organ bath to record isometric tension. Effects of ozone exposure on acetylcholine-induced contraction of smooth muscle were as follows. Contraction was not altered in normal Krebs solution, but was increased in Ca(2+)-free solution in ozone-exposed animals. Decline of tension on repetitive application of acetylcholine in Ca(2+)-free solution was reduced, while the tension decline rate while acetylcholine was washed out with Ca(2+)-free solution was facilitated in ozone-exposed animals. Tension decline during the continuous administration of acetylcholine in Ca(2+)-free solution was slowed. Contraction occurred more quickly in Ca(2+)-free solution in ozone-exposed animals. Results suggest that ozone has a direct action on airway smooth muscle by changing Ca(2+) mobilization; Ca(2+) refilling via a Ca(2+) pump and Ca(2+) release via Ca(2+) channels in the sarcoplasmic reticulum were increased, while Ca(2+) extrusion via the plasma membrane Ca(2+) pump was unchanged.

Acetylcholine↗
PubMed2002

Effect of suplatast tosilate on airway hyperresponsiveness and inflammation in asthma patients.

Because eosinophilic airway inflammation is a characteristic of bronchial asthma, the treatment of such inflammation is important in the management of this disease. Suplatast tosilate is a novel anti-asthma drug that suppresses eosinophil proliferation and infiltration through selective inhibition of Th2 cytokine synthesis. We investigated the effect of oral suplatast tosilate therapy in patients with mild and moderate asthma. Twenty-eight asthma patients were randomized into two groups with or without suplatast tosilate treatment (100 mg t.i.d. for 28 days). We examined the blood eosinophil counts, eosinophilic cationic protein level, sputum eosinophil count, exhaled nitric oxide level, and airway responsiveness before and after treatment. In patients treated with suplatast tosilate, the eosinophil count in the blood and sputum was significantly decreased after treatment, while there was no such change in the patients without suplatast treatment. The exhaled nitric oxide level and airway responsiveness (measured using an Astograph) were also decreased after treatment with suplatast tosilate, while there were no significant changes in patients without suplatast tosilate. These results strongly suggest that oral administration of suplatast tosilate suppresses airway hyperresponsiveness in asthma patients by reducing eosinophilic inflammation in the airways.

Adult↗
PubMed2002

NOR-1: a nitric oxide releasing agent for calibrating low levels of nitric oxide by the chemiluminescence method.

Nitric oxide (NO) is formed in small amounts in vivo and is rapidly oxidized by interacting with oxygen, making measurement of its level difficult. The chemiluminescence assay is the most widely used method for detecting NO and is extremely sensitive to very small amounts of NO. However, it is difficult to prepare small amounts of NO to be used as a standard for NO analysis. NOR-1, a derivative of NOR-3, is a newly discovered NO donor with rapid NO-releasing activity. We assessed the dynamics of NO release and decomposition using NOR-1. Our results demonstrate that NOR-1 is stable in dimethylsulfoxide (DMSO) and is able to dilute at lower concentration (to picomolar levels) by DMSO without decomposition. NOR-1 released persistently 1.4 more excess of NO with 15 min of incubation. There was a linear relationship between the concentration of NOR-1 and that of NO released from NOR-1 (r=0.997) These findings suggest that NOR-1 is a useful reagent for the calibration of lower NO detection.

Benzoates↗
PubMed2001

Early microcirculatory derangement in mild and severe pancreatitis models in mice.

An in vivo microscopic technique was used to clarify the increase in microvascular permeability and enhanced leukocyte-endothelium interaction of pancreatic microcirculation in experimental pancreatitis of differing severity. Using bovine albumin fluorescein isothiocyanate (FITC) and carboxyfluorescein diacetate succinimidyl ester (CFDASE) as tracers, the change in permeability and the behavior of leukocytes in the acinar microcirculation were quantified during the initial 1, 2, 6, and 12h after the induction of caerulein pancreatitis in mice. Cold stress was added to produce the severe model. It was revealed that the early microcirculatory changes in the pancreas of caerulein pancreatitis included the increased permeability of endothelial lining and an accumulation of extravasated fluid in the perilobular space, which were more severe if cold stress was added. A decrease in flow velocity was also noted 2h after the onset of severe pancreatitis. Leukocyte adherence to the endothelial cells was not observed during the first 12h in either model of severity. In contrast, observation of the hepatic microcirculation revealed a significant number of adherent leukocytes 2h after the induction of severe pancreatitis. These results suggest that during the early course of acute pancreatitis, leukocyte adherence in the pancreatic microcirculation is a secondary event following the increase in pancreatic vascular permeability.

Acute Disease↗
PubMed2001

PAF mediates cigarette smoke-induced goblet cell metaplasia in guinea pig airways.

Goblet cell metaplasia is an important morphological feature in the airways of patients with chronic airway diseases; however, the precise mechanisms that cause this feature are unknown. We investigated the role of endogenous platelet-activating factor (PAF) in airway goblet cell metaplasia induced by cigarette smoke in vivo. Guinea pigs were exposed repeatedly to cigarette smoke for 14 consecutive days. The number of goblet cells in each trachea was determined with Alcian blue-periodic acid-Schiff staining. Differential cell counts and PAF levels in bronchoalveolar lavage fluid were also evaluated. Cigarette smoke exposure significantly increased the number of goblet cells. Eosinophils, neutrophils, and PAF levels in bronchoalveolar lavage fluid were also significantly increased after cigarette smoke. Treatment with a specific PAF receptor antagonist, E-6123, significantly attenuated the increases in the number of airway goblet cells, eosinophils, and neutrophils observed after cigarette smoke exposure. These results suggest that endogenous PAF may play a key role in goblet cell metaplasia induced by cigarette smoke and that potential roles exist for inhibitors of PAF receptor in the treatment of hypersecretory airway diseases.

Animals↗
PubMed2001

Effect of a common mutation (D442G) of the cholesteryl ester transfer protein gene on lipids and lipoproteins in children.

Cholesteryl ester transfer protein (CETP) is thought to regulate plasma HDL. Patients with CETP deficiency caused by mutation of the CETP gene [D442G; a missense mutation (Asp442-->Gly)] have been reported to show high plasma HDL levels. However, there are no data available on children with D442G. To determine the effects of plasma CETP and CETP gene mutation (D442G) on lipids and lipoproteins in children, we screened children by PCR and restriction fragment length polymorphism analysis of the CETP gene. Plasma lipids, apolipoproteins, and CETP mass levels were also determined. In the current study, 22 children with D442G were found (21 heterozygotes and a homozygote). A homozygous child showed high plasma HDL level and very low plasma CETP mass. In heterozygous children, plasma concentrations of HDL cholesterol, apo A-I and apo A-II were not increased, whereas plasma CETP mass was significantly decreased. Plasma CETP mass in heterozygous children was correlated with plasma concentrations of total cholesterol, LDL cholesterol, and apo B. Plasma CETP mass in children without D442G was not correlated with the plasma concentration of any lipid or apolipoprotein. All of these data suggest that the D442G mutation, by itself, might not affect HDL metabolism in children. The CETP mass required for efficient HDL-cholesteryl ester clearance in children may be less than that in older subjects.

Base Sequence↗
PubMed2001

Asymptomatic atresia of the lobar bronchus of the lung: a case report.

A 64-year old woman presented with an asymptomatic occlusion of the intermediate bronchus associated with a peripheral mass occupying the entire middle and lower lobes. As malignancy was suspected, inferior bilobectomy was done. There was a complete atelectasis of both lobes, with massive parenchymal necrosis. Pathological examinations suggested a tuberculous granuloma in the bronchus and parenchyma although tuberculous bacilli were not found. This case was unusual as congenital anomaly, and was suspected as bronchial tuberculosis.

Bronchi↗
PubMed2001

[An autopsy case of idiopathic interstitial pneumonia with diffuse alveolar hemorrhage due to acute exacerbation].

There has hitherto been no report describing idiopathic interstitial pneumonia associated with diffuse alveolar hemorrhage, but we herein report one such rare case. A 75-year-old man who had received a diagnosis of idiopathic interstitial pneumonia had been followed in our hospital since 1995, and had been treated with cyclophosphamide since September 1999. He discontinued taking cyclophosphamide without informing us, and two months later he was admitted to our hospital with deterioration of dyspnea on September 13, 2000. Since chest radiography and CT findings demonstrated alveolar infiltrates in the right middle lung field, he was treated with antibiotic agents. Although no deterioration of symptoms occurred, on September 14 he began to suffer rapidly progressive dyspnea accompanied with production of bloody sputum, which eventually developed into full-blown hemoptysis in the evening of September 15. He died of respiratory failure early the next morning. The autopsy findings demonstrated diffuse alveolar hemorrhage, diffuse alveolar damage, interstitial pneumonia, and pulmonary fibrosis.

Aged↗
PubMed2001

[A case of inflammatory endotracheal polyps in an asthmatic subject].

A 60-year-old asthmatic woman was admitted to our department because of bloody sputum and pneumonia. She had been treated with inhaled becromethasone dipropionate (800 micrograms/day) on an outpatient basis for 3 years. Fiberoptic bronchoscopy revealed polypoid lesions in the trachea, most of which were removed with forceps during the procedure. Numerous lymphocytes were observed in the biopsy specimen. Because immunohistochemical staining denied a monoclonal origin for the accumulated lymphocytes, the lesion was diagnosed as an inflammatory polyp. The patient was treated successfully with antibiotics for her pneumonia, and on a follow-up bronchoscopy 6 months later, only a small remnant of the lesion was noted. This is the fourth report about inflammatory polyps in asthmatics. In the previous 3 cases, however, marked eosinophil infiltration was consistently reported. The lymphocyte predominance in the present case therefore suggests a distinct etiology rather than asthmatic airway inflammation.

Asthma↗
PubMed2000

Thapsigargin, a Ca(2+)-ATPase inhibitor, relaxes guinea pig tracheal smooth muscle by producing epithelium-dependent relaxing factors.

A non-phorbol ester-type tumor promoter, thapsigargin has been reported to deplete Ca(2+) stores in endothelial cells by inhibiting Ca(2+)-ATPase, which in turn increases intracellular Ca(2+) by mobilization of extracellular Ca(2+), leading to activation of constitutive nitric oxide synthase (cNOS) and resultant generation of nitric oxide (NO). In the present study, to evaluate the role of Ca(2+) in the release of epithelium-dependent relaxing factor (EpDRF), we determined the effect of thapsigargin (10(-6) M) on the contraction evoked by exogenous Ca(2+) or acetylcholine (10(-5) M) in epithelium-denuded or epithelium-intact smooth muscle from guinea pig trachea. The following results were obtained: (1) In epithelium-denuded smooth muscle, the contraction evoked by exogenous Ca(2+) in Ca(2+)-free solution or by acetylcholine (10(-5) M) in Ca(2+)-containing solution did not change within 20 min after thapsigargin application, but the contraction evoked by exogenous Ca(2+) increased markedly after 120 min, indicating that thapsigargin had no effect on smooth muscle itself within 20 min of application. The following experiments were performed within 20 min of thapsigargin application. (2) In epithelium-intact smooth muscle, thapsigargin significantly suppressed the contraction evoked by acetylcholine, suggesting that thapsigargin stimulate the epithelium to produce EpDRF. N(G)-nitro-L-arginine methylester (L-NAME) partly, but significantly, attenuated this inhibitory effect of thapsigargin. (3) In epithelium-denuded smooth muscle, atropine (10(-6) M) and L-NAME (10(-5) M) did not change the contraction evoked by exogenous Ca(2+) after application of thapsigargin, suggesting that thapsigargin did not stimulate acetylcholine and NO release from nerve terminals. These results suggest that thapsigargin (10(-6) M) may stimulate EpDRF, including NO and other factor(s) by Ca(2+)-dependent mechanisms.

Acetylcholine↗
PubMed2000

Cyclooxygenase-2 participates in the late phase of airway hyperresponsiveness after ozone exposure in guinea pigs.

We examined the role of cyclooxygenase in airway hyperresponsiveness and inflammation after ozone exposure in guinea pigs using a non-selective (indomethacin) and a selective (JTE-522) cyclooxygenase-2 inhibitor. Spontaneously breathing guinea pigs were exposed to ozone (3 ppm) for 2 h after treatment with vehicle, indomethacin (10 mg/kg) or JTE-522 (10 mg/kg). Airway responsiveness to inhaled histamine (PC(200)) and bronchoalveolar lavage were assessed before, immediately and 5 h after ozone exposure. Ozone caused a significant airway hyperresponsiveness immediately after exposure, which persisted after 5 h. Neither JTE-522 nor indomethacin affected airway hyperresponsiveness immediately after ozone exposure, but significantly attenuated airway hyperresponsiveness 5 h after exposure, suggesting that cyclooxygenase-2 may participate in the late phase of airway hyperresponsiveness but not in the early phase. Ozone caused a significant increase in the concentration of prostaglandin E(2) and thromboxane B(2) in bronchoalveolar lavage fluid immediately after exposure, which decreased to the basal level 5 h after exposure. This increase in prostaglandin E(2) and thromboxane B(2) was significantly inhibited by JTE-522. An expression of cyclooxygenase-2 was detected not only after ozone exposure but also before, and there was no difference in the number of cyclooxygenase-2-positive cells at any time point. An exogenously applied thromboxane A(2) mimetic, U-46619 (10(-5) M), induced airway hyperresponsiveness 5 h after inhalation, but not immediately or 3 h after inhalation. These data suggest that cyclooxygenase-2 may be constitutively expressed before ozone exposure in guinea pig airway and may synthesize prostaglandin E(2) and thromboxane A(2) transiently under ozone stimulation and that thromboxane A(2) may, in turn, induce the late phase of airway hyperresponsiveness.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

Effect of dimethylthiourea, a hydroxyl radical scavenger, on cigarette smoke-induced bronchoconstriction in guinea pigs.

Cigarette smoke exposure causes bronchoconstriction in guinea pigs by stimulating cholinergic and excitatory nonadrenergic, noncholinergic (eNANC)-nerves in vagus system. The aim of this study is to elucidate the role of hydroxyl radical (OH(-)), contained in cigarette smoke, in bronchoconstriction. Anaesthetized animals were exposed to 80 puffs of smoke for 4 min. Pretreatment with dimethylthiourea, a OH(-) scavenger, significantly inhibited cigarette smoke-induced bronchoconstriction. To investigate its site of action, effects of dimethylthiourea were examined on vagally mediated bronchcoconstriction by electrical stimulation and on the bronchoconstriction by intravenous acetylcholine and neurokinin-A. Dimethylthiourea did not inhibit bronchoconstriction evoked by vagal stimulation, acetylcholine or neurokinin-A. These results suggest that dimethylthiourea inhibits cigarette smoke-induced bronchoconstriction by scavenging the smoke-derived OH(-), but not by inhibiting airway nerve function.

Acetylcholine↗