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Biomedical subjects

Y Fukuchi

Publications and source records attributed to Y Fukuchi.

At least 73 records · Page 4Linked to original sources

The difference between Japan and other countries, in particular the United Kingdom, in views regarding the teaching of geriatrics to undergraduate medical students.

OBJECTIVES: To examine differences in views on geriatrics education at the undergraduate level between Japan and other industrialized countries, including the United Kingdom. DESIGN: We conducted a nationwide survey of professorial staff responsible for undergraduate education in all medical schools in Japan, and an international survey of 37 medical schools and geriatric institutes in other industrialized countries, including 16 medical schools in the United Kingdom. RESULTS: The results indicate that undergraduate education in geriatrics in Japan emphasizes the theoretical aspects of the aging process and the features of diseases in the elderly, and lacks attention to the practical aspects of care. In contrast, geriatrics education in the United Kingdom and other countries places emphasis on practical aspects of the care of the elderly. CONCLUSIONS: The introduction of practical aspects of management and care of the elderly to the undergraduate education programme in geriatrics in each medical school in Japan is strongly recommended. This is especially important to meet the needs of the rapid demographic shift towards an older population in this country.

Aged↗

DNA vaccination by mecA sequence evokes an antibacterial immune response against methicillin-resistant Staphylococcus aureus.

More than 90% of methicillin-resistant Staphylococcus aureus (MRSA) isolates produce a penicillin-binding protein PBP2' (or PBP2a) with low affinity for beta-lactam antibiotics. PBP2' is encoded by the mecA gene, a foreign gene integrated into the chromosome of methicillin-susceptible S. aureus (MSSA). DNA vaccination by injection of transgene-expressing plasmids has been demonstrated to elicit an immune response against transgene-encoded protein. We hypothesized that the application of DNA vaccination with the mecA sequence would elicit protective immunity against MRSA. This immunity was evoked by injection of a mecA-expressing plasmid into BALB/c mice. Anti-PBP2' antibody was detected in the sera obtained from the DNA-vaccinated mice. These sera produced a five-fold increase in phagocytosis of MRSA compared with sera from mice treated with control plasmid. However, there was no difference in phagocytosis of MSSA among these groups. In addition, the in-vivo antibacterial effect of DNA vaccination was demonstrated in mice infected with MRSA. Eight days after iv inoculation of 10(8) cfu of MRSA into mice, the number of bacteria in the kidneys obtained from mice vaccinated with mecA-expressing plasmid (1.48 +/- 0.27 x 10(5) cfu/mg kidney; n = 18) was significantly lower than that from mice vaccinated with negative control plasmid (3.59 +/- 0.57 x 10(5) cfu/mg kidney; n = 17) (P < 0.02) or that from sham-treated mice (3. 43 +/- 0.66 x 10(5) cfu/mg kidney; n = 9) (P < 0.02). Interestingly, PBP2' was found in both the bacterial membrane fraction and the supernatant, thus being accessible to serum antibodies. Together these observations indicate that PBP2' or the mecA sequence may be eligible as a candidate molecule for vaccination against MRSA.

Animals↗

Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor prevents ischemic brain injury after transient middle cerebral artery occlusion in rats.

To examine a possible protective effect of exogenous glial cell line-derived neurotrophic factor (GDNF) gene expression against ischemic brain injury, a replication-defective adenoviral vector containing GDNF gene (Ad-GDNF) was directly injected into the cerebral cortex at 1 day before 90 minutes of transient middle cerebral artery occlusion (MCAO) in rats. 2,3,5-Triphenyltetrazolium chloride staining showed that infarct volume of the Ad-GDNF-injected group at 24 hours after the transient MCAO was significantly smaller than that of vehicle- or Ad-LacZ-treated group. Enzyme-linked immunosorbent assay (ELISA) for immunoreactive GDNF demonstrated that GDNF gene products in the Ad-GDNF-injected group were higher than those of vehicle-treated group at 24 hours after transient MCAO. Immunoreactive GDNF staining was obviously detected in the cortex around the needle track just before or 24 hours after MCAO in the Ad-GDNF group, whereas no or slight GDNF staining was detected in the vehicle group. The numbers of TUNEL, immunoreactive caspase-3, and cytochrome c-positive neurons induced in the ipsilateral cerebral cortex at 24 hours after transient MCAO were markedly reduced by the Ad-GDNF group. These results suggest that the successful exogenous GDNF gene transfer ameliorates ischemic brain injury after transient MCAO in association with the reduction of apoptotic signals.

Adenoviruses, Human↗

E4021, a selective phosphodiesterase 5 inhibitor, potentiates the vasodilator effect of inhaled nitric oxide in isolated perfused rat lungs.

To test whether E4021, a potent selective cyclic guanosine 3'-5'-monophosphate (cGMP) phosphodiesterase inhibitor, causes pulmonary vasodilation and whether it enhances the vasodilator action of inhaled nitric oxide (NO), we studied its effects on pulmonary vascular tone and inhaled NO-induced pulmonary vasodilation in isolated perfused rat lungs. Lungs were perfused at a constant flow rate with salt-Ficoll solution and ventilated with air plus 5% CO2. After equilibration, vasodilator responses to either E4021, inhaled NO, or both were evaluated under conditions of increased perfusion pressure induced by infusion of U46619. E4021 had no effect on the baseline perfusion pressure, whereas it caused dose-dependent pulmonary vasodilation when the vasomotor tone was increased by U46619. Inhaled 1, 5, and 20 ppm NO reduced the increased perfusion pressure by 60+/-5%, 83+/-3%, and 92+/-2%, respectively. Pretreatment with E4021 significantly potentiated the vasodilator effect of 1 ppm NO (from 53+/-6% to 71+/-2%; p < 0.05) but did not alter that of 5 ppm NO (from 77+/-3% to 78+/-4%; p > 0.05). In addition, pretreatment with E4021 significantly augmented the vasodilator response to sodium nitroprusside but not to isoproterenol. These results indicate that E4021 causes pulmonary vasodilation and potentiates the vasodilator effect of low concentrations of inhaled NO, probably through a cGMP-dependent mechanism in salt-solution perfused rat lungs. We conclude that E4021 may possibly be useful for the treatment of pulmonary hypertension, either alone or in combination with inhaled NO.

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

Glutathione S-transferase P1 (GSTP1) polymorphism in patients with chronic obstructive pulmonary disease.

BACKGROUND: Enzymes that contribute to the local detoxification in alveoli and bronchioles have an important role in the defence mechanism against tobacco smoke. It has been suggested that genetic susceptibility to smoking injury may confer a risk for the development of chronic obstructive pulmonary disease (COPD). The polymorphisms in glutathione S-transferase P1 (GSTP1), a xenobiotic metabolising enzyme, were investigated in patients with COPD. METHODS: Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were performed to genotype GSTP1 polymorphisms in exon 5 (Ile105Val) and exon 6 (Ala114Val). Blood samples were taken from 53 patients with COPD and 50 control subjects at the Tokyo University Hospital, the Juntendo University Hospital, and the Tokyo Kenbikyoin Clinic for use in the study. RESULTS: The proportion of GSTP1/Ile105 homozygotes was significantly higher in the patients with COPD than in the control subjects (79% vs 52%). The odds ratio for GSTP1/Ile105 homozygotes versus all other genotypes was 3.5 (95% CI 2.7 to 4.6) for COPD. Polymorphism at residue 114 of GSTP1 was not found in either group. CONCLUSIONS: Genetic polymorphism of exon 5 of GSTP1 may be associated with COPD because the GSTP1/Ile105 genotype is predominantly found in COPD. It is suggested that the GSTP1/Ile105 genotype may be less protective against xenobiotics in tobacco smoke.

Aged↗

Chronic hypoxia augments endothelin-B receptor-mediated vasodilation in isolated perfused rat lungs.

To investigate whether chronic hypoxia affects endothelin-B (ETB) receptor-mediated pulmonary vasodilation, we compared the vasodilator responses to IRL-1620, a selective ETB-receptor agonist, in isolated perfused lungs from normoxic and chronically hypoxic adult male rats. IRL-1620 caused a dose-dependent vasodilation that was greater in the hypertensive lungs than in the normotensive lungs. In normotensive lungs, a nitric oxide (NO) synthase inhibitor, Nomega-nitro-L-arginine (L-NNA; 300 microM), and an ATP-sensitive potassium (KATP)-channel inhibitor, glibenclamide (Glib; 10 microM), each reduced the vasodilator response to IRL-1620 (1 nM), but the combination of L-NNA and Glib inhibited it more effectively than either drug alone. In contrast, L-NNA alone, but not Glib alone, completely blocked IRL-1620-induced vasodilation in hypertensive lungs. The vasodilator response to a KATP-channel opener, NIP-121 (1 microM), but not the response to sodium nitroprusside (1 microM), was enhanced in hypertensive lungs. We also found increased expression of mRNA for the ETB receptor in lung tissue after hypoxic exposure. In addition, semiquantitative immunohistochemistry demonstrated higher expression levels of ETB receptors in the endothelium of distal segments of the pulmonary artery in hypoxic than in normoxic rats. These results suggest that ETB receptor-mediated pulmonary vasodilation is augmented after chronic hypoxic exposure and that release of NO may be the sole mechanism of this vasodilation in hypertensive lungs, whereas both release of NO and activation of KATP channels are involved in normotensive lungs. We speculate that the underlying mechanism responsible for this augmentation may partly be related to upregulation of ETB receptors in the endothelium of pulmonary resistance arteries in hypertensive lungs.

Adenosine Triphosphate↗

E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats.

The purpose of this study was to determine whether E-4010, a newly synthesized potent and selective orally active phosphodiesterase (PDE) 5 inhibitor, would prevent the development of chronic hypoxia-induced pulmonary hypertension in rats. In conscious, pulmonary hypertensive rats, a single oral administration of E-4010 (1.0 mg/kg) caused an acute, long-lasting reduction in mean pulmonary arterial pressure (PAP), with no significant effects on systemic arterial pressure, cardiac output, and heart rate. In rats that received food containing 0.01 or 0.1% E-4010 during the 3-wk exposure to hypoxia, mean PAP was significantly decreased (mean PAP 24.0 +/- 0.9, 16.2 +/- 0.8, and 12.8 +/- 0.5 mmHg in rats treated with 0, 0.01, and 0.1% E-4010-containing food, respectively), whereas mean systemic arterial pressure was unchanged and cardiac output was slightly increased compared with chronically hypoxic control rats. Right ventricular hypertrophy, medial wall thickness in pulmonary arteries corresponding to the respiratory and terminal bronchioles, and the degree of muscularization of more distal arteries were less severe in E-4010-treated rats. Long-term treatment with E-4010 caused an increase in cGMP levels in lung tissue and plasma but not in aortic tissue and no significant change in cAMP levels in either lung, aorta, or plasma. These results suggest that long-term oral treatment with E-4010 reduced the increase in PAP, right ventricular hypertrophy, and pulmonary arterial remodeling induced by exposure to chronic hypoxia, probably through increasing cGMP levels in the pulmonary vascular smooth muscle.

Animals↗

Atopic asthma is dominant in elderly onset asthmatics: possibility for an alteration of mast cell function by aging through Fc receptor expression.

The morbidity and mortality of elderly onset asthma have recently been on the increase. To evaluate the allergic status of the elderly onset asthmatics, we performed skin tests for allergens and estimated serum total IgE levels of the patients. The proportion of the skin-test-positive patients among the elderly onset asthmatics was significantly larger than that in the younger onset group, whereas no significant difference was observed in the frequency of patients with serum total IgE levels higher than the normal range (287.2 IU/ml). On the other hand, in the experiments with aged mice, isolated peritoneal mast cells (PMC) showed a considerable decrease in the FcgammaRIIB/III expression and higher degranulation triggered by 2.4G2, as compared to the PMC derived from young mice. Since FcgammaRIIB has been shown to act as a negative regulator, we speculate that in the aged mice Fc receptor-mediated mast cell function may be upregulated by a release from the negative regulation as a result of decreased FcgammaRIIB expression. Our results obtained from a mouse model system may help to understand pathophysiological mechanisms underlying elderly onset asthma.

Adult↗

Localization and distribution of endothelin receptor subtypes in pulmonary vasculature of normal and hypoxia-exposed rats.

To clarify the roles of two different endothelin (ET) receptors in the pulmonary vasculature, the localization and distribution of endothelin-A (ETA) and ETB receptors were investigated in rat lung under normal and hypoxic conditions by an immunohistochemical method. We also carried out in situ hybridization for ETB receptor. In normal rats, ETA receptor is localized in the media of the pulmonary artery and vein with predominant distribution in such proximal segments as elastic arteries and large muscular arteries. ETB receptor is expressed in the intima and media of pulmonary vessels. The distribution of ETB receptor in the media predominates in the distal segments of the pulmonary artery, whereas its distribution in the intima is greater in the proximal segments. Immunoreactivity for ETA receptor increases in the media of the distal segments of the pulmonary artery after exposure to hypobaric hypoxia. Semiquantitative evaluation showed immunoreactivity for ETA receptor in the pulmonary arteries accompanying the terminal bronchioles, respiratory bronchioles, and alveolar ducts to be increased by 2.5-, 5-, and 20-fold after 14 d exposure to hypoxia, respectively. The messenger RNA and immunoreactivity for ETB receptor increased significantly in the intima of the distal segments of pulmonary artery after 7 and 14 d exposure to hypoxia. These results suggest that the vasoconstrictive effects of ET-1 are exerted mainly through ETA receptor in the proximal segments of the pulmonary artery and vein, whereas its effects in the distal segments are mediated by ETA and ETB receptors in normal rats. ETA receptors that increase in resistance arteries after exposure to hypoxia appear to play an important role in the vascular remodeling associated with hypoxic pulmonary hypertension. Because ETB receptors in the endothelium mediate ET-1-induced vasodilatory effects, the increase in endothelial ETB receptors may counteract the development of hypoxic pulmonary hypertension.

Animals↗

DNA vaccination against HuD antigen elicits antitumor activity in a small-cell lung cancer murine model.

There is a clinically significant correlation between the presence of an antibody against the paraneoplastic encephalomyelitis antigen HuD and the limitation of tumor spread in patients with small-cell lung cancer (SCLC). This suggests that HuD is a possible target molecule for antitumor immunotherapy against SCLC. We have hypothesized that anti-HuD immunity suppresses in vivo growth of HuD-expressing tumor cells. In this study, Colon 26, a murine adenocarcinoma cell line, stably transfected with the HuD gene (Colon 26/HuD cell) was used as a target cell, and the immunity against HuD was evoked by intramuscular injection of a HuD-expressing plasmid, a technique of DNA vaccination previously used in BALB/c mice. Colon 26/HuD cells were injected subcutaneously and tumor size was calculated as a product of width and length. Antitumor activity was investigated by using two different lots of Colon26/HuD cells in two protocols: Protocol 1, in which either Colon 26/HuD or Colon 26 cells were injected in each side, and Protocol 2, in which Colon 26/HuD cells alone were injected. The size of Colon 26/HuD tumors obtained from mice vaccinated with HuD-expressing plasmid was significantly smaller than those from negative control plasmid-vaccinated mice (86.6 +/- 29.9 versus 195.3 +/- 48.1 mm2, P < 0.05 in Protocol 1; 107.7 +/- 12.8 versus 156.6 +/- 22.8 mm2, P < 0.05 in Protocol 2). Moreover, the de novo DNA synthesis of spleen cells obtained from HuD-vaccinated mice was significantly enhanced. In addition, anti-HuD antibody was found in individual sera obtained from HuD-vaccinated mice. DNA vaccination with mouse HuD antigen suppressed HuD-expressing tumor growth in a murine SCLC model.

3T3 Cells↗

ICAM-1 mediates lung leukocyte recruitment but not pulmonary fibrosis in a murine model of bleomycin-induced lung injury.

Bleomycin-induced lung injury has been extensively used as a model of interstitial pneumonia and pulmonary fibrosis. Intercellular adhesion molecule (ICAM)-1 is a ligand for lymphocyte function-associated antigen (LFA)-1alpha and has been shown to be required for leukocyte migration into inflamed areas. The purpose of this report was to investigate the role of the ICAM-1/LFA-1alpha pathway in a murine model of bleomycin-induced lung injury. Animals received 75 mg x kg(-1) bleomycin (BLM) i.v. followed by treatment with phosphate-buffered saline (BLM group), anti-ICAM-1 and LFA-1alpha monoclonal antibodies (mAb) (BLM+mAb group). Inflammatory cell counts of bronchoalveolar lavage (BAL) fluid, hydroxyproline content and histological findings were compared between these groups. In the BLM group, significant increases in total cell count, macrophage count and neutrophil count of BAL fluid were observed on days 7 and 14. In the BLM+mAb group, bleomycin-induced accumulation of neutrophils was significantly reduced on days 7 and 14 (p<0.01). However, the administration of mAb to ICAM-1 and LFA-1alpha did not decrease the lung hydroxyproline content or the histopathological fibrosis grading score, indicating that the antagonism of ICAM-I and LFA-1alpha did not attenuate bleomycin-induced pulmonary fibrosis. This study suggests that the intercellular adhesion molecule-1/lymphocyte function-associated antigen-1alpha pathway mediates the accumulation of inflammatory cells in the injured lung caused by bleomycin; however, other mechanisms are important for the subsequent development of pulmonary fibrosis.

Animals↗

Impaired swallowing reflex in patients with obstructive sleep apnea syndrome.

BACKGROUND: The swallowing reflex is well coordinated with breathing patterns in normal humans. However, patients with obstructive sleep apnea syndrome (OSAS) may have a swallowing disorder that reflects the abnormal function of nerves and muscles in the suprapharynx. OBJECTIVE: To examine the relationship between the swallowing function and sleep-disordered breathing in patients with OSAS. PARTICIPANTS: Twenty patients with OSAS with a mean (+/-SD) age of 53.4+/-8.9 years old, and 20 age-matched control subjects with a mean age of 51.4+/-9.1 years old. METHODS: OSAS was diagnosed using the recordings of overnight polysomnography. The swallowing function in the subject was tested using a swallowing provocation test. The swallowing reflex was determined according to the following criteria: latent time (LT), the time following a bolus injection of distilled water at the suprapharynx to the onset of swallowing; inspiratory suppression time (IST), the time from the termination of swallowing to the next onset of inspiration; and threshold volume, the minimum volume of water (range, 0.4 to 2 mL) that could evoke the swallowing response. RESULTS: Whereas the LT values in patients with OSAS were larger than the LT values in the control subjects, the IST values (which may reflect the switching mechanism from deglutition apnea to breathing) were actually shorter. In addition, a greater bolus volume was necessary to elicit swallowing in patients with OSAS than was necessary in the control subjects. CONCLUSION: Patients with OSAS are likely to exhibit an impaired swallowing reflex, probably due to the perturbed neural and muscular function of the upper airways.

Case-Control Studies↗

Repeated ultrasonically guided needle biopsy of small subpleural nodules.

STUDY OBJECTIVE: To detect the significance of repeated ultrasonically guided needle biopsy (UGNB) for the diagnosis of nodular lesions </= 2 cm in diameter. DESIGN: Retrospective study to evaluate the diagnostic yield of UGNB. SETTING: University hospital, outpatients, and inpatients of the respiratory department. PATIENTS: One hundred seven cases with small nodular lesions </= 2 cm in diameter in contact with the pleura. Sixty-two of 107 cases were malignant, and the others were benign diseases. RESULTS: Initial UGNB identified 56% (35/62) of the malignant lesions and 16% (7/45) of the benign lesions, ie, 39% (42/107) of the total. In 35 of 65 cases that were not diagnosed by the initial UGNB, it was repeated. Diagnostic yields of the second UGNB were 68% (13/19) of the malignant cases, 25% (4/16) of the benign cases, yielding a total of 49% (17/35) in those reexamined. Furthermore, 51 of 65 patients with negative findings on the initial UGNB underwent fiberoptic bronchoscopy. The resulting diagnostic yields were 22% (5/23) from the malignant lesions and 18% (5/28) from the benign lesions, 20% (10/51) in total. Thus, among the malignant cases, the repetition of UGNB increased the definitive diagnostic yield from 56% (the initial UGNB) to 77%. In these small tumors, no serious complications were caused by the procedure. CONCLUSIONS: UGNB should be performed twice for a definitive diagnosis of small subpleural nodules before deciding on surgical biopsy or follow-up.

Biopsy, Needle↗

[A case of elderly onset sarcoidosis].

Although sarcoidosis is generally considered a disease of young and middle aged adults, there have been a certain number of cases among elderly. However it is unknown whether sarcoidosis in the elderly is recurrence of prior disease or initial onset at old ages. We present a 77-year-old woman with sarcoidosis the onset of which was considered to be in the last 6 months prior to the initial diagnosis. The patient was admitted to our hospital for further evaluation of bilateral hilar and mediastinal lymphadenopathy (BHL) and uveitis. BHL was not present in a chest radiograph taken 6 months prior to the admission. A clinical diagnosis of sarcoidosis was made by elevated serum angiotensin converting enzyme (ACE) and lysozyme (24.9 IU/L and 18.2 micrograms/ml, respectively), negative tuberculin skin test, concomitant presence of uveitis, and a high proportion of lymphocytes (33.2%) in bronchoalveolar lavage fluid with an elevated CD4/CD8 ratio (24.5). This is a noteworthy case of sarcoidosis in which we could confirm elderly onset of the disease.

Age of Onset↗

Cytotoxic activity and cytokine gene induction of Asp-hemolysin to murine macrophages.

We examined the effects of Asp-hemolysin from Aspergillus fumigatus Fresenius-Muramatsu strain on the viability and cytokine gene expression of mouse peritoneal macrophages. The cytotoxic activity of Asp-hemolysin to macrophages cultured in FCS-RPMI medium was increased in a dose-dependent manner. Treatment of Asp-hemolysin with N-ethylmaleimide or sulfo-N-hydroxy-sulfosuccinimide-acetate caused a remarkable loss of the cytotoxic activity, however, the cytotoxic activity of Asp-hemolysin to macrophages cultured in serum-free medium was significantly increased as compared with that in FCS-RPMI medium. As other biological activities of Asp-hemolysin, tumor necrosis factor-alfa (TNF-alfa), interleukin-1 beta(IL-l beta) and interleukin-1 alfa (IL-l alfa) mRNA expression were observed in macrophages cultured with 1 micro g/ml of Asp-hemolysin.

Animals↗

A novel retinoic acid-resistant acute promyelocytic leukemia model in vitro and in vivo (review).

Differentiation-inducing therapy by all-trans retinoic acid (RA) is now a standard therapy in patients with acute promyelocytic leukemia (APL). Nearly all patients achieve complete remission by the treatment of all-trans RA, however, clinical remissions are usually of brief duration, and these patients often develop RA-resistant disease. The mechanisms of RA-resistance in APL cells are poorly understood and most clinical approaches have not been successful in overcoming RA-resistance. We have recently established a novel APL cell line (UF-1) with RA-resistant features. In addition, we have established human GM-CSF-producing transgenic (hGMTg) SCID mice system. UF-1 cells were inoculated either intraperitoneally or subcutaneously into hGMTg SCID mice and made the first RA-resistant murine APL model. These RA-resistant APL model systems in vitro and in vivo may be useful for investigating the molecular studies on the block of leukemic cell differentiation and as means to investigate the mechanisms of RA-resistance. Moreover, this murine model system will be important for developing novel therapeutic strategies in RA-resistant APL.

Animals↗

[Intralobar pulmonary sequestration presenting increased serum CEA, CA 19-9, and CA 125, and associated with asymptomatic pulmonary aspergillosis].

A 44-year-old woman was admitted to our hospital for further evaluation of a consolidated shadow in the left lower lobe and the evaluation of serum tumor markers (CEA 46.3 ng/ml, CA 19-9 1911 U/ml, and CA 125 103 U/ml). Chest computed tomography revealed an irregular shaped, low density mass shadow in the left S10 region, suggesting the diagnosis of pulmonary sequestration or bronchial atresia. However digital subtraction angiography failed to demonstrate an anomalous feeding artery. We could not rule out the possibility that a malignant lesion was included in the consolidated shadow. A left thoracotomy revealed an intralobar pulmonary sequestration of the left lower lobe. Hyphae of aspergillus were found in the lumen of the cystic bronchus of the resected lung. Immunohistochemical studies showed strong expression of CEA, CA 19-9, and CA 125 by bronchial epithelia in the pulmonary sequenstration. The serum values of tumor markers returned to their normal ranges after surgery.

Adult↗