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Biomedical subjects

Atsushi Nagai

Publications and source records attributed to Atsushi Nagai.

At least 19 recordsLinked to original sources
PubMed2006

Alveolar cell senescence in patients with pulmonary emphysema.

RATIONALE AND OBJECTIVES: The prevalence of chronic obstructive pulmonary disease (COPD) is age-dependent, suggesting an intimate relationship between the pathogenesis of COPD and aging. In this study we investigated whether the senescence of alveolar epithelial and endothelial cells is accelerated in emphysematous lungs. METHODS: Samples of lung tissue were obtained from patients with emphysema, asymptomatic smokers, and asymptomatic nonsmokers. Paraffin-embedded lung tissue sections were evaluated for cellular senescence by quantitative fluorescence in situ hybridization to assess telomere shortening, and by immunohistochemistry to assess the expression of senescence-associated cyclin-dependent kinase inhibitors. Tissue sections were also immunostained for proliferating cell nuclear antigen (PCNA), surfactant protein A, and CD31. MAIN RESULTS: The patients with emphysema had significantly higher percentages of type II cells positive for p16INK4a and p21CIP1/WAF1/Sdi1 than the asymptomatic smokers and nonsmokers. They had also significantly higher percentages of endothelial cells positive for p16INK4a than the asymptomatic smokers and nonsmokers, and higher percentages of endothelial cells positive for p21CIP1/WAF1/Sdi1 than the asymptomatic nonsmokers. Telomere length in alveolar type II cells and endothelial cells was significantly shorter in the patients with emphysema than in the asymptomatic nonsmokers. The level of p16INK4a expression was negatively correlated with the level of PCNA expression. The level of alveolar cell senescence was positively correlated with airflow limitation. CONCLUSIONS: These results suggest that the senescence of alveolar epithelial and endothelial cells is accelerated in patients with emphysema. Cellular senescence may explain the abnormal cell turnover that promotes the loss of alveolar cells in emphysematous lungs.

Cell Proliferation↗
PubMed2006

Oxidative stress increases Fas ligand expression in endothelial cells.

BACKGROUND: Fas ligand (FasL) induces apoptosis in Fas-bearing target cells, such as leukocytes, and up-regulation of FasL expression on the endothelium may contribute to anti-inflammatory reactions that attenuate leukocyte extravasation during inflammation. Since oxidants generated during inflammation and cigarette smoking may modulate endothelial function, we examined the effect of H2O2 and cigarette smoke on endothelial FasL expression. METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to nontoxic concentrations of H2O2 and cigarette smoke extracts (CSE). Membrane FasL expression was assessed by immunostaining with anti-FasL antibody followed by either monolayer-cell-based spectrofluorimetry or flow cytometry. Soluble FasL in culture supernatants was measured by enzyme-linked immunosorbent assay. For the cytotoxic assay, HUVECs were exposed to H2O2 and co-cultured with neutrophils. Neutrophils were stained by a peroxidase/diaminobenzidine-based reaction, and apoptosis was evaluated on the basis of nuclear morphology after Giemsa staining. To analyze in vitro FasL expression in arteries, rat thoracic aortas were incubated with H2O2, and paraffin-embedded sections were prepared for immunohistochemistry with anti-FasL antibody. RESULTS: Exposure of HUVECs to H2O2 dose-dependently increased their levels of both membrane and soluble forms of FasL expression. CSE exposure also caused increased levels of FasL expression, but the increase was partially inhibited by the addition of catalase. When co-cultured with neutrophils, HUVECs exposed to H2O2 significantly promoted neutrophil apoptosis. Rat thoracic aortas incubated with H2O2 exhibited increased FasL expression on their endothelium. CONCLUSION: Low levels of oxidative stress increase FasL expression on endothelial cells, thereby potentially reducing leukocyte extravasation and tissue damage.

Journal Article↗
PubMed2006

Macrophage colony-stimulating factor aggravates rather than regenerates emphysematous lungs in mice.

BACKGROUND: Lung regeneration is an innovative strategy that may cure pulmonary emphysema. The bone marrow (BM) harbors pulmonary stem cells. Hematopoietic cytokine-driven mobilization of BM cells may thus support lung regeneration. OBJECTIVES: The aim of this study was to determine whether systemic administration of macrophage colony-stimulating factor (M-CSF) leads to the regeneration of lungs in a murine model of elastase-induced emphysema. METHODS: C57BL/6J mice were administered elastase intratracheally. Four weeks later, in the absence or presence of elastase treatment, mice were intraperitoneally given either M-CSF or saline on days 1-5 each week for 3 weeks. Lung tissue was harvested 24 h after the last injection. RESULTS: M-CSF administration without prior elastase did not affect the mean linear intercept, surface area, or surface area/lung volume. In contrast, M-CSF administration following elastase injury caused a greater increase in the mean linear intercept and greater decreases in surface area and surface area/lung volume than saline administration following elastase, indicating that M-CSF aggravated emphysema. This aggravation of emphysema was accompanied by accumulation of pulmonary alveolar macrophages (AMs) expressing metalloproteinase (MMP)-9 and MMP-12. M-CSF stimulated AMs to express MMPs in vitro. CONCLUSIONS: These results suggest that M-CSF administration does not support lung regeneration but rather aggravates the lung destruction associated with elastase injury.

Animals↗
PubMed2006

Somatosensory disinhibition and frontal alien hand signs following medial frontal damage.

We report augmentation of somatosensory evoked potentials (SEP) in a patient with frontal alien hand signs after left medial frontal lobe damage. The SEP components occurring later than 30 msec post stimuli were enhanced over the parietal and frontal scalp sites of the lesioned hemisphere. This finding suggests that deficits in inhibitory control of somatosensory processing in parietal and frontal lobes contributes in some way to frontal alien hand signs.

Aged, 80 and over↗
PubMed2006

C-reactive protein products generated by neutrophil elastase promote neutrophil apoptosis.

BACKGROUND: C-reactive protein (CRP), a prototypical acute phase protein, is increased as much as 1000-fold during acute inflammation, suggesting its biological role in that process. CRP can be modified at sites of inflammation where proteases have been released by neutrophils migrating to tissues. In this study, we investigated whether native CRP and neutrophil elastase-digested products of CRP modulate the rate of neutrophil apoptosis. METHODS: Neutrophils were isolated from venous blood of healthy volunteers and incubated with either native CRP (1, 10, or 30 microg/mL) or CRP digested with neutrophil elastase (1 U/mL). After 6 and 24 h of incubation, neutrophils were harvested and examined for apoptosis under light microscopy. RESULTS: We found that CRP degradation products generated by neutrophil elastase, but not native CRP, promoted neutrophil apoptosis and cell death. The rate of apoptosis was not affected by the addition of elastase that was not incubated with CRP. CONCLUSIONS: These results suggest that CRP degradation products generated by neutrophil elastase promote neutrophil apoptosis. Cleavage of CRP by neutrophil elastase may offer protection from inflammatory injury.

Apoptosis↗
PubMed2006

Penile reconstruction with bilateral superficial circumflex iliac artery perforator (SCIP) flaps.

The free radial forearm flap is a very common material for penile reconstruction. Its major problems are donor-site morbidity with large depressive scar after skin grafting, urethral fistula due to insufficiency of suture line for the urethra, and need for microvascular anastomosis. A new method using combined bilateral island SCIP flaps for the urethra and penis is developed for gender identity disorder (GID) patients. The advantages of this method are minimal donor-site morbidity with a concealed donor scar, and possible one-stage reconstruction for a longer urethra of 22 cm in length without insufficiency, even for GID female-to-male patients. A disadvantage is poor sensory recovery.

Adult↗
PubMed2006

Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase.

In the present study, we investigated the expression of protease-activated receptors (PARs), receptors for thrombin, in substantia nigra pars compacta (SNpc) of Parkinson disease (PD) brains and cultures of human neurons, astrocytes, oligodendrocytes, and microglia as determined by immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of PAR-1 was demonstrated only in glial fibrillary acidic protein-positive astrocytes in SNpc, and the number of astrocytes expressing PAR-1 increased in SNpc of PD as compared with nonneurologic control brain. Immunoreactivity for thrombin and prothrombin was stronger in astrocytes and the vessel walls in SNpc of PD brains. PAR-1 was expressed in human astrocytes and neurons, but not in oligodendrocytes or microglia as determined by RT-PCR. We investigated thrombin-mediated activation of human astrocytes. Thrombin treatment activates human astrocytes and induces morphologic change and a marked increase in proliferation of astrocytes. Increased expression of glial cell line-derived growth factor and glutathione peroxidase (GPx) but no change in the expression of nerve growth factor and inflammatory cytokines/chemokine (IL-1beta, IL-6, IL-8, MCP-1) was found in thrombin/PAR-activated astrocytes. Next, we studied the neuroprotective effect exerted by thrombin-activated astrocytes in human cerebral neuron x human neuroblastoma hybrid neurons. Although thrombin showed neurotoxicity against human hybrid neurons in a dose-dependent manner, the conditioned media derived from thrombin-pretreated astrocyte cultures promoted the survival of human hybrid neurons. The protective effect was completely inhibited with a GPx inhibitor, mercaptosuccinic acid, indicating that GPx released from thrombin/PAR-activated astrocytes is responsible for neuroprotection of hybrid neurons against thrombin cytotoxicity. The present study suggests that the increased expression of PAR-1 in astrocytes in SNpc of PD brain is the restorative move taken by the brain to provide neuroprotection against neuronal degeneration and cell death of dopaminergic neurons caused by noxious insults during the progression of PD pathology.

Aged↗
PubMed2006

Transbronchial needle aspiration cytology of subcarinal lymph nodes for the staging procedure in the diagnosis of lung cancer.

OBJECTIVE AND BACKGROUND: The aim of this study was to improve the staging of lung cancer with or without lymphadenopathy on chest CT by using transbronchial aspiration cytology (TBAC). METHODS: TBAC of the subcarinal lymph nodes was performed on 153 consecutive patients with lung cancer, with or without subcarinal lymphadenopathy on chest CT. RESULTS: Thirty-four patients had enlargement of the subcarinal lymph nodes (>1 cm). Eighteen of these had TBAC confirmation of metastases. Another seven patients with no mediastinal involvement on CT were positive for metastases on TBAC. TBAC was the only way to confirm lung cancer in two patients. Therefore, routinely performed subcarinal TBAC contributed to an improved non-operative staging of the patients and diagnosis in 16% (25/153) of the patients with lung cancer. Forty-nine patients with NSCLC had surgical resection of the tumour. Surgical procedure revealed metastases to the subcarinal lymph nodes in three patients in whom the preoperative TBAC diagnosis was normal. No significant complications due to TBAC occurred in any of the patients. CONCLUSION: TBAC of the subcarinal lymph nodes is a minimally invasive technique for staging of lung cancer and can provide useful information for the diagnosis of metastases to the subcarinal lymph nodes.

Biopsy, Fine-Needle↗
PubMed2006

Combination chemotherapy with estramustine phosphate, ifosfamide and cisplatin for hormone-refractory prostate cancer.

We evaluated the efficiency and toxicity of estramustine phosphate (ECT), ifosfamide (IFM) and cisplatin (CDDP) combination chemotherapy in twenty-one patients with hormone-refractory prostate cancer (HRPC), for which there is currently no effective treatment. Patients received a daily dose of 560 mg ECT in combination with 1.2 g/m2 IFM on days 1 to 5 and 70 mg/m2 CDDP on day 1. This combination therapy was given every 3 to 4 weeks. An objective response of more than 50% reduction in prostate-specific antigen was observed in 9 of 18 patients (50%), and a more than 50% reduction in bi-dimensionally measurable soft-tissue lesions was observed in 2 of 7 patients (29%). The median duration of response among the cases showing partial response was 40 weeks, while the median duration of response of overall partial-response plus stable cases was 30 weeks. The median survival duration of all cases was 47 weeks. Toxicity was modest and acceptable. In conclusion, the ECT, IFM and CDDP combination chemotherapy regimen is a viable treatment option for HRPC. However, in comparison with our previous chemotherapy regimen of IFM and CDDP, no additional long-lasting effects resulting from the inclusion of ECT could be affirmed.

Adult↗
PubMed2006

Elimination of IL-13 reverses established goblet cell metaplasia into ciliated epithelia in airway epithelial cell culture.

BACKGROUND: Interleukin (IL)-13 induces goblet cell metaplasia and plays an important role in mucus hypersecretion in asthma. We previously reported that IL-13 induced goblet cell differentiation along with less ciliated cell differentiation in guinea pig tracheal epithelial cells in vitro. In this study, we asked whether elimination of IL-13 could reverse the established goblet cell metaplasia into ciliated epithelia. METHODS: Primary epithelial cells from guinea pig tracheas were cultured at an air-liquid interface with the medium containing human recombinant IL-13 for 14 days, and continuously cultured with IL-13-eliminated medium, or cultured under the condition of neutralization of IL-13 with anti IL-13 antibody. RESULTS: 2 days after elimination of IL-13, the periodic acid-Schiff-positive area as well as MUC5AC protein level rapidly decreased. After 4 days, the number of goblet cells dramatically decreased, while that of ciliated cells inversely increased. The total number of epithelial cells did not change, and 5-bromo-2'-deoxyuridine uptake decreased after IL-13 elimination. Transitional cells with cilia and secretory granules increased after IL-13 elimination. Similarly, the neutralization of IL-13 with anti-IL-13 antibody for 5 days reversed the goblet cell metaplasia into ciliated epithelia, and transitional cells also increased. CONCLUSIONS: Elimination of IL-13 reverses goblet cell metaplasia into ciliated epithelia in vitro, and transition of goblet cells to other phenotypes, especially ciliated cells, may be involved in this phenomenon. IL-13 inhibition may be a therapeutic strategy of established goblet cell metaplasia in asthma.

Animals↗
PubMed2006

Hepsin shows inhibitory effects through apoptotic pathway on ovarian cancer cell lines.

In light of the poor prognosis for ovarian cancer patients, the research continues for innovative and efficacious treatment modalities. Along with surgical and chemotherapeutic regimens, gene therapy has emerged as one of the leading contenders in the treatment armamentarium. Hepsin is a type II transmembrane serine protease originally identified in the human liver as a cDNA clone. However, the biological function of Hepsin expression remains unclear. Apoptotic cell was increasingly common among higher proportions of Hepsin transfectants. We discovered that first-time stable transfectants of Hepsin significantly inhibited cell growth in the monolayer, anchorage-independent cell growth in the soft agar in vitro, and tumorigenicity in vivo in ovarian cancer cell lines. These results demonstrated that Hepsin has a potential therapeutic effect that inhibits through up-regulation of p53-dependent apoptosis and caspase-3, -6, and -7 activations. Our findings in this study identify Hepsin as a target for new approaches in ovarian cancer treatment.

Animals↗
PubMed2006

Accuracy of PET for diagnosis of solid pulmonary lesions with 18F-FDG uptake below the standardized uptake value of 2.5.

UNLABELLED: Benign and malignant pulmonary lesions usually are differentiated by 18F-FDG PET with a semiquantitative 18F-FDG standardized uptake value (SUV) of 2.5. However, the frequency of malignancies with an SUV of <2.5 is significant, and pulmonary nodules with low 18F-FDG uptake often present diagnostic challenges. METHODS: Among 360 consecutive patients who underwent 18F-FDG PET to evaluate pulmonary nodules found on CT, we retrospectively analyzed 43 who had solid pulmonary lesions (excluding lesions with ground-glass opacity, infiltration, or benign calcification) with an SUV of <2.5. The uptake of 18F-FDG was graded by a visual method (absent, faint, moderate, or intense) and 2 semiquantitative methods (SUV and contrast ratio [CR]). Final classification was based on histopathologic findings or at least 6 mo of clinical follow-up. RESULTS: We found 16 malignant (diameter, 8-32 mm) and 27 benign (7-36 mm) lesions. When faint visual uptake was the cutoff for positive 18F-FDG PET results, the receiver-operating-characteristic (ROC) analysis correctly identified all 16 malignancies and yielded false-positive results for 10 of 27 benign lesions. Sensitivity was 100%, specificity was 63%, and the positive and negative predictive values were 62% and 100%, respectively. When an SUV of 1.59 was the cutoff for positive 18F-FDG PET results, the ROC analysis revealed 81% sensitivity, 85% specificity, and positive and negative predictive values of 77% and 89%, respectively. At a cutoff for positive 18F-FDG PET results of a CR of 0.29, the ROC analysis revealed 75% sensitivity, 82% specificity, and positive and negative predictive values of 71% and 85%, respectively. The areas under the curve in ROC analyses did not differ significantly among the 3 analyses (visual, 0.84; SUV, 0.81; and CR, 0.82). Analyses of intra- and interobserver variabilities indicated that visual and SUV analyses were quite reproducible, whereas CR analysis was poorly reproducible. CONCLUSION: These results suggested that for solid pulmonary lesions with low 18F-FDG uptake, semiquantitative approaches do not improve the accuracy of 18F-FDG PET over that obtained with visual analysis. Pulmonary lesions with visually absent uptake indicate that the probability of malignancies is very low. In contrast, the probability of malignancy in any visually evident lesion is about 60%.

Adult↗
PubMed2006

[Clinical characteristics and prognosis in stroke patients with diabetes mellitus: retrospective evaluation using the Japanese Standard Stroke Registry database (JSSRS)].

We studied clinical characteristics and prognosis in acute stoke patients with diabetes mellitus registered on the Japanese Standard Stroke Registry database. A total of 16,630 acute stroke patients admitted to 56 hospitals in Japan. They were examined as to their stroke types, risk factors, their severity of stroke according to the NIH Stroke Scale (NIHSS) and Japan Stroke Scale (JSS), and outcomes by the modified Rankin Scale (m-RS). The incidence of subarachnoid hemorrhage was relatively high in the group of patients who had neither hypertension nor diabetes, and the incidence of brain hemorrhage was higher in the group of patients who had hypertension without diabetes. The frequencies of lacunar infarct and atherothrombotic infarct were also higher in the group of patients who had both hypertension and diabetes. In the diabetic group without hypertension, there were less numbers of hemorrhagic stroke. The ratio of good prognosis (m-RS 0-1) was significantly smaller in the diabetic patients with lacunar infarction, cardioembolic infarction, and subarachnoid hemorrhage. Additionally, there was significantly more stroke recurrence in the diabetic patients (33.0% vs. 26.9%, p<0.0001). The diabetic patients who received insulin therapy (-0.8 +/- 7.4), diet therapy (-0.4 +/- 9.4), or oral medicine (-0.9 +/- 7.2), showed significantly less improvements in the NIHSS compared to the non-diabetic patients (-1.6 +/- 8.2), respectively. Moreover, the poor-management diabetic patients showed significantly less improvements in the JSS compared to non diabetic patients (3.8 +/- 7.7 vs. 4.8 +/- 8.6, p<0.005). In conclusions, stroke patients with diabetes mellitus showed more stroke recurrence and resulted in poorer functional recovery compared to patients without diabetes.

Aged↗
PubMed2006

[A case of angioimmunoblastic T-cell lymphoma with interstitial shadow which disappeared after injection of hydrocortisone].

A case of angioimmunoblastic T-cell lymphoma (AITL) was reported. A 56-year-old woman was admitted because of high fever and systemic lymphademopathy. Her chest X-ray on admission showed mediastinal and bilateral hilar lymphademopathy (BHL) and interstitial shadows in both lower lung fields. Chest CT scan revealed thickening of interlobular septum and bronchovascular bundles. There was a remarkable elevation in serum soluble interleukin-2 receptor. A biopsy of cervical lymph nodes for histopathological examination revealed AITL. After intravenous injection of 200mg of hydrocortisone for 7 days, the interstitial shadows and BHL disappeared. It was suspected that interstitial shadow was caused by pulmonary infiltration of AITL.

Anti-Inflammatory Agents↗
PubMed2005

Neuronal cell death induced by cystatin C in vivo and in cultured human CNS neurons is inhibited with cathepsin B.

Cystatin C, a cysteine protease inhibitor, is implicated in pathogenesis of late-onset Alzheimer's disease and other neurological disorders. Our recent study showed that cystatin C injection into rat hippocampus induced neuronal cell death in granule cell layer of dentate gyrus in vivo. We further confirmed that cystatin C neurotoxicity was inhibited by simultaneous coapplication of cathepsin B, a cysteine protease. In vitro cytotoxicity was also studied in cultures of human CNS neurons, mixed cultures with astrocytes and A1 human hybrid neurons. Cystatin C induced neuronal cell death in a dose-dependent manner, which accompanied increased number of TUNEL (+) cells, up-regulation of active caspase-3 and DNA ladder. The results of the present study indicate that cystatin C participates in the process of apoptotic neuronal cell death in experimental conditions by means of inhibitory activity of cysteine proteases, and that cystatin C might be involved in the pathogenesis in human neurological disorders including Alzheimer's disease.

Animals↗