RESUMEN
Several recent studies have suggested that cancer stem cells (CSCs) are involved in resistance to gefitinib in non-small cell lung cancer (NSCLC). Oct4, a member of the POU-domain transcription factor family, has been shown to be involved in CSC properties of various cancers. We previously reported that Oct4 and the putative lung CSC marker CD133 were highly expressed in gefitinib-resistant persisters (GRPs) in NSCLC cells, and GRPs exhibited characteristic features of the CSCs phenotype. The aim of this study was to elucidate the role of Oct4 in the resistance to gefitinib in NSCLC cells with an activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9, which express the EGFR exon 19 deletion mutation, were transplanted into NOG mice, and were treated with gefitinib in vivo. After 14-17 days of gefitinib treatment, the tumors still remained; these tumors were referred to as gefitinib-resistant tumors (GRTs). PC9-GRTs showed higher expression of Oct4 and CD133. To investigate the role of Oct4 in the maintenance of gefitinib-resistant lung CSCs, we introduced the Oct4 gene into PC9 and HCC827 cells carrying an activating EGFR mutation by lentiviral infection. Transfection of Oct4 significantly increased CD133-positive GRPs and the number of sphere formation, reflecting the self-renewal activity, of PC9 and HCC827 cells under the high concentration of gefitinib in vitro. Furthermore, Oct4-overexpressing PC9 cells (PC9-Oct4) significantly formed tumors at 1 × 10 cells/injection in NOG mice as compared to control cells. In addition, PC9-Oct4 tumors were more resistant to gefitinib treatment as compared to control cells in vivo. Finally, immunohistochemical analysis revealed that Oct4 was highly expressed in tumor specimens of EGFR-mutant NSCLC patients with acquired resistance to gefitinib. Collectively, these findings suggest that Oct4 plays a pivotal role in the maintenance of lung CSCs resistant to gefitinib in EGFR mutation-positive NSCLC.
Asunto(s)
Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Resistencia a Antineoplásicos , Neoplasias Pulmonares/metabolismo , Células Madre Neoplásicas/citología , Factor 3 de Transcripción de Unión a Octámeros/fisiología , Quinazolinas/química , Antígeno AC133 , Animales , Antígenos CD/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Receptores ErbB/genética , Exones , Femenino , Gefitinib , Eliminación de Gen , Glicoproteínas/metabolismo , Humanos , Hipoxia , Inmunohistoquímica , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos NOD , Microscopía Fluorescente , Mutación , Trasplante de Neoplasias , Células Madre Neoplásicas/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Péptidos/metabolismo , Fenotipo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: The alteration of regional cerebral blood flow (rCBF) during wakefulness after the treatment for obstructive sleep apnea syndrome (OSA) using continuous positive airway pressure (CPAP) has not been elucidated. The aim of this study was to investigate rCBF characteristics and the effects of nasal CPAP in OSA patients. METHODS: Fifteen severe OSA patients (apnea-hypopnea index, 62.7 ± 22.4/h), when awake, underwent Technetium-99m ethyl cysteinate dimer single photon emission computed tomography before and after CPAP treatment, and the findings were compared to those of nine healthy controls matched for age and sex. RESULTS: Compared to controls, patients with OSA before CPAP treatment showed a significantly lower rCBF in the frontal lobe. After the treatment, no difference in rCBF was observed between the good CPAP compliance group and the controls. In the former group, there was a positive correlation between the 3% oxygen desaturation index on diagnostic polysomnogram and the increase of rCBF after CPAP treatment in the frontal lobe. CONCLUSIONS: When awake, patients with severe OSA were shown to have reversible decreases in rCBF, especially in the frontal lobe, and an appropriate CPAP treatment was thought to improve rCBF in this area. Our results support the importance of appropriate CPAP treatment for severe OSA patients.
Asunto(s)
Presión de las Vías Aéreas Positiva Contínua , Lóbulo Frontal/irrigación sanguínea , Apnea Obstructiva del Sueño/fisiopatología , Vigilia/fisiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Valores de Referencia , Flujo Sanguíneo Regional/fisiología , Apnea Obstructiva del Sueño/terapia , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Dendriform pulmonary ossification (DPO) is a rare condition characterized by heterotopic bone production of unknown origin within the pulmonary tissue. Many cases are asymptomatic with slow progression and are often diagnosed incidentally during autopsy. Thus, only few cases are diagnosed while the patient is still alive since surgical lung biopsy is often needed for pathological diagnosis. This is the case of a 37-year-old man treated at our hospital due to abnormal findings on chest x-ray without any symptoms. His high-resolution computed tomography revealed diffuse reticular shadows and micronodules, consistent with calcification. He underwent transbronchial lung cryobiopsy (TBLC) and was diagnosed with idiopathic DPO based on pathological findings. To our knowledge, this is the first reported case of DPO diagnosed using TBLC. TBLC can be a useful yet minimally invasive diagnostic tool to diagnose DPO and other interstitial lung diseases.
RESUMEN
We reviewed the clinicopathological characteristics of lung abscesses retrospectively. We analyzed 89 patients hospitalized from July 1984 to May 2009. Most were men (76/89). There were large proportions with alcohol consumption (29.2%) and dental caries or gingivitis (60.7%). Furthermore, those without other diseases accounted for only 13.5%. Predominant infectious species were clear in 43 cases (48.3%) including identification of bacteria. The identification rate of predominant bacteria improved from 38.5% to 56.0% after initiation of the introduction of expectoration culture, bronchoscopic specimen collection and gingival culture in 2003, facilitating clarification of the predominant bacteria. The Streptococcus anginosus group with predominant bacteria being slightly aerobic streptococci, anaerobic bacterium, and aerobic bacterium was detected in 10, 12, and 31 cases, respectively. The improvement in the identification rate of predominant bacteria was achieved by carrying out examination with close liaison with the staff of our inspection room. In selecting antimicrobials based on diagnostic significance, we should focus on positive identification of predominant bacteria, a factor which appears to have major clinical significance.
Asunto(s)
Absceso Pulmonar/microbiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bacterias Aerobias/aislamiento & purificación , Comorbilidad , Femenino , Humanos , Absceso Pulmonar/complicaciones , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Streptococcus anginosus/aislamiento & purificaciónRESUMEN
In a disease-state-dependent manner, the histamine-resistant itch in dry skin-based skin diseases such as atopic dermatitis (AD) and xerosis is mainly due to hyperinnervation in the epidermis. Semaphorin 3A (Sema3A) is a nerve repulsion factor expressed in keratinocytes and it suppresses nerve fiber elongation in the epidermis. Our previous studies have shown that Sema3A ointment inhibits epidermal hyperinnervation and scratching behavior and improves dermatitis scores in AD model mice. Therefore, we consider Sema3A as a key therapeutic target for improving histamine-resistant itch in AD and xerosis. This study was designed to screen a library of herbal plant extracts to discover compounds with potential to induce Sema3A in normal human epidermal keratinocytes (NHEKs) using a reporter gene assay, so that positive samples were found. Among the positive samples, only the extract of S. baicalensis was found to consistently increase Sema3A levels in cultured NHEKs in assays using quantitative real-time PCR and ELISA. In evaluation of reconstituted human epidermis models, the level of Sema3A protein in culture supernatants significantly increased by application of the extract of S. baicalensis. In addition, we investigated which components in the extract of S. baicalensis contributed to Sema3A induction and found that baicalin and baicalein markedly increased the relative luciferase activity, and that baicalein had higher induction activity than baicalin. Thus, these findings suggest that S. baicalensis extract and its compounds, baicalin and baicalein, may be promising candidates for improving histamine-resistant itch via the induction of Sema3A expression in epidermal keratinocytes.
Asunto(s)
Extractos Vegetales/química , Scutellaria baicalensis/química , Semaforina-3A/metabolismo , Línea Celular , Flavanonas/genética , Flavanonas/metabolismo , Flavonoides/genética , Flavonoides/metabolismo , Genes Reporteros , Humanos , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Modelos Biológicos , Extractos Vegetales/farmacología , ARN Mensajero/metabolismo , Scutellaria baicalensis/metabolismo , Semaforina-3A/genéticaRESUMEN
Lung to finger circulation time (LFCT) has been used to estimate cardiac function. We developed a new LFCT measurement device using a laser sensor at fingertip. We measured LFCT by measuring time from re-breathing after 20 s of breath hold to the nadir of the difference of transmitted red light and infrared light, which corresponds to percutaneous oxygen saturation. Fifty patients with heart failure were enrolled. The intrasubject stability of the measurement was assessed by the intraclass correlation coefficient (ICC). The ICC calculated from 44 cases was 0.85 (95% confidence interval: 0.77-0.91), which means to have "Excellent reliability." By measuring twice, at least one clear LFCT value was obtained in 89.1% of patients and the overall measurability was 95.7%. We conducted all LFCT measurements safely. High ICCs were obtained even after dividing patients according to age, cardiac index (CI); 0.85 and 0.84 (≥ 75 or < 75 years group, respectively), 0.81 and 0.84 (N = 26, ≥ or < 2.2 L/min/M2). These results show that our new method to measure LFCT is highly stable and feasible for any type of heart failure patients.
Asunto(s)
Tiempo de Circulación Sanguínea/métodos , Pruebas de Función Cardíaca/instrumentación , Pruebas de Función Cardíaca/métodos , Anciano , Contencion de la Respiración , Femenino , Dedos/irrigación sanguínea , Dedos/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Humanos , Rayos Láser , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Circulación Pulmonar , Reproducibilidad de los Resultados , RespiraciónRESUMEN
BACKGROUND: Zinc-finger E-box-binding homeobox 1 (ZEB1) is an important regulator of epithelial-mesenchymal transition (EMT) and is involved in the maintenance of cancer stem cells (CSCs) via miR-200c and BMI1 pathway. Recent studies revealed that ZEB1 contributes to the EMT-mediated acquired resistance to gefitinib in EGFR-mutant non-small cell lung cancer (NSCLC). However, the precise role of ZEB1 in the maintenance of lung CSCs that lead to acquired resistance to gefitinib remains unclear. METHODS: PC9 and HCC827 NSCLC cell lines were treated with high concentrations of gefitinib, and surviving cells were referred to as "gefitinib-resistant persisters" (GRPs). ZEB1 knockdown or overexpression was performed to determine the biological significance of ZEB1 in the CSC features of GRPs, and animal models were studied for in vivo validation. Expression of ZEB1, BMI1, and ALDH1A1 was analyzed by immunohistochemistry in tumor specimens from NSCLC patients with acquired resistance to gefitinib. RESULTS: GRPs had characteristic features of mesenchymal and CSC phenotypes with high expression of ZEB1 and BMI1, and decreased miR-200c, in vitro and in vivo. ZEB1 silencing attenuated the suppression of miR-200c, resulting in the reduction in BMI1 and reversed the mesenchymal and CSC features of GRPs. Furthermore, ZEB1 overexpression induced EMT and increased the levels of CD133- and BMI1-positive GRPs in vitro and gefitinib resistance in vivo. Finally, ZEB1, BMI1, and ALDH1A1 were highly expressed in tumor specimens from EGFR-mutant NSCLC patients with gefitinib resistance. CONCLUSIONS: ZEB1 plays an important role in gefitinib-resistant lung CSCs with EMT features via regulation of miR-200c and BMI1.
Asunto(s)
Gefitinib/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Femenino , Xenoinjertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos NOD , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
As timely measurement of the cardiac index (CI) is one of the key elements in heart failure management, a noninvasive, simple, and inexpensive method of estimating CI is keenly needed. We attempted to develop a new device that can estimate CI from the data of lung-to-finger circulation time (LFCT) obtained after a brief breath hold in the awake state. First, we attempted to estimate CI from the LFCT value by utilizing the correlation between 1/LFCT and CI estimated with MRI. Although we could obtain LFCT from 45 of 53 patients with cardiovascular diseases, we could not find the anticipated relation between 1/LFCT and CI. However, we realized that when we adopted only LFCT from patients with a finger temperature of ≥31°C, we could obtain a consistent and clear correlation with CI (correlation coefficient, r = .81). Thus, we next measured LFCT before and after warming the forearm. We found that LFCT decreased after the local temperature increased (from 27.5 ± 13.6 to 18.4 ± 5.3 s, p < 0.01). The correlation between the inverse of LFCT and CI improved after warming (1/LFCT vs. CI, from r = .69 to r = .82). The final Bland-Altman analysis between the measured and estimated CI values revealed that the bias and precision were -0.05 and 0.37 L min-1 m-2 , respectively, and the percentage error was 34.3%. This study clarified that estimating CI using a simple measurement of LFCT is feasible in most patients and a low fingertip temperature strongly affects the CI-1/LFCT relationship, causing an error that can be corrected by proper local warming.
Asunto(s)
Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/fisiopatología , Dedos/irrigación sanguínea , Pulmón/irrigación sanguínea , Adulto , Anciano , Anciano de 80 o más Años , Contencion de la Respiración , Gasto Cardíaco , Estudios de Casos y Controles , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Temperatura , Adulto JovenRESUMEN
Lysophosphatidylcholine (LPC) has diverse biological activities through different mechanisms including its conversion into other types of lipid mediators such as lysophosphatidic acid and 2-arachidonoylglycerol. Previously, we found that a large portion of the fluorescent analog of alkyl type LPC (Bodipy-lysoPAF) on porcine kidney epithelial cells (LLC-PK1) was degraded to monoalkylglycerol by lysophospholipase C-like activity and then quickly internalized into the cells. In this study, we investigated whether exogenous fluorescently labeled LPC (NBD-LPC) itself was also metabolized and internalized by a similar mechanism. LLC-PK1 cells converted NBD-LPC to either NBD-MG, possibly due to lysophospholipase C-like activity of ecto-nucleotide pyrophosphatase/phosphodiesterase-6, or to free fatty acid (FA), due to lysophospholipase activity in the culture medium at both sites. The resultant NBD-MG was further degraded to NBD-FA by lipase activity before or after its uptake into the cells, and a portion of NBD-FA was finally released into the culture medium on the opposite side.
Asunto(s)
Células Epiteliales/enzimología , Lisofosfolipasa/metabolismo , Lisofosfolípidos/metabolismo , Animales , Línea Celular , Riñón/citología , Espectrometría de Masas , Porcinos , Factores de TiempoRESUMEN
Systemic sclerosis (SSc) is an often fatal disease characterized by autoimmunity and inflammation, leading to widespread vasculopathy and fibrosis. Lysophosphatidic acid (LPA), a bioactive phospholipid in serum, is generated from lysophospholipids secreted from activated platelets in part by the action of lysophospholipase D (lysoPLD). Sphingosine 1-phosphate (S1P), a member of the bioactive lysophospholipid family, is also released from activated platelets. Because activated platelets are a hallmark of SSc, we wanted to determine whether subjects with SSc have altered serum lysophospholipid levels or lysoPLD activity. Lysophospholipid levels were measured using mass spectrometric analysis. LysoPLD activity was determined by quantifying choline released from exogenous lysophosphatidylcholine (LPC). The major results were that serum levels of arachidonoyl (20:4)-LPA and S1P were significantly higher in SSc subjects versus controls. Furthermore, serum LPA:LPC ratios of two different polyunsaturated phospholipid molecular species, and also the ratio of all species combined, were significantly higher in SSc subjects versus controls. No significant differences were found between other lysophospholipid levels or lysoPLD activities. Elevated 20:4 LPA, S1P levels and polyunsaturated LPA:LPC ratios may be markers for and/or play a significant role in the etiology of SSc and may be future pharmacological targets for SSc treatment.
Asunto(s)
Lisofosfolípidos/sangre , Hidrolasas Diéster Fosfóricas/sangre , Esclerodermia Sistémica/sangre , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , Esclerodermia Sistémica/inmunología , Esfingosina/análogos & derivados , Esfingosina/sangre , Adulto JovenRESUMEN
BACKGROUND: Loxoprofen is a nonsteroidal anti-inflammatory drug used in the treatment of many diseases. However, there are no case reports about loxoprofen-induced pneumonia. We have encountered a rare case of loxoprofen-induced pneumonia. CASE PRESENTATION: We report the case of a 71-year-old Japanese woman who was initially treated with loxoprofen for fever. She was admitted to our hospital because of worsening of her symptoms, including fever and dyspnea. Her symptoms improved after treatment with ceftriaxone. Seven days after admission, she again developed high fever. She was again treated with loxoprofen and levofloxacin. However, acute respiratory failure developed after initiation of loxoprofen treatment. Chest computed tomography showed peribronchovascular consolidation. She was diagnosed with loxoprofen-induced pneumonia for which she was administered steroids. After treatment, her dyspnea and radiological findings improved. CONCLUSIONS: The findings in this case report reveal an association between treatment with a nonsteroidal anti-inflammatory drug and pneumonia. This rare case was diagnosed after accidental retreatment with loxoprofen. This is the first report of loxoprofen-induced pneumonia.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Enfermedades Pulmonares Intersticiales/inducido químicamente , Fenilpropionatos/efectos adversos , Anciano , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Radiografía Torácica , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been successfully used to treat patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, despite an initial excellent response, recurrence within one or two years is common. Diagnosis and treatment of leptomeningeal metastasis (LM), a form of NSCLC recurrence, remains particularly difficult. Here, we analyzed the EGFR mutation status of cerebrospinal fluid (CSF) directly using real-time polymerase chain reaction (PCR) and evaluated the efficacy of therapy with erlotinib, an EGFR TKI. PATIENTS AND METHODS: Seven NSCLC patients harboring activating EGFR mutations who had developed LM during or after therapy with gefitinib, an EGFR TKI, were retrospectively analyzed. CSF was obtained and subjected to cytological examination and EGFR mutation analysis, including detection of the resistance-associated T790M mutation, using real-time PCR. RESULTS: In all seven cases, the EGFR mutation detected in the CSF was the same as that detected in the primary tumor (sensitivity, 100%). Conversely, cytology results were positive in only two patients (sensitivity, 28.6%). No additional T790M mutations were detected. Erlotinib was efficacious in all cases, and improved performance status was achieved for five of the seven patients. The effect of erlotinib treatment was temporary, however, with time to treatment failure (TTF) ranging from 29 to 278 days (median, 65 days) and the interval between commencement of erlotinib treatment and death ranging from 45 to 347 days (median, 168 days). CONCLUSIONS: Analysis of EGFR mutations in CSF using a highly sensitive real-time PCR assay is a potentially powerful diagnostic method for LM.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Meníngeas/secundario , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/secundario , Análisis Mutacional de ADN , Receptores ErbB/líquido cefalorraquídeo , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Gefitinib , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Factores de Tiempo , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Th1 stimulus for Th2-skewed immune response during infancy is important for reduction of incidence of allergic diseases. We examined effects of oral administration of bovine colostrum on local immunity in intestine in adult mice. C57BL/6 mice were orally given bovine colostrum or control milk for 1, 3 or 6 months and intestinal microflora, fecal IgA, and lymphocyte population of gut-associated lymphoid tissues and their abilities of cytokine production were examined. Although the cell populations of intestinal intraepithelial lymphocytes (i-IEL) were not remarkably changed, the T cells in i-IEL were polarized to Th1 type after oral administration of bovine colostrum. Intestinal microflora and IgA levels in feces were not changed by oral administration of bovine colostrum. These results suggest that colostrum stimulates directly to i-IEL to polarize Th1 type, which may protect from infectious diseases and allergic diseases mediated by Th2 type responses.
Asunto(s)
Calostro/inmunología , Intestinos/inmunología , Linfocitos/inmunología , Células TH1/inmunología , Administración Oral , Animales , Antígenos CD/análisis , Bacterias/aislamiento & purificación , Bovinos , Citocinas/metabolismo , Heces/química , Femenino , Citometría de Flujo , Inmunoglobulina A/análisis , Inmunofenotipificación , Intestinos/citología , Intestinos/microbiología , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Ratones , Ratones Endogámicos C57BL , Embarazo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Two Japanese brothers were diagnosed in their 20s with familial pulmonary fibrosis, the pathological findings of which were consistent with usual interstitial pneumonia (UIP). However, an atypical characteristic was observed in the lungs of these brothers; 2-mm areas of 'honeycomb' were identified throughout the lungs, which is smaller than the generally observed 5-10 mm honeycombing seen in UIP. Fibroblastic foci were demonstrated in the second eldest brother, but not in the eldest, which indicates that the lungs of the eldest brother was in a more advanced stage of fibrosis. Their youngest brother and parents have no clinical evidence of pulmonary fibrosis. All five family members had low values for the diffusion capacity of the lung for carbon monoxide (DLCO), suggesting the presence of an inheritable disease and the existence of different phenotypes. The genomic DNA of the affected brothers was sequenced for the reported surfactant protein C (SP-C) gene mutations in patients with familial pulmonary fibrosis, but none was documented. It is necessary to clarify the presence of novel gene mutations of SP-C or other genes to explain these particular pathological findings and the low DLCO observed in this family.
Asunto(s)
Predisposición Genética a la Enfermedad , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/patología , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patología , Adulto , Monóxido de Carbono/metabolismo , Consanguinidad , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/metabolismo , Masculino , Linaje , Capacidad de Difusión Pulmonar , Fibrosis Pulmonar/metabolismo , Proteína C Asociada a Surfactante Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/metabolismo , Radiografía Torácica , HermanosRESUMEN
An asymptomatic patient with exogenous lipoid pneumonia (ELP) due to silent aspiration of liquid paraffin ingested as a lubricant was diagnosed by bronchoalveolar lavage (BAL). BAL fluid separated into oily upper phase and lower aqueous phase spontaneously. Microscopic analysis of BAL cells revealed the presence of lipid-laden alveolar macrophages. Classic histochemical staining and electron microscope examination indicated that neutral lipid was dominant but phospholipid was also present in the lipid-laden macrophages. Together with the history of ingestion of liquid paraffin, we identified that the ingested liquid paraffin was the origin of the neutral lipid in the lipid-laden macrophages observed in the BAL fluid.
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Macrófagos Alveolares/ultraestructura , Parafina/efectos adversos , Neumonía Lipoidea/etiología , Soluciones Esclerosantes/efectos adversos , Adulto , Líquido del Lavado Bronquioalveolar , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Microscopía Electrónica , Neumonía Lipoidea/diagnóstico por imagen , Neumonía Lipoidea/patología , Radiografía Torácica , Tomografía Computarizada por Rayos XRESUMEN
Previous studies have shown a high prevalence of obstructive sleep apnea (OSA) among patients with Alzheimer's disease (AD). However, it is poorly assessed whether chronic intermittent hypoxia (CIH), which is a characteristic of OSA, affects the pathophysiology of AD. We aimed to investigate the direct effect of intermittent hypoxia (IH) in pathophysiology of AD in vivo and in vitro. In vivo, 15 male triple transgenic AD mice were exposed to either CIH or normoxia (5% O2 and 21% O2 every 10 min, 8 h/day for 4 weeks). Amyloid-ß (Aß) profile, cognitive brain function, and brain pathology were evaluated. In vitro, human neuroblastoma SH-SY5Y cells stably expressing wild-type amyloid-ß protein precursor were exposed to either IH (8 cycles of 1% O2 for 10 min followed by 21% O2 for 20 min) or normoxia. The Aß profile in the conditioned medium was analyzed. CIH significantly increased levels of Aß42 but not Aß40 in the brains of mice without the increase in hypoxia-inducible factor 1, alpha subunit (HIF-1α) expression. Furthermore, CIH significantly increased intracellular Aß in the brain cortex. There were no significant changes in cognitive function. IH significantly increased levels of Aß42 in the medium of SH-SY5Y cells without the increase in the HIF-1α expression. CIH directly and selectively increased levels of Aß42 in the AD model. Our results suggest that OSA would aggravate AD. Early detection and intervention of OSA in AD may help to alleviate the progression of the disease.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Oxigenoterapia Hiperbárica , Hipoxia/metabolismo , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Línea Celular Tumoral , Trastornos del Conocimiento/etiología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuroblastoma/patologíaRESUMEN
BACKGROUND: Recently, driver oncogenes in adenocarcinoma of the lung were identified, and several molecular target agents were introduced in the clinical setting. However, there are few reports on the frequency of gene abnormalities in young patients with lung cancer. MATERIALS AND METHODS: Twelve patients with lung adenocarcinoma aged 40 or younger at Juntendo University Urayasu Hospital or Juntendo University Hospital from July 2004 to March 2010 were analyzed for driver oncogene status including EGFR activating mutation, EML4-ALK fusion gene, and K-ras mutation. RESULTS: Four patients showed EGFR gene mutation. Five out of 7 EGFR mutation-negative patients showed positive results for EML4-ALK gene fusion. One case whose EGFR mutation was indeterminate. CONCLUSIONS: Driver oncogene including EGFR mutation and EML4-ALK fusion gene was identified in 9 of 12 cases (75%). Examination of gene abnormalities is essential in young patients with non-small cell lung cancer to provide the best treatment.
RESUMEN
The extract of cultured Lentinula edodes mycelia (LEM) is a medicinal food ingredient that has hepatoprotective effects. In this study, we fractionated the LEM extract to explore novel active compounds related to hepatoprotection by using primary cultures of rat hepatocytes exposed to carbon tetrachloride (CCl(4)). The LEM extract and the fractions markedly inhibited the release of alanine aminotransferase (ALT) from hepatocytes damaged by CCl(4) into the culture medium. The strongest hepatocyte-protective activity was seen in a fraction (Fr. 2) in which a 50% ethanol extract was further eluted with 50% methanol and separated using reverse-phase HPLC. Fr. 2 had an average molecular weight of 2753, and the main components are lignin (49%) and saccharides (36%, of which xylose comprises 41%). Therefore, Fr. 2 was presumed to be a low-molecular-weight compound consisting mainly of lignin and xylan-like polysaccharides. The hepatocyte-protective activity was observed even after digestion of xylan-like polysaccharides in Fr.2 and confirmed with low-molecular-weight lignin (LM-lignin) alone. In addition, Fr. 2, the xylan-digested Fr. 2 and LM-lignin showed higher superoxide dismutase (SOD)-like activity than the LEM extract. These results suggested that the effective fraction in the LEM extract related to hepatocyte protection consisted mainly of LM-lignin, and its antioxidant activity partially contributes to the hepatocyte-protective activity of the LEM extract.
Asunto(s)
Antioxidantes/farmacología , Tetracloruro de Carbono/toxicidad , Hepatocitos/efectos de los fármacos , Lignina/farmacología , Hongos Shiitake , Alanina Transaminasa/metabolismo , Animales , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Biomarcadores/metabolismo , Células Cultivadas , Fraccionamiento Químico , Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Citoprotección , Etanol/química , Hepatocitos/enzimología , Hepatocitos/patología , Lignina/química , Lignina/aislamiento & purificación , Masculino , Metanol/química , Peso Molecular , Ratas , Ratas Sprague-Dawley , Hongos Shiitake/química , Solventes/química , Superóxido Dismutasa/metabolismoRESUMEN
The L/N-type calcium channel blocker cilnidipine has unique effects including sympathetic nerve suppression and the balanced vasodilatation of arteries and veins that may alleviate morning hypertension (MHT) or peripheral edema caused by calcium channel antagonists. We used ambulatory blood pressure monitoring (ABPM) and a unique peripheral edema measurement to evaluate the effect of morning and bedtime cilnidipine in patients with MHT. Forty-three patients with MHT (60 ± 12 years) were randomly assigned to a morning or bedtime cilnidipine (10-20 mg/day). MHT was defined as a mean systolic blood pressure (SBP) ≥ 135 mm Hg by ABPM within 2 hours after awaking. After 3 months, greater SBP reductions were observed in the bedtime administration group (versus the morning administration group) at 3:30-6:00 AM (-24 ± 20 mm Hg vs. -10 ± 4 mm Hg; P < .05) and at 6:30-9:00 AM (-26 ± 15 mm Hg vs. -14 ± 17 mm Hg; P < .05). Although physical examinations showed leg edema in 16% of the patients, quantitative evaluations did not reveal significant volume gains. Cilnidipine had a greater effect on MHT, without causing significant leg edema, when administered at bedtime.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/farmacología , Edema/prevención & control , Anciano , Monitoreo Ambulatorio de la Presión Arterial , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/complicaciones , Hipertensión/prevención & control , Pierna , Masculino , Persona de Mediana Edad , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
To evaluate the toxicological safety of extract from cultured Lentinula edodes mycelia (L.E.M.), repeated doses (2,000 mg/kg/day) were administered to male and female Wistar rats for 28 days. No mortality or abnormality in the general status or appearance was observed in rats administered L.E.M extract. Body weight and food consumption decreased slightly, particularly in the case of male rats, although the degree of decrease was not as prominent toward the end of administration. Examination of hematology, serum biochemistry, absolute and relative organ weights, autopsy and histopathology revealed only a few statistically significant differences between the treatment and control groups; these differences suggested no clinically significant changes related to toxicity. Consequently, the no observed adverse effect level (NOAEL) of L.E.M. extract was considered to be more than 2,000 mg/kg/day under the conditions of the present study.