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BACKGROUND: The self-reporting of asthma frequently leads to patient misidentification in epidemiological studies. Strategies combining the triangulation of data sources may help to improve the identification of people with asthma. We aimed to combine information from the self-reporting of asthma, medication use and symptoms to identify asthma patterns in the users of an mHealth app. METHODS: We studied MASK-air® users who reported their daily asthma symptoms (assessed by a 0-100 visual analogue scale - "VAS Asthma") at least three times (either in three different months or in any period). K-means cluster analysis methods were applied to identify asthma patterns based on: (i) whether the user self-reported asthma; (ii) whether the user reported asthma medication use and (iii) VAS asthma. Clusters were compared by the number of medications used, VAS asthma levels and Control of Asthma and Allergic Rhinitis Test (CARAT) levels. FINDINGS: We assessed a total of 8,075 MASK-air® users. The main clustering approach resulted in the identification of seven groups. These groups were interpreted as probable: (i) severe/uncontrolled asthma despite treatment (11.9-16.1% of MASK-air® users); (ii) treated and partly-controlled asthma (6.3-9.7%); (iii) treated and controlled asthma (4.6-5.5%); (iv) untreated uncontrolled asthma (18.2-20.5%); (v) untreated partly-controlled asthma (10.1-10.7%); (vi) untreated controlled asthma (6.7-8.5%) and (vii) no evidence of asthma (33.0-40.2%). This classification was validated in a study of 192 patients enrolled by physicians. INTERPRETATION: We identified seven profiles based on the probability of having asthma and on its level of control. mHealth tools are hypothesis-generating and complement classical epidemiological approaches in identifying patients with asthma.
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Asma , Aplicaciones Móviles , Rinitis Alérgica , Humanos , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/epidemiología , Asma/diagnóstico , Asma/epidemiología , Proyectos de InvestigaciónRESUMEN
Stroke can be a cause of death, while in non-fatal cases it is a common cause of various disabilities resulting from associated brain damage. However, whether a specific periodontal pathogen is associated with increased risk of unfavorable outcome after stroke remains unknown. We examined risk factors for unfavorable outcome following stroke occurrence, including serum antibody titers to periodontal pathogens. The enrolled cohort included 534 patients who had experienced an acute stroke, who were divided into favorable (n = 337) and unfavorable (n = 197) outcome groups according to modified ranking scale (mRS) score determined at 3 months after onset (favorable = score 0 or 1; unfavorable = score 2-6). The associations of risk factors with unfavorable outcome, including serum titers of IgG antibodies to 16 periodontal pathogens, were examined. Logistic regression analysis showed that the initial National Institutes of Health stroke scale score [odds ratio (OR) = 1·24, 95% confidence interval (CI) = 1·18-1·31, P < 0·001] and C-reactive protein (OR = 1·29, 95% CI = 1·10-1·51, P = 0·002) were independently associated with unfavorable outcome after stroke. Following adjustment with those, detection of the antibody for Fusobacterium nucleatum ATCC 10953 in serum remained an independent predictor of unfavorable outcome (OR = 3·12, 95% CI = 1·55-6·29, P = 0·002). Determination of the antibody titer to F. nucleatum ATCC 10953 in serum may be useful as a predictor of unfavorable outcome after stroke.
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Anticuerpos Antibacterianos/sangre , Fusobacterium nucleatum/metabolismo , Inmunoglobulina G/sangre , Accidente Cerebrovascular/sangre , Anciano , Anciano de 80 o más Años , Anticuerpos Antibacterianos/inmunología , Femenino , Fusobacterium nucleatum/inmunología , Humanos , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Accidente Cerebrovascular/inmunologíaRESUMEN
Secretory IgA (SIgA) is a well-known mucosal-surface molecule in first-line defense against extrinsic pathogens and antigens. Its immunomodulatory and pathological roles have also been emphasized, but it is unclear whether it plays a pathological role in lung diseases. In the present study, we aimed to determine the distribution of IgA in idiopathic pulmonary fibrosis (IPF) lungs and whether IgA affects the functions of airway epithelial cells. We performed immunohistochemical analysis of lung sections from patients with IPF and found that mucus accumulated in the airspaces adjacent to the hyperplastic epithelia contained abundant SIgA. This was not true in the lungs of non-IPF subjects. An in-vitro assay revealed that SIgA bound to the surface of A549 cells and significantly promoted production of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-ß and interleukin (IL)-8, important cytokines in the pathogenesis of IPF. Among the known receptors for IgA, A549 cells expressed high levels of transferrin receptor (TfR)/CD71. Transfection experiments with siRNA targeted against TfR/CD71 followed by stimulation with SIgA suggested that TfR/CD71 may be at least partially involved in the SIgA-induced cytokine production by A549 cells. These phenomena were specific for SIgA, distinct from IgG. SIgA may modulate the progression of IPF by enhancing synthesis of VEGF, TGF-ß and IL-8.
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Fibrosis Pulmonar Idiopática/inmunología , Inmunoglobulina A Secretora/inmunología , Interleucina-8/inmunología , Pulmón/inmunología , Factor de Crecimiento Transformador beta/inmunología , Factor A de Crecimiento Endotelial Vascular/inmunología , Células A549 , Anciano , Anciano de 80 o más Años , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos CD/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Inmunoglobulina A Secretora/metabolismo , Inmunoglobulina A Secretora/farmacología , Interleucina-8/genética , Interleucina-8/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Persona de Mediana Edad , Interferencia de ARN , Receptores de Transferrina/genética , Receptores de Transferrina/inmunología , Receptores de Transferrina/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Investigating slow earthquake activity in subduction zones provides insight into the slip behavior of megathrusts, which can provide important clues about the rupture extent of future great earthquakes. Using the S-net ocean-bottom seismograph network along the Japan Trench, we mapped a detailed distribution of tectonic tremors, which coincided with very-low-frequency earthquakes and a slow slip event. Compiling these and other related observations, including repeating earthquakes and earthquake swarms, we found that the slow earthquake distribution is complementary to the Tohoku-Oki earthquake rupture. We used our observations to divide the megathrust in the Japan Trench into three along-strike segments characterized by different slip behaviors. We found that the rupture of the Tohoku-Oki earthquake, which nucleated in the central segment, was terminated by the two adjacent segments.
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Immunoglobulin (Ig)A is the most abundant immunoglobulin in humans, and in the airway mucosa secretory IgA (sIgA) plays a pivotal role in first-line defense against invading pathogens and antigens. IgA has been reported to also have pathogenic effects, including possible worsening of the prognosis of idiopathic pulmonary fibrosis (IPF). However, the precise effects of IgA on lung fibroblasts remain unclear, and we aimed to elucidate how IgA activates human lung fibroblasts. We found that sIgA, but not monomeric IgA (mIgA), induced interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production by normal human lung fibroblasts (NHLFs) at both the protein and mRNA levels. sIgA also promoted proliferation of NHLFs and collagen gel contraction comparable to with transforming growth factor (TGF)-ß, which is involved in fibrogenesis in IPF. Also, Western blot analysis and real-time quantitative polymerase chain reaction (PCR) revealed that sIgA enhanced production of α-smooth muscle actin (α-SMA) and collagen type I (Col I) by NHLFs. Flow cytometry showed that NHLFs bound sIgA, and among the known IgA receptors, NHLFs significantly expressed CD71 (transferrin receptor). Transfection of siRNA targeting CD71 partially but significantly suppressed cytokine production by NHLFs co-cultured with sIgA. Our findings suggest that sIgA may promote human lung inflammation and fibrosis by enhancing production of inflammatory or fibrogenic cytokines as well as extracellular matrix, inducing fibroblast differentiation into myofibroblasts and promoting human lung fibroblast proliferation. sIgA's enhancement of cytokine production may be due partially to its binding to CD71 or the secretory component.
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Citocinas/biosíntesis , Inmunoglobulina A Secretora/farmacología , Pulmón/inmunología , Actinas/biosíntesis , Antígenos CD/fisiología , Células Cultivadas , Fibroblastos/inmunología , Humanos , Fibrosis Pulmonar Idiopática/etiología , Pulmón/citología , Receptores de Transferrina/fisiologíaRESUMEN
SETTING: The number of patients with non-tuberculous mycobacterial lung disease (NTM-LD) worldwide has been increasing. Mycobacterium avium complex lung disease (MAC-LD) accounts for 90% of NTM-LD. MAC-LD necessitates long-term treatment, but adverse reactions with long-term administration of drugs are poorly understood. OBJECTIVE: To evaluate adverse reactions with long-term administration of drugs for MAC-LD. DESIGN: We conducted a retrospective single-centre medical chart review of 364 patients administered two or more drugs between July 2010 and June 2015. RESULTS: The prevalence and median time to onset of adverse reactions were as follows: hepatotoxicity 19.5%, 55 days; leucocytopaenia 20.0%, 41 days; thrombocytopaenia 28.6%, 61.5 days; cutaneous reactions 9.3%, 30 days; ocular toxicity 7.7%, 278 days; and increase in serum creatinine 12.4%, 430.5 days. Multivariate analysis showed that rifampicin use was independently associated with thrombocytopaenia, and ethambutol use was independently associated with increases in serum creatinine. CONCLUSION: The main adverse reactions appeared within 3 months after start of treatment. Most patients were able to continue treatment with liver-supporting therapy, antihistamine agents or desensitisation therapy; however, ocular toxicity must be monitored for up to 1 year after start of treatment.
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Antibacterianos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Enfermedades Pulmonares/tratamiento farmacológico , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Esquema de Medicación , Etambutol/efectos adversos , Femenino , Humanos , Japón/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Complejo Mycobacterium avium , Estudios Retrospectivos , Rifampin/efectos adversos , Esputo/microbiología , Factores de Tiempo , Adulto JovenRESUMEN
AIMS: Public stigma alters attitudes towards people with mental illness, and is a particular concern for young people since most mental health problems occur in adolescence and young adulthood. However, little is known about the long-term effects of repeated filmed social contact (FSC) on reducing mental health-related stigma among young adults in the general population, compared with self-instructional Internet search (INS) and control interventions. METHODS: This study is a parallel-group randomised controlled trial over 12 months conducted in Tokyo, Japan. A total of 259 university students (male n = 150, mean age = 20.0 years, s.d. = 1.2) were recruited from 20 colleges and universities between November 2013 and July 2014, without being provided information about the mental health-related survey or trial. Participants were assigned to one of three groups before completion of the baseline survey (FSC/INS/control = 89/83/87). The FSC group received a computer-based 30-min social contact film with general mental health education and five follow-up web-based FSCs at 2-month intervals. The INS group undertook a 30-min search for mental health-related information with five follow-up web-based reminders for self-instructional searches at 2-month intervals. The control group played PC games and had no follow-up intervention. The main outcome measures were the future (intended behaviour) domain of the Reported and Intended Behaviour Scale at 12 months after the intervention. Analysis was conducted in September 2015. RESULTS: At the 12-month follow-up, 218 participants completed the survey (84.1%, 75:70:73). The FSC group showed the greatest change at the 12-month follow-up (FSC: mean change 2.11 [95% CI 1.49, 2.73], INS: 1.04 [0.29, 1.80], control: 0.71 [0.09, 1.33]; FSC v. INS p = 0.037, FSC v. controls p = 0.004). No adverse events were reported during the follow-up period. CONCLUSIONS: FSC was more successful in reducing stigma at 12 months after intervention than INS or control interventions. FSC could be used to reduce stigma in educational lectures and anti-stigma campaigns targeted at young people. STUDY REGISTRATION: This study is registered at UMIN-CTR (No. UMIN000012239).
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Educación en Salud/métodos , Conocimientos, Actitudes y Práctica en Salud , Medios de Comunicación de Masas , Trastornos Mentales/psicología , Discriminación Social , Estigma Social , Adolescente , Adulto , Femenino , Humanos , Japón , Evaluación de Procesos y Resultados en Atención de Salud , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVE: The purpose of this study was to characterize the mechanisms of Günther Tulip filter (GTF) tilting during transfemoral placement in an experimental model with further validation in a clinical series. MATERIALS AND METHODS: In an experimental study, 120 GTF placements in an inferior vena cava (IVC) model were performed using 6 configurations of pre-deployment filter position. The angle between the pre-deployment filter axis and IVC axis, and the proximity of the constrained filter legs to IVC wall prior to deployment were evaluated. The association of those pre-deployment factors with post-deployment filter tilting was analyzed. The association noted in the experimental study was then evaluated in a retrospective clinical series of 21 patients. RESULTS: In the experimental study, there was a significant association between the pre-deployment angle and post-deployment filter tilting (P<0.0001). With a low pre-deployment angle (≤5°), a significant association was noted between filter tilting and the proximity of the constrained filter legs to the far IVC wall (P=0.001). In a retrospective clinical study, a significant association between the pre-deployment angle and post-deployment filter tilting was also noted with a linear regression model (P=0.026). CONCLUSION: Significant association of the pre-deployment angle with post-deployment GTF tilting was shown in both the experimental and clinical studies. The experimental study also showed that proximity of filter legs is relevant when pre-deployment angle is small. Addressing these factors may result in a lower incidence of filter tilting.
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OBJECTIVE: Ameloblastoma (AM) shows locally invasive behaviour. However, biological investigations regarding regulation of gene expression associated with AM pathological features are difficult to perform, because AM cells can be passaged for a few generations due to senescence. We report a newly established immortalized AM cell line, AMB cells, by transfection with human telomerase reverse transcriptase (hTERT). Furthermore, we examined whether TNF-α modulates bone resorption-related genes, IL-6 and MMP-9 in cooperation with TGF-ß or IFN-γ. MATERIALS AND METHODS: Following transfection of an hTERT expression vector into AM cells using a non-viral method, the effects of cytokines on the expressions of IL-6 and MMP-9 mRNA were examined using real-time PCR. TNF-α-induced NF-κB activity was examined by western blotting and transcription factor assays. RESULTS: AMB cells continued to grow for more than 100 population doublings. Stimulation with TNF-α increased IL-6 and MMP-9 mRNA expressions, as well as NF-κB activation. Furthermore, TGF-ß and IFN-γ dramatically increased TNF-α-mediated expressions of MMP-9 and IL-6 mRNA, respectively, while those responses were suppressed by NF-κB inhibitor. CONCLUSION: We established an immortalized AM cell line by hTERT transfection. TNF-α-mediated regulation of MMP-9 and IL-6 via NF-κB may play an important role in the pathological behaviour of AMs, such as bone resorption.
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Ameloblastoma/genética , Expresión Génica/efectos de los fármacos , Interleucina-6/genética , Neoplasias Maxilomandibulares/genética , Metaloproteinasa 9 de la Matriz/genética , Factor de Necrosis Tumoral alfa/farmacología , Adulto , Ameloblastoma/metabolismo , Línea Celular Tumoral , Proliferación Celular , Senescencia Celular/genética , Femenino , Humanos , Interferón gamma/farmacología , Neoplasias Maxilomandibulares/metabolismo , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Nitrilos/farmacología , ARN Mensajero/metabolismo , Sulfonas/farmacología , Telomerasa/genética , Transfección , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
We have developed an analysis method to improve the accuracies of electron temperature measurement by employing a fitting technique for the raw Thomson scattering (TS) signals. Least square fitting of the raw TS signals enabled reduction of the error in the electron temperature measurement. We applied the analysis method to a multi-pass (MP) TS system. Because the interval between the MPTS signals is very short, it is difficult to separately analyze each Thomson scattering signal intensity by using the raw signals. We used the fitting method to obtain the original TS scattering signals from the measured raw MPTS signals to obtain the electron temperatures in each pass.
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The Thomson scattering diagnostic systems are widely used for the measurements of absolute local electron temperatures and densities of fusion plasmas. In order to obtain accurate and reliable temperature and density data, careful calibrations of the system are required. We have tried several calibration methods since the second LHD experiment campaign in 1998. We summarize the current status of the calibration methods for the electron temperature and density measurements by the LHD Thomson scattering diagnostic system. Future plans are briefly discussed.
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Evidence that enables us to identify, assess, and access the small airways in asthma and chronic obstructive pulmonary disease (COPD) has led INTERASMA (Global Asthma Association) and WAO to take a position on the role of the small airways in these diseases. Starting from an extensive literature review, both organizations developed, discussed, and approved the manifesto, which was subsequently approved and endorsed by the chairs of ARIA and GA2LEN. The manifesto describes the evidence gathered to date and defines and proposes issues on small airway involvement and management in asthma and COPD with the aim of challenging assumptions, fostering commitment, and bringing about change. The small airways (defined as those with an internal diameter <2 mm) are involved in the pathogenesis of asthma and COPD and are the major determinant of airflow obstruction in these diseases. Various tests are available for the assessment of the small airways, and their results must be integrated to confirm a diagnosis of small airway dysfunction. In asthma and COPD, the small airways play a key role in attempts to achieve disease control and better outcomes. Small-particle inhaled formulations (defined as those that, owing to their size [usually <2 µm], ensure more extensive deposition in the lung periphery than large molecules) have proved beneficial in patients with asthma and COPD, especially those in whom small airway involvement is predominant. Functional and biological tools capable of accurately assessing the lung periphery and more intensive use of currently available tools are necessary. In patients with suspected COPD or asthma, small airway involvement must be assessed using currently available tools. In patients with subotpimal disease control and/or functional or biological signs of disease activity, the role of small airway involvement should be assessed and treatment tailored. Therefore, the choice between large- and small-particle inhaled formulations must reflect the physician's considerations of disease features, phenotype, and response to previous therapy. This article is being co-published in Asthma Research and Practice and the World Allergy Organization Journal.
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BACKGROUND: Omalizumab, a humanized anti-IgE monoclonal antibody, has demonstrated efficacy in patients with severe allergic asthma. However, treatment responses vary widely among individuals. Despite a lack of data, free serum IgE levels following omalizumab treatment have been proposed as a marker of treatment responsiveness. METHODS: In this prospective, observational study, we assessed the utility of biomarkers of type 2 inflammation in predicting omalizumab treatment responses, as determined by the absence of asthma exacerbation during the first year of treatment. Free serum IgE levels were monitored for 2 years to examine their association with baseline biomarker levels and the number of exacerbations. RESULTS: We enrolled thirty patients who had been treated with omalizumab for at least 1 year, of whom 27 were treated for 2 years. Baseline serum periostin levels and blood eosinophil counts were significantly higher in patients without exacerbations during the first year of treatment than in patients with exacerbations. Baseline serum periostin levels, but not eosinophil counts, were negatively associated with free serum IgE levels after 16 or 32 weeks of treatment. Reduced free serum IgE levels during treatment from those at baseline were associated with reduced exacerbation numbers at 2 years. In 14 patients who continued to have exacerbations during the first year of treatment, exacerbation numbers gradually and significantly decreased over the 2-year study period, with concurrent significant reductions in free serum IgE levels. CONCLUSION: Baseline serum periostin levels and serum free IgE levels during treatment follow-up may be useful in evaluating responses to omalizumab treatment.
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Antiasmáticos/uso terapéutico , Asma/sangre , Asma/tratamiento farmacológico , Moléculas de Adhesión Celular/sangre , Inmunoglobulina E/sangre , Omalizumab/uso terapéutico , Adulto , Anciano , Antiasmáticos/farmacología , Asma/diagnóstico , Asma/inmunología , Biomarcadores , Progresión de la Enfermedad , Femenino , Humanos , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana Edad , Omalizumab/farmacología , Curva ROC , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Tetherin (BST-2/CD317/HM1.24) is an antiviral membrane protein that prevents the release of enveloped viruses from the cell surface. We found that the growth of human parainfluenza virus type 2 (hPIV-2), but not that of V protein-deficient recombinant hPIV-2, was inhibited by tetherin. V protein immunoprecipitates with tetherin, and this interaction requires its C-terminal Trp residues. The glycosyl phosphatidylinositol attachment signal of tetherin, but not its cytoplasmic tail, was necessary for its binding with V. The distribution of the V protein clearly changed when co-expressed with tetherin in plasmid-transfected cells. hPIV-2 infection of HeLa cells reduced cell surface tetherin without affecting total cellular tetherin. This reduction also occurred in HeLa cells constitutively expressing V, whereas mutated V protein did not affect the cell surface tetherin. Our results suggest that hPIV-2 V protein antagonizes tetherin by binding it and reducing its presence at the cell surface.
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Antígenos CD/metabolismo , Crup/metabolismo , Virus de la Parainfluenza 2 Humana/metabolismo , Proteínas Virales/metabolismo , Secuencias de Aminoácidos , Antígenos CD/química , Antígenos CD/genética , Crup/genética , Crup/virología , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/química , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Interacciones Huésped-Patógeno , Humanos , Virus de la Parainfluenza 2 Humana/química , Virus de la Parainfluenza 2 Humana/genética , Unión Proteica , Proteínas Virales/química , Proteínas Virales/genéticaRESUMEN
The primary function of the upper urinary tract is to propel urine and various water-soluble toxic compounds from the kidneys to the bladder for storage and evacuation to maintain body ionic balance and contribute to the regulation of blood volume and pressure. The mechanism by which the upper urinary tract propels urine has long been considered to be myogenic in origin as peristaltic contractions in vivo and in vitro (pyeloureteric peristalsis) propagate in a manner little affected by drugs that block nerve conduction or the sympathetic and parasympathetic transmission. However, it is now well established that the release of intrinsic prostaglandins and neuropeptides from primary sensory nerves (PSNs) helps to maintain pyeloureteric peristalsis. Electrical field stimulation of PSNs evokes species-specific positive inotropic and chronotropic effects that have been attributed to release of excitatory tachykinins superimposed on negative inotropic and chronotropic effects associated with the release of calcitonin gene related peptide (CGRP), a rise in cellular cyclic-adenosine monophosphate (cAMP) and a protein kinase A-dependent activation of glibenclamide-sensitive ATP-dependent K+ (KATP) channels. This review summarises the existing evidence of the nervous control of the upper urinary tract and recent evidence suggesting that the autonomic innervation may indirectly modulate pyeloureteric peristalsis via the activation of PSN nicotinic receptors and via the modulation of KV7 channels located on interstitial cells within the renal pelvis wall.
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Sistema Nervioso Autónomo/fisiología , Pelvis Renal/fisiología , Músculo Liso/fisiología , Miocitos del Músculo Liso/fisiología , Peristaltismo/fisiología , Animales , Humanos , Contracción Muscular/fisiologíaRESUMEN
BACKGROUND: The safety profile of roflumilast, a phosphodiesterase 4 inhibitor, has been extensively researched in patients with chronic obstructive pulmonary disease (COPD). Adverse events (AEs) including headache, diarrhoea and weight loss have been reported. Much less is known about the safety of roflumilast treatment in patients with bronchial asthma. AIM: To evaluate the safety and tolerability of roflumilast using safety data from one open-label and ten pooled placebo-controlled phase II and III clinical studies completed between 1997 and 2005. SUBJECTS AND METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 40 weeks. Data for 5169 patients between 12 and 70 years of age, of whom 2851 received roflumilast at doses of 125, 250 and 500 µg, were analyzed. At randomization patients had a forced expiratory flow of 45-100%. RESULTS: Headache was the most frequent AE with an incidence rate of 50 and 29.2 per 100 patient-years in the 500 µg roflumilast and placebo groups, respectively. Gastrointestinal AEs were common. Nausea and diarrhoea occurred in 28.7 and 28.3 per 100 patient-years in the 500 µg roflumilast and placebo groups, respectively. The extent of weight loss in roflumilast-treated patients was small. AEs reported in 465 patients in the 4-week open-label follow-up study reflected those of the pooled studies. CONCLUSIONS: The severity and incidence of AEs reported from this pooled safety analysis confirm that roflumilast is generally well tolerated by patients with asthma. This reflects the general safety profile reported previously in patients with COPD. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177, NCT00076076, NCT00163527.
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Aminopiridinas/efectos adversos , Asma/tratamiento farmacológico , Benzamidas/efectos adversos , Inhibidores de Fosfodiesterasa 4/efectos adversos , Adolescente , Adulto , Anciano , Niño , Ciclopropanos/efectos adversos , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: The role of roflumilast as a potential asthma treatment is not yet fully understood. A series of placebo-controlled trials were undertaken in order to investigate the safety and efficacy of roflumilast in asthma. AIM: To evaluate the efficacy of roflumilast in nine randomized proof-of-concept, placebo-controlled monotherapy and combination therapy phase II and III clinical studies performed between 1997 and 2005. METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 24 weeks. Data were analyzed from 4873 patients, 12-70 years of age, of whom 2668 received roflumilast. At randomization patients had a forced expiratory flow (FEV1) of 45-90%. Roflumilast was investigated at doses of 125, 250 and 500 µg versus placebo. In two studies, 500 µg roflumilast was added on top of standard therapy with inhaled corticosteroids (ICS), 250 µg fluticasone propionate, or 400 µg beclomethasone dipropionate (BDP). Improvement in FEV1 from baseline was the primary endpoint in seven studies. Key secondary endpoints included asthma symptom scores and time to first severe exacerbation. RESULTS: Roflumilast consistently improved FEV1 across the nine studies compared with placebo, reaching statistical significance in three studies. When given in addition to ICS, roflumilast provided additional improvements in FEV1 which was statistically significant for 500 µg roflumilast/400 µg BDP versus placebo/400 µg BDP. CONCLUSION: Together these studies show that roflumilast has potential as an effective anti-inflammatory therapy for the treatment of asthma. Additional beneficial effects are observed when given in combination with ICS, which warrant further investigation. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177, NCT00076076, NCT00163527.
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Aminopiridinas/uso terapéutico , Asma/tratamiento farmacológico , Benzamidas/uso terapéutico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Adolescente , Adulto , Anciano , Aminopiridinas/efectos adversos , Asma/fisiopatología , Asma/psicología , Beclometasona/uso terapéutico , Benzamidas/efectos adversos , Niño , Ciclopropanos/efectos adversos , Ciclopropanos/uso terapéutico , Método Doble Ciego , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Persona de Mediana Edad , Calidad de Vida , Adulto JovenRESUMEN
OBJECTIVE: Itraconazole (ICZ) has a broad spectrum of antifungal activity including a wide range of Candida spp. TNF-α, an inflammatory cytokine associated with Th1-mediated oral inflammatory disease, enhances inflammatory mediators, such as CXCR3-agonistic chemokines including CXCL10. We examined the anti-inflammatory potential of ICZ against TNF-α-induced chemokines in oral fibroblasts. MATERIALS AND METHODS: We investigated the effects of ICZ on mRNA expressions of various TNF-α-induced chemokines in immortalized oral keratinocytes (RT7) and oral fibroblasts (GT1) using quantitative PCR analysis. Subsequently, the effects of ICZ and fluconazole (FLZ) on TNF-α-induced CXCL10 proteins in GT1 and primary fibroblasts were examined using enzyme-linked immunosorbent assays (ELISA). The effect of ICZ on signal transduction protein phosphorylation involved in CXCL10 production from TNF-α-stimulated GT1 was examined by western blotting. RESULTS: ICZ inhibited TNF-α-induced CXCL10 mRNA in GT1, but not RT7. Although ICZ did not affect TNF-α-induced IL-8 mRNA, the mRNAs of TNF-α-induced CXCR3-agonistic chemokines such as CXCL9 and CXCL11 were inhibited by ICZ in GT1. TNF-α-induced CXCL10 protein production in GT1 and primary fibroblasts was inhibited by ICZ, but not FLZ. Finally, ICZ inhibited TNF-α-induced phosphorylation of c-JUN, which is related to CXCL10 production by TNF-α-stimulated GT1. CONCLUSION: ICZ may be useful as therapy for Th1-mediated oral inflammatory disease.
Asunto(s)
Antifúngicos/farmacología , Quimiocina CXCL10/biosíntesis , Fibroblastos/fisiología , Itraconazol/farmacología , Queratinocitos/fisiología , Boca/citología , Factor de Necrosis Tumoral alfa/farmacología , Western Blotting , Línea Celular , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fluconazol/farmacología , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Long-duration γ-ray bursts are associated with the explosions of massive stars and are accordingly expected to reside in star-forming regions with molecular gas (the fuel for star formation). Previous searches for carbon monoxide (CO), a tracer of molecular gas, in burst host galaxies did not detect any emission. Molecules have been detected as absorption in the spectra of γ-ray burst afterglows, and the molecular gas is similar to the translucent or diffuse molecular clouds of the Milky Way. Absorption lines probe the interstellar medium only along the line of sight, so it is not clear whether the molecular gas represents the general properties of the regions where the bursts occur. Here we report spatially resolved observations of CO line emission and millimetre-wavelength continuum emission in two galaxies hosting γ-ray bursts. The bursts happened in regions rich in dust, but not particularly rich in molecular gas. The ratio of molecular gas to dust (<9-14) is significantly lower than in star-forming regions of the Milky Way and nearby star-forming galaxies, suggesting that much of the dense gas where stars form has been dissipated by other massive stars.