RESUMEN
BACKGROUND: Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). METHODS: CRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed. RESULTS: Abca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aß) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aß-associated inflammation, gliosis, and neuronal damage. DISCUSSION: Overall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aß pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology. HIGHLIGHTS: ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.
Asunto(s)
Transportadoras de Casetes de Unión a ATP , Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratones Transgénicos , Placa Amiloide , Animales , Ratones , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Placa Amiloide/patología , Placa Amiloide/genética , Placa Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Neuronas/metabolismo , Neuronas/patología , Modelos Animales de Enfermedad , Humanos , Encéfalo/patología , Encéfalo/metabolismo , Microglía/metabolismo , Microglía/patología , Fagocitosis/genética , Precursor de Proteína beta-Amiloide/genéticaRESUMEN
Triggering receptor on myeloid cells 2 (TREM2) is an innate immune receptor, upregulated on the surface of microglia associated with amyloid plaques in Alzheimer's disease (AD). Individuals heterozygous for the R47H variant of TREM2 have greatly increased risk of developing AD. We examined the effects of wild-type (WT), R47H and knock-out (KO) of human TREM2 expression in three microglial cell systems. Addition of mouse BV-2 microglia expressing R47H TREM2 to primary mouse neuronal cultures caused neuronal loss, not observed with WT TREM2. Neuronal loss was prevented by using annexin V to block exposed phosphatidylserine, an eat-me signal and ligand of TREM2, suggesting loss was mediated by microglial phagocytosis of neurons exposing phosphatidylserine. Addition of human CHME-3 microglia expressing R47H TREM2 to LUHMES neuronal-like cells also caused loss compared to WT TREM2. Expression of R47H TREM2 in BV-2 and CHME-3 microglia increased their uptake of phosphatidylserine-beads and synaptosomes versus WT TREM2. Human iPSC-derived microglia with heterozygous R47H TREM2 had increased phagocytosis of synaptosomes vs common-variant TREM2. Additionally, phosphatidylserine liposomes increased activation of human iPSC-derived microglia expressing homozygous R47H TREM2 versus common-variant TREM2. Finally, overexpression of TREM2 in CHME-3 microglia caused increased expression of cystatin F, a cysteine protease inhibitor, and knock-down of cystatin F increased CHME-3 uptake of phosphatidylserine-beads. Together, these data suggest that R47H TREM2 may increase AD risk by increasing phagocytosis of synapses and neurons via greater activation by phosphatidylserine and that WT TREM2 may decrease microglial phagocytosis of synapses and neurons via cystatin F.
Asunto(s)
Enfermedad de Alzheimer , Sinaptosomas , Animales , Humanos , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Cistatinas/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Microglía/metabolismo , Neuronas/patología , Fagocitosis/genética , Fosfatidilserinas/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Sinaptosomas/metabolismo , Sinaptosomas/patologíaRESUMEN
BACKGROUND: Reduction in glucocorticoid exposure is the primary benefit of new biologic treatments in severe asthma, but there is currently no evidence that reduction in glucocorticoid exposure corresponds to a proportionate reduction in associated toxicity. OBJECTIVES: To use the validated Glucocorticoid Toxicity Index (GTI) to assess change in glucocorticoid toxicity after 12â months treatment with mepolizumab, and compare toxicity change to glucocorticoid reduction and change in patient-reported outcome measures (PROMs). METHODS: A longitudinal, real-world prospective cohort of 101 consecutive patients with severe asthma commenced on mepolizumab in a specialist UK regional severe asthma clinic. GTI toxicity assessment, cumulative glucocorticoid exposure and PROMs were recorded on commencing mepolizumab (V1), and after 12â months treatment (V2). RESULTS: There was significant reduction in oral glucocorticoid exposure (V1 median 4280â mg prednisolone per year (interquartile range 3083-5475 mg) versus V2 2450â mg prednisolone per year (1243-3360â mg), p<0.001). Substantial improvements in individual toxicities were observed, but did not correlate with oral glucocorticoid reduction. Mean±sd GTI aggregate improvement score (AIS) was -35.7±57.8 with a wide range in toxicity change at individual patient level (AIS range -165 to +130); 70% (71 out of 101) had a reduction in toxicity (AIS <0); 3% (three out of 101) had no change (AIS=0); and 27% (27 out of 101) an increase in overall toxicity. 62% (62 out of 101) of patients met the AIS minimally clinically important difference of ≤-10, but AIS did not correlate with glucocorticoid reduction or change in PROMs. CONCLUSION: Mepolizumab resulted in substantial oral glucocorticoid reduction, but this did not correlate with reduction in oral glucocorticoid toxicity, which varies widely at the individual patient level. Oral glucocorticoid reduction is not a comprehensive measure of response to mepolizumab.
Asunto(s)
Antiasmáticos , Glucocorticoides , Anticuerpos Monoclonales Humanizados , Humanos , Estudios ProspectivosRESUMEN
There is growing evidence that excessive microglial phagocytosis of neurons and synapses contributes to multiple brain pathologies. RNA-seq and genome-wide association (GWAS) studies have linked multiple phagocytic genes to neurodegenerative diseases, and knock-out of phagocytic genes has been found to protect against neurodegeneration in animal models, suggesting that excessive microglial phagocytosis contributes to neurodegeneration. Here, we review recent evidence that microglial phagocytosis of live neurons and synapses causes neurodegeneration in animal models of Alzheimer's disease and other tauopathies, Parkinson's disease, frontotemporal dementias, multiple sclerosis, retinal degeneration and neurodegeneration induced by ischaemia, infection or ageing. We also review factors regulating microglial phagocytosis of neurons, including: nucleotides, frackalkine, phosphatidylserine, calreticulin, UDP, CD47, sialylation, complement, galectin-3, Apolipoprotein E, phagocytic receptors, Siglec receptors, cytokines, microglial epigenetics and expression profile. Some of these factors may be potential treatment targets to prevent neurodegeneration mediated by excessive microglial phagocytosis of live neurons and synapses.
Asunto(s)
Encéfalo/metabolismo , Microglía/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Neuronas/metabolismo , Fagocitosis/fisiología , Animales , Encéfalo/patología , Humanos , Microglía/patología , Enfermedades Neurodegenerativas/patología , Neuronas/patología , Transducción de Señal/fisiologíaRESUMEN
Severe asthma represents a major unmet clinical need; understanding the pathophysiology is essential for the development of new therapies. Using microarray analysis, we previously found three immunological clusters in asthma: Th2-high, Th17-high, and Th2/17-low. Although new therapies are emerging for Th2-high disease, identifying molecular pathways in Th2-low disease remains an important goal. Further interrogation of our previously described microarray dataset revealed upregulation of gene expression for carcinoembryonic Ag cell adhesion molecule (CEACAM) family members in the bronchi of patients with severe asthma. Our aim was therefore to explore the distribution and cellular localization of CEACAM6 using immunohistochemistry on bronchial biopsy tissue obtained from patients with mild-to-severe asthma and healthy control subjects. Human bronchial epithelial cells were used to investigate cytokine and corticosteroid in vitro regulation of CEACAM6 gene expression. CEACAM6 protein expression in bronchial biopsies was increased in airway epithelial cells and lamina propria inflammatory cells in severe asthma compared with healthy control subjects. CEACAM6 in the lamina propria was localized to neutrophils predominantly. Neutrophil density in the bronchial mucosa was similar across health and the spectrum of asthma severity, but the percentage of neutrophils expressing CEACAM6 was significantly increased in severe asthma, suggesting the presence of an altered neutrophil phenotype. CEACAM6 gene expression in cultured epithelial cells was upregulated by wounding and neutrophil elastase. In summary, CEACAM6 expression is increased in severe asthma and primarily associated with airway epithelial cells and tissue neutrophils. CEACAM6 may contribute to the pathology of treatment-resistant asthma via neutrophil and airway epithelial cell-dependent pathways.
Asunto(s)
Antígenos CD/inmunología , Asma/inmunología , Moléculas de Adhesión Celular/inmunología , Células Epiteliales/inmunología , Neutrófilos/inmunología , Mucosa Respiratoria/inmunología , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Proteínas Ligadas a GPI/inmunología , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa , TranscriptomaRESUMEN
Severe asthma represents a major unmet clinical need. Eosinophilic inflammation persists in the airways of many patients with uncontrolled asthma, despite high-dose inhaled corticosteroid therapy. Suppressors of cytokine signalling (SOCS) are a family of molecules involved in the regulation of cytokine signalling via inhibition of the Janus kinase-signal transducers and activators of transcription pathway. We examined SOCS expression in the airways of asthma patients and investigated whether this is associated with persistent eosinophilia.Healthy controls, mild/moderate asthmatics and severe asthmatics were studied. Whole genome expression profiling, quantitative PCR and immunohistochemical analysis were used to examine expression of SOCS1, SOCS2 and SOCS3 in bronchial biopsies. Bronchial epithelial cells were utilised to examine the role of SOCS1 in regulating interleukin (IL)-13 signalling in vitroSOCS1 gene expression was significantly lower in the airways of severe asthmatics compared with mild/moderate asthmatics, and was inversely associated with airway eosinophilia and other measures of T-helper type 2 (Th2) inflammation. Immunohistochemistry demonstrated SOCS1 was predominantly localised to the bronchial epithelium. SOCS1 overexpression inhibited IL-13-mediated chemokine ligand (CCL) 26 (eotaxin-3) mRNA expression in bronchial epithelial cells.Severe asthma patients with persistent airway eosinophilia and Th2 inflammation have reduced airway epithelial SOCS1 expression. SOCS1 inhibits epithelial IL-13 signalling, supporting its key role in regulating Th2-driven eosinophilia in severe asthma.
Asunto(s)
Asma/metabolismo , Células Epiteliales/metabolismo , Interleucina-13/metabolismo , Eosinofilia Pulmonar/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Adulto , Asma/tratamiento farmacológico , Biopsia , Bronquios/metabolismo , Broncoscopía , Estudios de Casos y Controles , Línea Celular , Quimiocina CCL26/metabolismo , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Eosinofilia Pulmonar/tratamiento farmacológico , Mucosa Respiratoria/metabolismo , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Células Th2/citología , Adulto JovenRESUMEN
BACKGROUND: The airway epithelium is exposed to a range of physical and chemical irritants in the environment that are known to trigger asthma. Transient receptor potential (TRP) cation channels play a central role in sensory responses to noxious physical and chemical stimuli. Recent genetic evidence suggests an involvement of transient receptor potential vanilloid 1 (TRPV1), one member of the vanilloid subfamily of TRP channels, in the pathophysiology of asthma. The functional expression of TRPV1 on airway epithelium has yet to be elucidated. OBJECTIVE: In this study we examined the molecular, functional, and immunohistochemical expression of TRPV1 in asthmatic and healthy airways. METHODS: Bronchial biopsy specimens and bronchial brushings were obtained from healthy volunteers (n = 18), patients with mild-to-moderate asthma (n = 24), and patients with refractory asthma (n = 22). Cultured primary bronchial epithelial cells from patients with mild asthma (n = 4), nonasthmatic coughers (n = 4), and healthy subjects (n = 4) were studied to investigate the functional role of TRPV1. RESULTS: Quantitative immunohistochemistry revealed significantly more TRPV1 expression in asthmatic patients compared with healthy subjects, with the greatest expression in patients with refractory asthma (P = .001). PCR and Western blotting analysis confirmed gene and protein expression of TRPV1 in cultured primary bronchial epithelial cells. Patch-clamp electrophysiology directly confirmed functional TRPV1 expression in all 3 groups. In functional assays the TRPV1 agonist capsaicin induced dose-dependent IL-8 release, which could be blocked by the antagonist capsazepine. Reduction of external pH from 7.4 to 6.4 activated a capsazepine-sensitive outwardly rectifying membrane current. CONCLUSIONS: Functional TRPV1 channels are present in the human airway epithelium and overexpressed in the airways of patients with refractory asthma. These channels might represent a novel therapeutic target for the treatment of uncontrolled asthma.
Asunto(s)
Asma/metabolismo , Bronquios/química , Canales Catiónicos TRPV/fisiología , Adulto , Anciano , Células Cultivadas , Femenino , Humanos , Concentración de Iones de Hidrógeno , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Canales Catiónicos TRPV/análisis , Canales Catiónicos TRPV/genéticaRESUMEN
Burkholderia cepacia complex organisms are important transmissible pathogens found in cystic fibrosis (CF) patients. In recent years, the rates of cross-infection of epidemic strains have declined due to effective infection control efforts. However, cases of sporadic B. cepacia complex infection continue to occur in some centers. The acquisition pathways and clinical outcomes of sporadic B. cepacia complex infection are unclear. We sought to determine the patient clinical characteristics, outcomes, incidence, and genotypic relatedness for all cases of B. cepacia complex infection at two CF centers. We also sought to study the external conditions that influence the acquisition of infection. From 2001 to 2011, 67 individual organisms were cultured from the respiratory samples of 64 patients. Sixty-five percent of the patients were adults, in whom chronic infections were more common (68%) (P = 0.006). The incidence of B. cepacia complex infection increased by a mean of 12% (95% confidence interval [CI], 3 to 23%) per year. The rates of transplantation and death were similar in the incident cases who developed chronic infection compared to those in patients with chronic Pseudomonas aeruginosa infection. Multilocus sequence typing revealed 50 individual strains from 65 isolates. Overall, 85% of the patients were infected with unique strains, suggesting sporadic acquisition of infection. The yearly incidence of nonepidemic B. cepacia complex infection was positively correlated with the amount of rainfall in the two sites examined: subtropical Brisbane (r = 0.65, P = 0.031) and tropical Townsville (r = 0.82, P = 0.002). This study demonstrates that despite strict cohort segregation, new cases of unrelated B. cepacia complex infection continue to occur. These data also support an environmental origin of infection and suggest that climate conditions may be associated with the acquisition of B. cepacia complex infections.
Asunto(s)
Infecciones por Burkholderia/epidemiología , Complejo Burkholderia cepacia/aislamiento & purificación , Fibrosis Quística/complicaciones , Adolescente , Adulto , Infecciones por Burkholderia/microbiología , Complejo Burkholderia cepacia/clasificación , Complejo Burkholderia cepacia/genética , Niño , Preescolar , Análisis por Conglomerados , Femenino , Genotipo , Humanos , Incidencia , Masculino , Tipificación de Secuencias Multilocus , Factores de Riesgo , Adulto JovenRESUMEN
RATIONALE: Upregulation of glucocorticoid receptor ß (GRß) has been implicated in steroid resistance in severe asthma, although previous studies are conflicting. GRß has been proposed as a dominant negative isoform of glucocorticoid receptor α (GRα) but it has also been suggested that GRß can cause steroid resistance via reduced expression of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness in the airway. OBJECTIVES: To examine GRß, GRα, HDAC1 and HDAC2 expression at transcript and protein levels in bronchial biopsies from a large series of patients with severe asthma, and to compare the findings with those of patients with mild to moderate asthma and healthy volunteers. METHODS: Bronchoscopic study in two UK centres with real-time PCR and immunohistochemistry performed on biopsies, western blotting of bronchial epithelial cells and immunoprecipitation with anti-GRß antibody. MEASUREMENTS AND MAIN RESULTS: Protein and mRNA expression for GRα and HDAC2 did not differ between groups. GRß mRNA was detected in only 13 of 73 samples (seven patients with severe asthma), however immunohistochemistry showed widespread epithelial staining in all groups. Western blotting of bronchial epithelial cells with GRß antibody detected an additional 'cross-reacting' protein, identified as clathrin. HDAC1 expression was increased in patients with severe asthma compared with healthy volunteers. CONCLUSIONS: GRß mRNA is expressed at low levels in a minority of patients with severe asthma. HDAC1 and HDAC2 expression was not downregulated in severe asthma. These data do not support upregulated GRß and resultant reduced HDAC expression as the principal mechanism of steroid resistance in severe asthma. Conflicting GRß literature may be explained in part by clathrin cross-reactivity with commercial antibodies.
Asunto(s)
Asma/metabolismo , Bronquios/metabolismo , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/metabolismo , ARN Mensajero/metabolismo , Receptores de Glucocorticoides/metabolismo , Mucosa Respiratoria/metabolismo , Adulto , Western Blotting , Broncoscopía , Femenino , Expresión Génica , Histona Desacetilasa 1/genética , Histona Desacetilasa 2/genética , Humanos , Inmunohistoquímica , Inmunoprecipitación , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Glucocorticoides/genética , Adulto JovenAsunto(s)
Fibrosis Quística/complicaciones , Fibrosis Quística/microbiología , Infecciones por Mycobacterium no Tuberculosas/epidemiología , Micobacterias no Tuberculosas/aislamiento & purificación , Antibacterianos/uso terapéutico , Australia/epidemiología , Humanos , Modelos Logísticos , Análisis Multivariante , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Sistema de RegistrosRESUMEN
Calreticulin is a chaperone, normally found in the endoplasmic reticulum, but can be released by macrophages into the extracellular medium. It is also found in cerebrospinal fluid bound to amyloid beta (Aß). We investigated whether brain cells release calreticulin, and whether extracellular calreticulin had any effects on microglia and neurons relevant to neuroinflammation and neurodegeneration. We found that microglia release nanomolar levels of calreticulin when inflammatory-activated with lipopolysaccharide, when endoplasmic reticulum stress was induced by tunicamycin, or when cell death was induced by staurosporine, and that neurons release calreticulin when crushed. Addition of nanomolar levels of extracellular calreticulin was found to chemoattract microglia, and activate microglia to release cytokines TNF-α, IL-6 and IL-1ß, as well as chemokine (C-C motif) ligand 2. Calreticulin blocked Aß fibrillization and modified Aß oligomerization, as measured by thioflavin T fluorescence and transmission electron microscopy. Extracellular calreticulin also altered microglial morphology and proliferation, and prevented Aß-induced neuronal loss in primary neuron-glial cultures. Thus, calreticulin is released by microglia and neurons, and acts: as an alarmin to recruit and activate microglia, as an extracellular chaperone to prevent Aß aggregation, and as a neuroprotectant against Aß neurotoxicity.
Asunto(s)
Péptidos beta-Amiloides , Síndromes de Neurotoxicidad , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Calreticulina/metabolismo , Células Cultivadas , Humanos , Microglía/metabolismo , Síndromes de Neurotoxicidad/metabolismoRESUMEN
PURPOSE OF REVIEW: Despite increased clinician awareness, nonadherence to inhaled corticosteroid treatment presents a major challenge to successful asthma management and risks inappropriate treatment escalation, particularly in severe disease. In patients with Type-2 mediated biology, fractional exhaled nitric oxide (FeNO) has a role in assessment and monitoring of adherence to inhaled corticosteroids. RECENT FINDINGS: Asthmatic patients with elevated FeNO are at an increased risk of exacerbation. High FeNO is often secondary to suboptimal adherence to inhaled corticosteroid treatment, whether intentional or nonintentional. FENO-suppression can 'unmask' underlying adherence issues and is a useful test in the presence of Type-2 biology in the 'difficult-to-control' asthma population. Identification of nonadherence can improve asthma control and prevent inappropriate commencement of costly biologic therapies. SUMMARY: Assessment of adherence and FeNO response to monitored inhaled corticosteroid in Type-2 biomarker high asthmatic individuals may prevent unnecessary escalation to biologic therapy. Establishing an 'optimised' FeNO may alert clinicians to the possibility of underlying nonadherence at future clinical assessments.
Asunto(s)
Antiasmáticos/administración & dosificación , Asma/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Óxido Nítrico/análisis , Administración por Inhalación , Pruebas Respiratorias/métodos , Espiración , HumanosRESUMEN
RATIONALE: The utility of fractional exhaled nitric oxide (F ENO) suppression (FeNOSuppT) to identify non-adherence to inhaled corticosteroid (ICS) treatment has previously been reported, but whether it can predict clinical outcome remains unclear. OBJECTIVES: We examined the utility of FeNOSuppT in prediction of progression to biologic agents or discharge from specialist care. METHODS: FeNOSuppT was measured at home using remote monitoring technology of inhaler use alongside daily F ENO measurement over 7â days. Long-term clinical outcomes in terms of progression to biologic agent or discharge from specialist care were compared for non-suppressors and suppressors. MEASUREMENTS AND MAIN RESULTS: Of the 162 subjects, 135 successfully completed the test with 81 (60%) positive F ENO suppression tests. Subjects with a negative FeNOSuppT were more likely to proceed to biologic therapy (39 of 54 patients, 72%) compared to those with a positive FeNOSuppT (35 of 81 patients, 43%, p=0.001). In subjects with a positive FeNOSuppT, predictors of progression to biologic therapy included higher dose of maintenance steroid at initial assessment and prior intensive care unit admission. These subjects had a significant rise in F ENO between post-suppression test and follow-up (median, 33 (IQR 25-55) versus 71 (IQR 24-114); p=0.009), which was not explained by altered corticosteroid dose. CONCLUSIONS: A negative FeNOSuppT correlates with progression to biologic therapy. A positive FeNOSuppT, with subsequent maintenance of "optimised" F ENO, predicts a subgroup of patients in whom asthma control is preserved with adherence to high-dose ICS/long-acting ß2 agonist and who can be discharged from specialist care.
RESUMEN
BACKGROUND: Glucocorticoid (GC)-associated morbidity in severe asthma (SA) is well recognized but varies in individual patients; systematic measurement of GC toxicity is important to measure improvement with steroid-sparing monoclonal antibodies. OBJECTIVE: To describe for the first time individual patient GC toxicity in steroid-dependent SA using the Glucocorticoid Toxicity Index (GTI). METHODS: An observational consecutive patient cohort study was performed at a UK Regional SA Specialist clinic for systematic assessment of GC-associated morbidity using the GTI in routine clinical care. GTI was correlated with commonly used patient-reported outcome measures. An approach to GTI scoring, calculation of minimal clinically important difference (MCID), and development of digital GTI application in routine clinical care are described. RESULTS: All patients had significant oral GC exposure (cumulative prednisolone/prior year, 4280 [3083, 5475] mg) with wide distribution of toxicity in individual patients (mean GTI score, 177.5 [73.7]). GTI score had only modest correlation with recent prednisolone exposure: maintenance prednisolone dose (rho = 0.26, P = .01), cumulative exposure/prior year (rho = 0.38, P < .001), and GC boosts/prior year (rho = 0.25, P = .01). GTI toxicity demonstrated stronger associations with asthma-related quality of life (mini-Asthma Quality of Life Questionnaire [mini-AQLQ] r = -0.50, P < .001 and St. George's Respiratory Questionnaire r = 0.42, P < .001). GTI MCID was calculated as 10 points. Multiple linear regression demonstrated that age and mini-AQLQ were strongest predictors of GC toxicity. CONCLUSIONS: The GTI is a useful tool to systematically capture and quantify GC toxicity at the individual patient level. GC toxicity varies widely between individual patients with SA and correlated only modestly with GC exposure over the preceding year. Age and mini-AQLQ are better predictors of GC toxicity. The GTI and MCID will facilitate assessment of individual SA response to steroid-sparing agents in clinical trials and routine care.
Asunto(s)
Asma , Glucocorticoides , Asma/tratamiento farmacológico , Asma/epidemiología , Glucocorticoides/uso terapéutico , Humanos , Morbilidad , Calidad de Vida , Encuestas y CuestionariosRESUMEN
Chronic obstructive pulmonary disease represents a major global health care burden for both primary and secondary care providers and is the most common respiratory condition necessitating hospital admission. Short-acting bronchodilators play a vital role in immediate relief of symptoms, while inhaled long-acting bronchodilators and inhaled corticosteroids are advocated for regular use in individuals with persistent symptoms and exacerbations. Theophylline is a nonspecific phosphodiesterase inhibitor and is usually reserved for patients with ongoing symptoms despite optimum inhaled bronchodilator treatment or when difficulty is encountered with inhaler devices. However, it is often not widely used mainly due to frequency of dose-related adverse effects, numerous drug interactions and narrow therapeutic index. This in turn has lead to the development of more selective phosphodiesterase inhibitors in an attempt to create a drug which patients can use with beneficial effects but without the problems associated with theophylline. Current data do indicate that phosphodiesterase 4 inhibitors confer some benefits in chronic obstructive pulmonary disease when compared to placebo in terms of lung function, quality of life and exacerbations. They are also generally well tolerated. Further studies are required to determine fully their long-term beneficial and adverse effect profiles and ultimately where they might comfortably sit in management algorithms.
Asunto(s)
Inhibidores de Fosfodiesterasa/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Teofilina/administración & dosificación , Administración por Inhalación , Administración Oral , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Mortality rates from lung cancer are known to vary considerably between countries. Differences in patients, disease, investigation and treatment are thought to account for some survival shortfalls but it is not known whether differences in collection or processing of data also contribute. METHODOLOGY: We searched recognised sources where information regarding mortality rates have been published for the United Kingdom, Europe and United States (US). Data regarding patient selection, demographics and mortality rates were extracted. RESULTS: Published international 5-year survival for patients with lung cancer varies from 5% to 16%. The survival figures quoted in the literature are based on data which varies widely in its collection and statistical analysis and this information is not always in the public domain. Data from the US suggests an overall 5-year survival rate of up to 16% although this figure covers only a quarter of the general population and excludes patients without histological confirmation. Many European countries report higher mortality rates although in most, data includes patients without proven histology. European datasets have variable population coverage. CONCLUSION: Selective data collection and variable population coverage may account for some of the differences in lung cancer survival between countries. More transparent description of data collection and analysis would be helpful but ideally a uniform method of reporting data is required in order to make valid comparisons in mortality rates.
Asunto(s)
Recolección de Datos , Neoplasias Pulmonares/mortalidad , Interpretación Estadística de Datos , Europa (Continente)/epidemiología , Humanos , Proyectos de Investigación , Tasa de Supervivencia , Reino Unido/epidemiología , Estados Unidos/epidemiologíaRESUMEN
Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Asunto(s)
Asma/inmunología , Asma/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Animales , Células Cultivadas , Femenino , Humanos , Interleucina-13/metabolismo , Interleucina-17/metabolismo , Ratones , Ratones Endogámicos BALB C , Transducción de SeñalRESUMEN
Over the past number of decades there has been considerable interest in the role of neurogenic inflammation in asthma with the identification of many biologically active neuropeptides in the lung. Whilst there is convincing evidence of neurogenic inflammation in various animal models of asthma, the evidence in humans is less clear and replicating the experimental approaches in humans has proven difficult with different studies producing conflicting results. In terms of human studies, research has focused on whether pro-inflammatory neuropeptides are elevated in the asthmatic airway, and if so, what their functional effects are. There have also been studies to assess the efficacy of tachykinin receptor antagonists in improving indices of asthma control. Information to date would suggest that neuropeptides are present in human airways and are possibly upregulated in asthma, but this effect does not appear to be specific and may occur in other inflammatory airways conditions (chronic obstructive pulmonary disease (COPD) and smoking). At present there is insufficient evidence to suggest that tachykinin receptor antagonists confer any additional benefit over inhaled corticosteroid regimes for asthmatic patients.