One-year treatment with mometasone furoate in chronic obstructive pulmonary disease

Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing

Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma

<p>Abstract</p> <p>Background</p> <p>Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma.</p> <p>Methods</p> <p>509 people (6–50 yr) were enrolled, 78% were atopic, median FEV₁92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a ≥ 10% fall in FEV₁on at least one of two tests, to methacholine a PC₂₀≤ 16 mg/ml and to mannitol a 15% fall in FEV₁at ≤ 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results.</p> <p>Results</p> <p>Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV₁in subjects positive to exercise was 19%, (SD 9.2), mannitol PD₁₅158 (CI:129,193) mg, and methacholine PC₂₀2.1(CI:1.7, 2.6)mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive.</p> <p>Conclusion</p> <p>In this group with normal FEV₁, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations.</p> <p>Trial registration</p> <p>This was a multi-center trial comprising 25 sites across the United States of America. (NCT0025229).</p

Extracellular Matrix Aggregates from Differentiating Embryoid Bodies as a Scaffold to Support ESC Proliferation and Differentiation

Embryonic stem cells (ESCs) have emerged as potential cell sources for tissue engineering and regeneration owing to its virtually unlimited replicative capacity and the potential to differentiate into a variety of cell types. Current differentiation strategies primarily involve various growth factor/inducer/repressor concoctions with less emphasis on the substrate. Developing biomaterials to promote stem cell proliferation and differentiation could aid in the realization of this goal. Extracellular matrix (ECM) components are important physiological regulators, and can provide cues to direct ESC expansion and differentiation. ECM undergoes constant remodeling with surrounding cells to accommodate specific developmental event. In this study, using ESC derived aggregates called embryoid bodies (EB) as a model, we characterized the biological nature of ECM in EB after exposure to different treatments: spontaneously differentiated and retinoic acid treated (denoted as SPT and RA, respectively). Next, we extracted this treatment-specific ECM by detergent decellularization methods (Triton X-100, DOC and SDS are compared). The resulting EB ECM scaffolds were seeded with undifferentiated ESCs using a novel cell seeding strategy, and the behavior of ESCs was studied. Our results showed that the optimized protocol efficiently removes cells while retaining crucial ECM and biochemical components. Decellularized ECM from SPT EB gave rise to a more favorable microenvironment for promoting ESC attachment, proliferation, and early differentiation, compared to native EB and decellularized ECM from RA EB. These findings suggest that various treatment conditions allow the formulation of unique ESC-ECM derived scaffolds to enhance ESC bioactivities, including proliferation and differentiation for tissue regeneration applications. © 2013 Goh et al

Onset of relief of dyspnoea with budesonide/formoterol or salbutamol following methacholine-induced severe bronchoconstriction in adults with asthma: a double-blind, placebo-controlled study

BACKGROUND: The long-acting β(2)-agonist (LABA) formoterol has an onset of effect comparable to that of salbutamol. Consequently, the combination of formoterol and budesonide in one inhaler, approved for maintenance use, can potentially be used for reliever therapy. This study compared the onset of relief from induced bronchospasm with a single dose of budesonide/formoterol versus standard salbutamol therapy in patients with asthma. METHODS: In this randomised, double-blind, placebo-controlled, cross-over study, 32 patients with asthma underwent a methacholine provocation test leading to a fall in forced expiratory volume in 1 second (FEV(1)) of ≥30% at enrolment (Visit 1) and three subsequent study visits (Visits 2–4). Immediately after each provocation at Visits 2–4, patients received one of three test treatments: one inhalation of budesonide/formoterol 160/4.5 μg (via Turbuhaler(®)), two inhalations of salbutamol 100 μg (via a pressurised metered-dose inhaler [pMDI]) or placebo. All patients received each of the test treatments in a randomised order, after separate methacholine provocations. The effect of treatment on FEV(1 )and breathlessness (using the Borg scale) was measured at 1, 3, 5, 10, 15, 20, 25 and 30 minutes after test treatment. RESULTS: Following methacholine provocation, Borg score increased from a baseline value of below 0.5 to 3.03, 3.31 and 3.50 before treatment with budesonide/formoterol, salbutamol and placebo, respectively. Budesonide/formoterol and salbutamol reversed methacholine-induced dyspnoea (breathlessness) rapidly. At 1 minute after inhalation, statistically significant decreases in Borg score were observed for budesonide/formoterol and salbutamol (p = 0.0233 and p < 0.0001, respectively, versus placebo), with similar rapid increases in FEV(1 )(both active treatments p < 0.0001 versus placebo). The median time to 50% recovery in Borg score after methacholine provocation was 3 minutes with budesonide/formoterol, 2 minutes with salbutamol and 10 minutes with placebo. All treatments and procedures were well tolerated. CONCLUSION: Single doses of budesonide/formoterol and salbutamol both provided rapid relief of dyspnoea and reversal of severe airway obstruction in patients with asthma with experimentally induced bronchoconstriction. The perception of relief, as confirmed by objective lung function assessment, provides evidence that budesonide/formoterol can be used as reliever medication in asthma

Genetic Association and Risk Scores in a COPD Meta-Analysis of 16,707 Subjects

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine 1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD, and 2) the impact of genetic risk scores on COPD. We genotyped 3,346 single nucleotide polymorphisms (SNP) in 2,588 cases (1,803 severe COPD) and 1,782 controls from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 controls. Additionally, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (p=1.28x10-8) and PPP4R4/SERPINA1 (p=1.01x10-8) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (AUC ~0.6), and accounted for a mean 0.9-1.9% lower FEV1 percent-predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest but significant effects on risk of COPD and lung function

Erythroid-Specific Transcriptional Changes in PBMCs from Pulmonary Hypertension Patients

Gene expression profiling of peripheral blood mononuclear cells (PBMCs) is a powerful tool for the identification of surrogate markers involved in disease processes. The hypothesis tested in this study was that chronic exposure of PBMCs to a hypertensive environment in remodeled pulmonary vessels would be reflected by specific transcriptional changes in these cells.The transcript profiles of PBMCs from 30 idiopathic pulmonary arterial hypertension patients (IPAH), 19 patients with systemic sclerosis without pulmonary hypertension (SSc), 42 scleroderma-associated pulmonary arterial hypertensio patients (SSc-PAH), and 8 patients with SSc complicated by interstitial lung disease and pulmonary hypertension (SSc-PH-ILD) were compared to the gene expression profiles of PBMCs from 41 healthy individuals. Multiple gene expression signatures were identified which could distinguish various disease groups from controls. One of these signatures, specific for erythrocyte maturation, is enriched specifically in patients with PH. This association was validated in multiple published datasets. The erythropoiesis signature was strongly correlated with hemodynamic measures of increasing disease severity in IPAH patients. No significant correlation of the same type was noted for SSc-PAH patients, this despite a clear signature enrichment within this group overall. These findings suggest an association of the erythropoiesis signature in PBMCs from patients with PH with a variable presentation among different subtypes of disease.In PH, the expansion of immature red blood cell precursors may constitute a response to the increasingly hypoxic conditions prevalent in this syndrome. A correlation of this erythrocyte signature with more severe hypertension cases may provide an important biomarker of disease progression

Deficiency in type 1 insulin-like growth factor receptor in mice protects against oxygen-induced lung injury

BACKGROUND: Cellular responses to aging and oxidative stress are regulated by type 1 insulin-like growth factor receptor (IGF-1R). Oxidant injury, which is implicated in the pathophysiology of a number of respiratory diseases, acutely upregulates IGF-1R expression in the lung. This led us to suspect that reduction of IGF-1R levels in lung tissue could prevent deleterious effects of oxygen exposure. METHODS: Since IGF-1R null mutant mice die at birth from respiratory failure, we generated compound heterozygous mice harboring a hypomorphic (Igf-1r(neo)) and a knockout (Igf-1r(-)) receptor allele. These IGF-1R(neo/- )mice, strongly deficient in IGF-1R, were subjected to hyperoxia and analyzed for survival time, ventilatory control, pulmonary histopathology, morphometry, lung edema and vascular permeability. RESULTS: Strikingly, after 72 h of exposure to 90% O(2), IGF-1R(neo/- )mice had a significantly better survival rate during recovery than IGF-1R(+/+ )mice (77% versus 53%, P < 0.05). The pulmonary injury was consistently, and significantly, milder in IGF-1R(neo/- )mice which developed conspicuously less edema and vascular extravasation than controls. Also, hyperoxia-induced abnormal pattern of breathing which precipitated respiratory failure was elicited less frequently in the IGF-1R(neo/- )mice. CONCLUSION: Together, these data demonstrate that a decrease in IGF-1R signaling in mice protects against oxidant-induced lung injury

Rapid production of human liver scaffolds for functional tissue engineering by high shear stress oscillation-decellularization

The development of human liver scaffolds retaining their 3-dimensional structure and extra-cellular matrix (ECM) composition is essential for the advancement of liver tissue engineering. We report the design and validation of a new methodology for the rapid and accurate production of human acellular liver tissue cubes (ALTCs) using normal liver tissue unsuitable for transplantation. The application of high shear stress is a key methodological determinant accelerating the process of tissue decellularization while maintaining ECM protein composition, 3D-architecture and physico-chemical properties of the native tissue. ALTCs were engineered with human parenchymal and non-parenchymal liver cell lines (HepG2 and LX2 cells, respectively), human umbilical vein endothelial cells (HUVEC), as well as primary human hepatocytes and hepatic stellate cells. Both parenchymal and non-parenchymal liver cells grown in ALTCs exhibited markedly different gene expression when compared to standard 2D cell cultures. Remarkably, HUVEC cells naturally migrated in the ECM scaffold and spontaneously repopulated the lining of decellularized vessels. The metabolic function and protein synthesis of engineered liver scaffolds with human primary hepatocytes reseeded under dynamic conditions were maintained. These results provide a solid basis for the establishment of effective protocols aimed at recreating human liver tissue in vitro

Immune enhancement by novel vaccine adjuvants in autoimmune-prone NZB/W F1 mice: relative efficacy and safety

<p>Abstract</p> <p>Background</p> <p>Vaccines have profoundly impacted global health although concerns persist about their potential role in autoimmune or other adverse reactions. To address these concerns, vaccine components like immunogens and adjuvants require critical evaluation not only in healthy subjects but also in those genetically averse to vaccine constituents. Evaluation in autoimmune-prone animal models of adjuvants is therefore important in vaccine development. The objective here was to assess the effectiveness of experimental adjuvants: two phytol-derived immunostimulants PHIS-01 (phytanol) and PHIS-03 (phytanyl mannose), and a new commercial adjuvant from porcine small intestinal submucosa (SIS-H), relative to a standard adjuvant alum. Phytol derivatives are hydrophobic, oil-in water diterpenoids, while alum is hydrophilic, and SIS is essentially a biodegradable and collagenous protein cocktail derived from extracellular matrices.</p> <p>Results</p> <p>We studied phthalate -specific and cross-reactive anti-DNA antibody responses, and parameters associated with the onset of autoimmune disorders. We determined antibody isotype and cytokine/chemokine milieu induced by the above experimental adjuvants relative to alum. Our results indicated that the phytol-derived adjuvant PHIS-01 exceeded alum in enhancing anti-phthalate antibody without much cross reactivity with ds-DNA. Relatively, SIS and PHIS-03 proved less robust, but they were also less inflammatory. Interestingly, these adjuvants facilitated isotype switching of anti-hapten, but not of anti-DNA response. The current study reaffirms our earlier reports on adjuvanticity of phytol compounds and SIS-H in non autoimmune-prone BALB/c and C57BL/6 mice. These adjuvants are as effective as alum also in autoimmune-prone NZB/WF1 mice, and they have little deleterious effects.</p> <p>Conclusion</p> <p>Although all adjuvants tested impacted cytokine/chemokine milieu in favor of Th1/Th2 balance, the phytol compounds fared better in reducing the onset of autoimmune syndromes. However, SIS is least inflammatory among the adjuvants evaluated.</p