Patient-Centered Specialty Practice: Defining the Role of Specialists in Value-Based Health Care.

Health care is at a crossroads and under pressure to add value by improving patient experience and health outcomes and reducing costs to the system. Efforts to improve the care model in primary care, such as the patient-centered medical home, have enjoyed some success. However, primary care accounts for only a small portion of total health-care spending, and there is a need for policies and frameworks to support high-quality, cost-efficient care in specialty practices of the medical neighborhood. The Patient-Centered Specialty Practice (PCSP) model offers ambulatory-based specialty practices one such framework, supported by a formal recognition program through the National Committee for Quality Assurance. The key elements of the PCSP model include processes to support timely access to referral requests, improved communication and coordination with patients and referring clinicians, reduced unnecessary and duplicative testing, and an emphasis on continuous measurement of quality, safety, and performance improvement for a population of patients. Evidence to support the model remains limited, and estimates of net costs and value to practices are not fully understood. The PCSP model holds promise for promoting value-based health care in specialty practices. The continued development of appropriate incentives is required to ensure widespread adoption.

A Comparison of Usage and Outcomes Between Nurse Practitioner and Resident-Staffed Medical ICUs.

OBJECTIVE: To compare usage patterns and outcomes of a nurse practitioner-staffed medical ICU and a resident-staffed physician medical ICU. DESIGN: Retrospective chart review of 1,157 medical ICU admissions from March 2012 to February 2013. SETTING: Large urban academic university hospital. SUBJECTS: One thousand one hundred fifty-seven consecutive medical ICU admissions including 221 nurse practitioner-staffed medical ICU admissions (19.1%) and 936 resident-staffed medical ICU admissions (80.9%). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data obtained included age, gender, race, medical ICU admitting diagnosis, location at time of ICU transfer, code status at ICU admission, and severity of illness using both Acute Physiology and Chronic Health Evaluation II scores and a model for relative expected mortality. Primary outcomes compared included ICU mortality, in-hospital mortality, medical ICU length of stay, and post-ICU discharge hospital length of stay. Patients admitted to the nurse practitioner-staffed medical ICU were older (63 ± 16.5 vs 59.2 ± 16.9 yr for resident-staffed medical ICU; p = 0.019), more likely to be transferred from an inpatient unit (52.0% vs 40.0% for the resident-staffed medical ICU; p = 0.002), and had a higher severity of illness by relative expected mortality (21.3 % vs 17.2 % for the resident-staffed medical ICU; p = 0.001). There were no differences among primary outcomes except for medical ICU length of stay (nurse practitioner-resident-staffed 7.9 ± 7.5 d vs resident-staffed medical ICU 5.6 ± 6.5 d; p = 0.0001). Post-hospital discharge to nonhome location was also significantly higher in the nurse practitioner-ICU (31.7% in nurse practitioner-staffed medical ICU vs 23.9% in resident-staffed medical ICU; p = 0.24). CONCLUSIONS: We found no difference in mortality between an nurse practitioner-staffed medical ICU and a resident-staffed physician medical ICU. Our study adds further evidence that advanced practice providers can render safe and effective ICU care.

Eosinophil Peroxidase Catalyzed Protein Carbamylation Participates in Asthma.

The biochemical mechanisms through which eosinophils contribute to asthma pathogenesis are unclear. Here we show eosinophil peroxidase (EPO), an abundant granule protein released by activated eosinophils, contributes to characteristic asthma-related phenotypes through oxidative posttranslational modification (PTM) of proteins in asthmatic airways through a process called carbamylation. Using a combination of studies we now show EPO uses plasma levels of the pseudohalide thiocyanate (SCN-) as substrate to catalyze protein carbamylation, as monitored by PTM of protein lysine residues into Nϵ-carbamyllysine (homocitrulline), and contributes to the pathophysiological sequelae of eosinophil activation. Studies using EPO-deficient mice confirm EPO serves as a major enzymatic source for protein carbamylation during eosinophilic inflammatory models, including aeroallergen challenge. Clinical studies similarly revealed significant enrichment in carbamylation of airway proteins recovered from atopic asthmatics versus healthy controls in response to segmental allergen challenge. Protein-bound homocitrulline is shown to be co-localized with EPO within human asthmatic airways. Moreover, pathophysiologically relevant levels of carbamylated protein either incubated with cultured human airway epithelial cells in vitro, or provided as an aerosolized exposure in non-sensitized mice, induced multiple asthma-associated phenotypes including induction of mucin, Th2 cytokines, IFNγ, TGFß, and epithelial cell apoptosis. Studies with scavenger receptor-A1 null mice reveal reduced IL-13 generation following exposure to aerosolized carbamylated protein, but no changes in other asthma-related phenotypes. In summary, EPO-mediated protein carbamylation is promoted during allergen-induced asthma exacerbation, and can both modulate immune responses and trigger a cascade of many of the inflammatory signals present in asthma.

Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells.

BACKGROUND: Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease. METHODS: We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs. CONTROLS: To better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles. RESULTS: Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis. CONCLUSIONS: BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression.

Early recognition of obstructive sleep apnea in patients hospitalized with COPD exacerbation is associated with reduced readmission.

OBJECTIVES: The combination of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease is known as the "overlap syndrome", and results in frequent hospitalizations and worse prognosis. We hypothesized that early detection and treatment of this condition in hospitalized patients may reduce clinical events (hospital admissions and emergency room visits) Methods: Between April 2013 and January 2014 all patients consulted for COPD exacerbation and having a BMI of > 30 kg/m(2) were screened for OSA. If high risk, patients underwent a polysomnography on discharge. Readmission rate in patients compliant with positive airway pressure was compared to patients who were deemed non-compliant based on objective data from the device. RESULTS: Full polysomnogram data and compliance was available on 24 patients. The baseline characteristics were comparable between the compliant and non-compliant groups. The mean change in the total clinical events 6 months prior to intervention compared to 6 months following intervention was -2.1 ± 0.3 in the compliant group, compared to -0.8 ± 0.5 in the non-compliant group (p = 0.01). The mean change in the total clinical events 12 months prior to intervention compared to 12 months following intervention was -2.7 ± 0.5 in the compliant group, compared to -0.8 ± 0.6 in the non-compliant group (p = 0.03) CONCLUSION: In conclusion, our data suggest that early recognition and treatment of OSA in patients admitted with COPD exacerbation and compliant with PAP therapy is associated with reduced 6-month hospital readmission rates and emergency room visits. Screening for OSA in patients admitted with COPD exacerbation is a simple and early intervention that should be encouraged to help reduce hospital readmissions in this patient population.

A pneumocyte-macrophage paracrine lipid axis drives the lung toward fibrosis.

Lipid-laden macrophages, or "foam cells," are observed in the lungs of patients with fibrotic lung disease, but their contribution to disease pathogenesis remains unexplored. Here, we demonstrate that fibrosis induced by bleomycin, silica dust, or thoracic radiation promotes early and sustained accumulation of foam cells in the lung. In the bleomycin model, we show that foam cells arise from neighboring alveolar epithelial type II cells, which respond to injury by dumping lipids into the distal airspaces of the lungs. We demonstrate that oxidized phospholipids accumulate within alveolar macrophages (AMs) after bleomycin injury and that murine and human AMs treated with oxidized phosphatidylcholine (oxPc) become polarized along an M2 phenotype and display enhanced production of transforming growth factor-ß1. The direct instillation of oxPc into the mouse lung induces foam cell formation and triggers a severe fibrotic reaction. Further, we show that reducing pulmonary lipid clearance by targeted deletion of the lipid efflux transporter ATP-binding cassette subfamily G member 1 increases foam cell formation and worsens lung fibrosis after bleomycin. Conversely, we found that treatment with granulocyte-macrophage colony-stimulating factor attenuates fibrotic responses, at least in part through its ability to decrease AM lipid accumulation. In summary, this work describes a novel mechanism leading to foam cell formation in the mouse lung and suggests that strategies aimed at blocking foam cell formation might be effective for treating fibrotic lung disorders.

Lung cancer screening beyond low-dose computed tomography: the role of novel biomarkers.

Lung cancer is the most common and lethal malignancy in the world. The landmark National lung screening trial (NLST) showed a 20% relative reduction in mortality in high-risk individuals with screening low-dose computed tomography. However, the poor specificity and low prevalence of lung cancer in the NLST provide major limitations to its widespread use. Furthermore, a lung nodule on CT scan requires a nuanced and individualized approach towards management. In this regard, advances in high through-put technology (molecular diagnostics, multi-gene chips, proteomics, and bronchoscopic techniques) have led to discovery of lung cancer biomarkers that have shown potential to complement the current screening standards. Early detection of lung cancer can be achieved by analysis of biomarkers from tissue samples within the respiratory tract such as sputum, saliva, nasal/bronchial airway epithelial cells and exhaled breath condensate or through peripheral biofluids such as blood, serum and urine. Autofluorescence bronchoscopy has been employed in research setting to identify pre-invasive lesions not identified on CT scan. Although these modalities are not yet commercially available in clinic setting, they will be available in the near future and clinicians who care for patients with lung cancer should be aware. In this review, we present up-to-date state of biomarker development, discuss their clinical relevance and predict their future role in lung cancer management.

Readmissions after hospital discharge with acute exacerbation of COPD: are we missing something?

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an important part of the disease's morbidity, mortality, and progression, and is associated with increasing utilization of health care resources. The concept of integrated care based on a chronic care model is relatively new to chronic obstructive pulmonary disease, but has proved successful in improving clinical outcomes and probably in decreasing health care utilization in other chronic conditions. A comprehensive approach is needed to target a change in behavioral patterns in patients, increase physician's awareness and adherence to evidence-based recommendations, and address system related issues. This article discusses the evidence for various facets of nonpharmacological management of AECOPD and proposes a model of care that might be the missing link for reducing hospital readmissions for AECOPD. This model may decrease the morbidity, slow disease progression, and curb the increasing health care resource utilization without compromising patient care.

Carbon nanotube-induced pulmonary granulomatous disease: Twist1 and alveolar macrophage M1 activation.

Sarcoidosis, a chronic granulomatous disease of unknown cause, has been linked to several environmental risk factors, among which are some that may favor carbon nanotube formation. Using gene array data, we initially observed that bronchoalveolar lavage (BAL) cells from sarcoidosis patients displayed elevated mRNA of the transcription factor, Twist1, among many M1-associated genes compared to healthy controls. Based on this observation we hypothesized that Twist1 mRNA and protein expression might become elevated in alveolar macrophages from animals bearing granulomas induced by carbon nanotube instillation. To address this hypothesis, wild-type and macrophage-specific peroxisome proliferator-activated receptor gamma (PPARγ) knock out mice were given oropharyngeal instillation of multiwall carbon nanotubes (MWCNT). BAL cells obtained 60 days later exhibited significantly elevated Twist1 mRNA expression in granuloma-bearing wild-type or PPARγ knock out alveolar macrophages compared to sham controls. Overall, Twist1 expression levels in PPARγ knock out mice were higher than those of wild-type. Concurrently, BAL cells obtained from sarcoidosis patients and healthy controls validated gene array data: qPCR and protein analysis showed significantly elevated Twist1 in sarcoidosis compared to healthy controls. In vitro studies of alveolar macrophages from healthy controls indicated that Twist1 was inducible by classical (M1) macrophage activation stimuli (LPS, TNFα) but not by IL-4, an inducer of alternative (M2) macrophage activation. Findings suggest that Twist1 represents a PPARγ-sensitive alveolar macrophage M1 biomarker which is induced by inflammatory granulomatous disease in the MWCNT model and in human sarcoidosis.

Alveolar macrophages of GM-CSF knockout mice exhibit mixed M1 and M2 phenotypes.

BACKGROUND: Activin A is a pleiotrophic regulatory cytokine, the ablation of which is neonatal lethal. Healthy human alveolar macrophages (AMs) constitutively express activin A, but AMs of patients with pulmonary alveolar proteinosis (PAP) are deficient in activin A. PAP is an autoimmune lung disease characterized by neutralizing autoantibodies to Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF). Activin A can be stimulated, however, by GM-CSF treatment of AMs in vitro. To further explore pulmonary activin A regulation, we examined AMs in bronchoalveolar lavage (BAL) from wild-type C57BL/6 compared to GM-CSF knockout mice which exhibit a PAP-like histopathology. Both human PAP and mouse GM-CSF knockout AMs are deficient in the transcription factor, peroxisome proliferator activated receptor gamma (PPARγ). RESULTS: In sharp contrast to human PAP, activin A mRNA was elevated in mouse GM-CSF knockout AMs, and activin A protein was increased in BAL fluid. Investigation of potential causative factors for activin A upregulation revealed intrinsic overexpression of IFNγ, a potent inducer of the M1 macrophage phenotype, in GM-CSF knockout BAL cells. IFNγ mRNA was not elevated in PAP BAL cells. In vitro studies confirmed that IFNγ stimulated activin A in wild-type AMs while antibody to IFNγ reduced activin A in GM-CSF knockout AMs. Both IFNγ and Activin A were also reduced in GM-CSF knockout mice in vivo after intratracheal instillation of lentivirus-PPARγ compared to control lentivirus vector. Examination of other M1 markers in GM-CSF knockout mice indicated intrinsic elevation of the IFNγ-regulated gene, inducible Nitrogen Oxide Synthetase (iNOS), CCL5, and interleukin (IL)-6 compared to wild-type. The M2 markers, IL-10 and CCL2 were also intrinsically elevated. CONCLUSIONS: Data point to IFNγ as the primary upregulator of activin A in GM-CSF knockout mice which in addition, exhibit a unique mix of M1-M2 macrophage phenotypes.

Extracorporeal membrane oxygenation to support whole-lung lavage in pulmonary alveolar proteinosis: salvage of the drowned lungs.

Pulmonary alveolar proteinosis is a rare lung disease characterized by accumulation of lipoproteinaceous material within the alveoli. Therapeutic whole-lung lavage (WLL) under general anesthesia is the standard treatment in patients with progressive symptomatic disease. Severe hypoxemic respiratory failure is uncommon, yet when present poses a technical challenge to performing WLL without further compromising respiratory status. Rarely, hyperbaric chamber or extracorporeal membrane oxygenation (ECMO) has been utilized to perform WLL to manage severe hypoxemia, with venovenous ECMO being used more often. We present a case of hypoxemic and hypercarbic respiratory failure from pulmonary alveolar proteinosis successfully managed by placing the patient on venoarterial ECMO to facilitate the performance of bilateral WLL.

Alveolar macrophage cathelicidin deficiency in severe sarcoidosis.

BACKGROUND: Dysfunctional immune responses characterize sarcoidosis, but the status of cathelicidin, a potent immunoregulatory and antimicrobial molecule, has not been established in clinical disease activity. METHODS: Alveolar macrophage cathelicidin expression was determined in biopsy-proven sarcoidosis patients classified clinically as 'severe' (requiring systemic treatment) or 'non-severe' (never requiring treatment). Bronchoalveolar lavage (BAL) cells from sarcoidosis patients and healthy controls were analyzed for mRNA expression of cathelicidin, vitamin D receptor (VDR) and the VDR coactivator steroid receptor coactivator-3 (SRC3) by quantitative PCR. Cathelicidin-derived peptide LL-37 was determined by immunocytochemistry. Serum calcidiol (25-hydroxyvitamin D2; vitD2) and calcitriol (1,25-dihydroxyvitamin D3; vitD3) were quantified. RESULTS: The results indicated reduced BAL cell expression of cathelicidin and SRC3 in severe but not non-severe sarcoidosis compared to controls. Serum levels of biologically active vitD3 in both severe and non-severe patients were within the control range even though vitD2 levels in both groups were below the recommended level (30 ng/ml). Sarcoidosis and control alveolar macrophages were studied in vitro to determine cathelicidin responses to vitD3 and tumor necrosis factor-α (TNFα), a vitD3 antagonist elevated in active sarcoidosis. Alveolar macrophage cathelicidin was stimulated by vitD3 but repressed by TNFα, which also repressed SRC3. CONCLUSIONS: These findings suggest that TNFα-mediated repression of SRC3 contributes to alveolar macrophage cathelicidin deficiency in severe sarcoidosis despite healthy vitD3 levels. Deficiency of cathelicidin, a multifunctional regulator of immune cells and proinflammatory cytokines, may impede resolution of inflammation in the lungs of patients with severe sarcoidosis.

Rituximab therapy in pulmonary alveolar proteinosis improves alveolar macrophage lipid homeostasis.

RATIONALE: Pulmonary Alveolar Proteinosis (PAP) patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and the PPARγ-regulated ATP binding cassette (ABC) lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL) fluid, and 7/9 patients completing the trial demonstrated clinical improvement as measured by arterial blood oxygenation. OBJECTIVES: This study sought to determine whether rituximab therapy would restore lipid metabolism in PAP alveolar macrophages. METHODS: BAL samples were collected from patients pre- and 6-months post-rituximab infusion for evaluation of mRNA and lipid changes. RESULTS: Mean PPARγ and ABCG1 mRNA expression increased 2.8 and 5.3-fold respectively (p ≤ 0.05) after treatment. Lysosomal phospholipase A2 (LPLA2) (a key enzyme in surfactant degradation) mRNA expression was severely deficient in PAP patients pre-treatment but increased 2.8-fold post-treatment. In supplemental animal studies, LPLA2 deficiency was verified in GM-CSF KO mice but was not present in macrophage-specific PPARγ KO mice compared to wild-type controls. Oil Red O intensity of PAP alveolar macrophages decreased after treatment, indicating reduced intracellular lipid while extracellular free cholesterol increased in BAL fluid. Furthermore, total protein and Surfactant protein A were significantly decreased in the BAL fluid post therapy. CONCLUSIONS: Reduction in GM-CSF autoantibodies by rituximab therapy improves alveolar macrophage lipid metabolism by increasing lipid transport and surfactant catabolism. Mechanisms may involve GM-CSF stimulation of alveolar macrophage ABCG1 and LPLA2 activities by distinct pathways.

Alveolar macrophage activation in obese patients with obstructive sleep apnea.

BACKGROUND: Classically, activated macrophages in adipose tissue, liver, and muscle have been implicated in many conditions associated with obesity, including insulin resistance and the metabolic syndrome. Despite numerous pulmonary comorbidities and the sentinel role alveolar macrophages play in innate immunity and lung homeostasis, their activation status has not been examined in these patients. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) has been shown to be a negative regulator of inflammation in addition to regulating lipid and glucose metabolism. PPAR-γ is expressed constitutively in healthy alveolar macrophages and decreased on activation. We hypothesized that PPAR-γ would be downregulated in alveolar macrophages from obese patients with obstructive sleep apnea (OSA) in the absence of overt lung disease. METHODS: Alveolar macrophages were obtained by bronchoalveolar lavage from obese individuals with and without OSA and healthy controls. RESULTS: Data indicated that PPAR-γ functional activity was decreased by 48% in obese with OSA and 26% without OSA (P < .05). In obese patients with OSA, PPAR-γ mRNA was decreased 2-fold compared with controls (P < .05), whereas obese patients without OSA, it was not different. Regardless of OSA, alveolar macrophages of obese patients demonstrated increased interleukin-6 mRNA. CONCLUSION: These findings are consistent with the presence of classic macrophage activation and an inflammatory lung environment. Data from this study suggest that alveolar macrophage dysfunction becomes aggravated in OSA and may increase pulmonary disease susceptibility.

Inflammatory profile and response to anti-tumor necrosis factor therapy in patients with chronic pulmonary sarcoidosis.

Sarcoidosis is an inflammatory, granulomatous disease of unknown etiology that most commonly afflicts the lungs. Despite aggressive immunosuppressive therapies, many sarcoidosis patients still chronically present significant symptoms. Infliximab, a therapeutic tumor necrosis factor alpha (TNF-α) monoclonal antibody (MAb), produced a small but significant improvement in forced vital capacity (FVC) in sarcoidosis patients in a double-blind, placebo-controlled, phase II clinical trial. In the current study, serum samples from this clinical trial were assessed to evaluate the underlying hypothesis that treatment with infliximab would reduce systemic inflammation associated with sarcoidosis, correlating with the extent of clinical response. A 92-analyte multiplex panel was used to assess the expression of serum proteins in 134 sarcoidosis patients compared with sera from 50 healthy controls. A strong systemic inflammatory profile was associated with sarcoidosis, with 29 analytes significantly elevated in sarcoidosis (false-discovery rate, <0.05 and >50% higher than controls). The associated analytes included chemokines, neutrophil-associated proteins, acute-phase proteins, and metabolism-associated proteins. This profile was evident despite patients receiving corticosteroids and immunosuppressive therapies. Following infliximab treatment, sarcoidosis patients expressing the highest levels of TNF-α, who had more severe disease, had the greatest improvement in FVC and reduction in serum levels of the inflammatory proteins MIP-1ß and TNF-RII. This study supports the need for further exploration of anti-TNF therapy for chronic sarcoidosis patients, particularly for those expressing the highest serum levels of TNF-α.

Novel murine model of chronic granulomatous lung inflammation elicited by carbon nanotubes.

Lung granulomas are associated with numerous conditions, including inflammatory disorders, exposure to environmental pollutants, and infection. Osteopontin is a chemotactic cytokine produced by macrophages, and is implicated in extracellular matrix remodeling. Furthermore, osteopontin is up-regulated in granulomatous disease, and osteopontin null mice exhibit reduced granuloma formation. Animal models currently used to investigate chronic lung granulomatous inflammation bear a pathological resemblance, but lack the chronic nature of human granulomatous disease. Carbon nanoparticles are generated as byproducts of combustion. Interestingly, experimental exposures to carbon nanoparticles induce pulmonary granuloma-like lesions. However, the recruited cellular populations and extracellular matrix gene expression profiles within these lesions have not been explored. Because of the rapid resolution of granulomas in current animal models, the mechanisms responsible for persistence have been elusive. To overcome the limitations of previous models, we investigated whether a model using multiwall carbon nanoparticles would resemble chronic human lung granulomatous inflammation. We hypothesized that pulmonary exposure to multiwall carbon nanoparticles would induce granulomas, elicit a macrophage and T-cell response, and mimic other granulomatous disorders with an up-regulation of osteopontin. This model demonstrates: (1) granulomatous inflammation, with macrophage and T-cell infiltration; (2) resemblance to the chronicity of human granulomas, with persistence up to 90 days; and (3) a marked elevation of osteopontin, metalloproteinases, and cell adhesion molecules in granulomatous foci isolated by laser-capture microdissection and in alveolar macrophages from bronchoalveolar lavage. The establishment of such a model provides an important platform for mechanistic studies on the persistence of granuloma.

Restoration of PPARγ reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice.

Pulmonary alveolar proteinosis (PAP) is a lung disease characterized by a deficiency of functional granulocyte macrophage colony-stimulating factor (GM-CSF) resulting in surfactant accumulation and lipid-engorged alveolar macrophages. GM-CSF is a positive regulator of PPARγ that is constitutively expressed in healthy alveolar macrophages. We previously reported decreased PPARγ and ATP-binding cassette transporter G1 (ABCG1) levels in alveolar macrophages from PAP patients and GM-CSF knockout (KO) mice, suggesting PPARγ and ABCG1 involvement in surfactant catabolism. Because ABCG1 represents a PPARγ target, we hypothesized that PPARγ restoration would increase ABCG1 and reduce macrophage lipid accumulation. Upregulation of PPARγ was achieved using a lentivirus expression system in vivo. GM-CSF KO mice received intratracheal instillation of lentivirus (lenti)-PPARγ or control lenti-eGFP. Ten days postinstillation, 79% of harvested alveolar macrophages expressed eGFP, demonstrating transduction. Alveolar macrophages showed increased PPARγ and ABCG1 expression after lenti-PPARγ instillation, whereas PPARγ and ABCG1 levels remained unchanged in lenti-eGFP controls. Alveolar macrophages from lenti-PPARγ-treated mice also exhibited reduced intracellular phospholipids and increased cholesterol efflux to HDL, an ABCG1-mediated pathway. In vivo instillation of lenti-PPARγ results in: 1) upregulating ABCG1 and PPARγ expression of GM-CSF KO alveolar macrophages, 2) reducing intracellular lipid accumulation, and 3) increasing cholesterol efflux activity.

Sleep and metabolism: an overview.

Sleep and its disorders are increasingly becoming important in our sleep deprived society. Sleep is intricately connected to various hormonal and metabolic processes in the body and is important in maintaining metabolic homeostasis. Research shows that sleep deprivation and sleep disorders may have profound metabolic and cardiovascular implications. Sleep deprivation, sleep disordered breathing, and circadian misalignment are believed to cause metabolic dysregulation through myriad pathways involving sympathetic overstimulation, hormonal imbalance, and subclinical inflammation. This paper reviews sleep and metabolism, and how sleep deprivation and sleep disorders may be altering human metabolism.

Montelukast added to fluticasone propionate does not alter inflammation or outcomes.

BACKGROUND: Airway inflammation is a key pathological feature of asthma which underlies its clinical presentation. OBJECTIVES: To examine whether adding a leukotriene modifier to an inhaled corticosteroid produces further clinical and/or anti-inflammatory benefits in patients symptomatic on short-acting beta(2)-agonists. METHODS: Patients uncontrolled on short-acting beta(2)-agonists were treated for 12 weeks with either fluticasone propionate (100mcg BD) or fluticasone propionate (100mcg BD) and montelukast (10mg QD) in a randomized, double-blind, parallel group study. Bronchoscopy with endobronchial biopsy and bronchoalveolar lavage (BAL) was performed before and after treatment to compare effects on airway inflammation. RESULTS: Of 103 subjects enrolled, 89 subjects completed treatment and 82 subjects had matched pair biopsy samples. Submucosal eosinophil counts, the primary endpoint, and asthma control improved to similar extents after both treatments (p