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Life Years Gained From Smoking-Cessation Counseling After Myocardial Infarction

Wed, 05/31/2017 - 11:44pm

INTRODUCTION: Hospitalization for acute myocardial infarction (AMI) is an opportune time to counsel smokers to quit. Studies have demonstrated lower short-term mortality for counseled versus non-counseled smokers; yet, little is known about the long-term survival benefits of post-AMI smoking-cessation counseling (SCC).

METHODS: Data from the Cooperative Cardiovascular Project, a prospective cohort study of elderly patients with AMI between 1994 and 1996 with >17 years of follow-up, were used to evaluate the association of SCC with short- and long-term mortality in smokers with AMI. Life expectancy and years of potential life gained were used to quantify the long-term survival benefits of SCC. Cox proportional hazards models with exponential extrapolation were used to estimate life expectancy.

RESULTS: The analysis included 13,815 smokers, of whom 5,695 (41.2%) received SCC. Non-counseled smokers had higher crude mortality than counseled smokers over all 17 years of follow-up. After adjustment for patient and hospital characteristics, SCC was associated with a 22.6% lower 30-day mortality and a 7.5% lower mortality over 17 years. These survival differences produced higher life expectancy estimates for counseled smokers than non-counseled smokers at all ages, which resulted in average gains in life years of 0.13 (95% CI=-0.31, 0.56) to 0.58 (95% CI=0.25, 0.91) years, with the largest gains observed in older smokers.

CONCLUSIONS: SCC is associated with longer life expectancy and gains in life years in elderly smokers with AMI, supporting the importance of post-AMI counseling efforts.

Osteoporosis in the Women's Health Initiative: Another Treatment Gap

Wed, 05/31/2017 - 11:44pm

BACKGROUND: Osteoporotic fractures are associated with high morbidity, mortality, and cost.

METHODS: We performed a post hoc analysis of the Women's Health Initiative (WHI) clinical trials data to assess osteoporosis treatment and identify participant characteristics associated with utilization of osteoporosis medication(s) after new diagnoses of osteoporosis or fracture. Information from visits prior to and immediately subsequent to the first fracture event or osteoporosis diagnosis were evaluated for medication use. A full logistic regression model was used to identify factors predictive of osteoporosis medication use after a fracture or a diagnosis of osteoporosis.

RESULTS: The median length of follow-up from enrollment to the last WHI clinic visit for the study cohort was 13.9 years. Among the 13,990 women who reported new diagnoses of osteoporosis or fracture between enrollment and their final WHI visit, and also had medication data available, 21.6% reported taking an osteoporosis medication other than estrogen. Higher daily calcium intake, diagnosis of osteoporosis alone or both osteoporosis and fracture (compared with diagnosis of fracture alone), Asian or Pacific Islander race/ethnicity (compared with White/Caucasian), higher income, and hormone therapy use (past or present) were associated with significantly higher likelihood of osteoporosis pharmacotherapy. Women with Black/African American race/ethnicity (compared with White/Caucasian), body mass index >/=30 (compared with body mass index of 18.5-24.9), current tobacco use (compared with past use or lifetime nonusers), and history of arthritis were less likely to use osteoporosis treatment.

CONCLUSION: Despite well-established treatment guidelines in postmenopausal women with osteoporosis or history of fractures, pharmacotherapy use was suboptimal in this study. Initiation of osteoporosis treatment after fragility fracture may represent an opportunity to improve later outcomes in these high-risk women. Specific attention needs to be paid to increasing treatment among women with fragility fractures, obesity, current tobacco use, history of arthritis, or of Black race/ethnicity.

Changes in the inflammatory potential of diet over time and risk of colorectal cancer in postmenopausal women

Wed, 05/31/2017 - 11:44pm

We examined the associations between changes in dietary inflammatory potential and risk of colorectal cancer (CRC) in 87,042 postmenopausal women recruited from 1993-1998 into the Women's Health Initiative. Food frequency questionnaire data were used to compute patterns of change in dietary inflammatory index (DII) scores and cumulative average DII scores over 3 years. Cox regression models were used to estimate hazard ratios for CRC risk. After a median 16.2 years follow-up, 1,038 CRC cases were diagnosed. DII changes were not substantially associated with overall CRC, but proximal colon cancer risk was higher in the pro-inflammatory change DII compared to the anti-inflammatory stable DII groups (hazard ratio = 1.32; 95% confidence interval: 1.01, 1.74). Among non-users of nonsteroidal anti-inflammatory drugs (NSAID) (Pinteraction = 0.055) the pro-inflammatory stable DII group was at increased risk of overall CRC and proximal colon cancer. Also among non-users of NSAID, risks of overall CRC, colon cancer, and proximal colon cancer were higher in the highest quintile compared to the lowest cumulative average DII quintile (65%, 61%, and 91% increased risk, respectively). Dietary changes towards, or a history of, pro-inflammatory diets are associated with an elevated risk of colon cancer, particularly for proximal colon cancer and among non-users of NSAID.

Instrumental-Variables Simultaneous Equations Model of Physical Activity and Body Mass Index: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Wed, 05/31/2017 - 11:44pm

We used full-system-estimation instrumental-variables simultaneous equations modeling (IV-SEM) to examine physical activity relative to body mass index (BMI; weight (kg)/height (m)(2)) using 25 years of data (1985/1986 to 2010/2011) from the Coronary Artery Risk Development in Young Adults (CARDIA) Study (n = 5,115; ages 18-30 years at enrollment). Neighborhood environment and sociodemographic instruments were used to characterize physical activity, fast-food consumption, smoking, alcohol consumption, marriage, and childbearing (women) and to predict BMI using semiparametric full-information maximum likelihood estimation to control for unobserved time-invariant and time-varying residual confounding and differential measurement error through model-derived discrete random effects. Comparing robust-variance ordinary least squares, random-effects regression, fixed-effects regression, single-equation-estimation IV-SEM, and full-system-estimation IV-SEM, estimates from random- and fixed-effects models and the full-system-estimation IV-SEM were unexpectedly similar, despite the lack of control for residual confounding with the random-effects estimator. Ordinary least squares tended to overstate the significance of health behaviors in BMI, while results from single-equation-estimation IV-SEM were notably different, revealing the impact of weak instruments in standard instrumental-variable methods. Our robust findings for fixed effects (which does not require instruments but has a high cost in lost degrees of freedom) and full-system-estimation IV-SEM (vs. standard IV-SEM) demonstrate potential for a full-system-estimation IV-SEM method even with weak instruments.

Elderly patients are at increased risk for treatment failure in outpatient management of purulent skin infections

Wed, 05/31/2017 - 11:44pm

OBJECTIVE: Current Infectious Disease Society of America (IDSA) guidelines for the management of purulent skin or soft tissue infections do not account for patient age in treatment recommendations. The study objective was to determine if age was associated with outpatient treatment failure for purulent skin infection after adjusting for IDSA treatment guidelines.

METHODS: We conducted a multicenter retrospective study of adult patients treated for a purulent skin infection and discharged home from four emergency departments between April and September 2014. Patients were followed for one month to assess for treatment failure (defined as need for a change in antibiotics, surgical intervention, or hospitalization). We used multivariable logistic regression to examine the role of patient age on treatment failure adjusting for demographic variables (gender, race), comorbidities and severity of infection.

RESULTS: A total of 467 patients met inclusion criteria (mean age 37.9years [SD 14.0], 48.2% of whom were women). Overall, 12.4% failed initial therapy. Patients 65 years and older (n=35) were almost 4 times more likely to fail initial ED therapy in follow-up compared with younger patients (adjusted Odds Ratio (OR) 3.87, 95% Confidence Interval (CI) 1.24-12.10). After adjustment, for every 10years of advancing age there was a 43% increased odds of failing initial treatment (OR 1.43 95% CI 1.09-1.88).

CONCLUSION: Elderly patients with purulent skin infections, whose providers followed the 2014 IDSA guidelines, were more likely to fail initial treatment than younger patients. This study suggests that there is a need to re-evaluate treatment guidelines in elderly patients.

Metabolomic Profiling in Relation to New-Onset Atrial Fibrillation (from the Framingham Heart Study)

Wed, 05/31/2017 - 11:44pm

Previous studies have shown several metabolic biomarkers to be associated with prevalent and incident atrial fibrillation (AF), but the results have not been replicated. We investigated metabolite profiles of 2,458 European ancestry participants from the Framingham Heart Study without AF at the index examination and followed them for 10 years for new-onset AF. Amino acids, organic acids, lipids, and other plasma metabolites were profiled by liquid chromatography-tandem mass spectrometry using fasting plasma samples. We conducted Cox proportional hazard analyses for association between metabolites and new-onset AF. We performed hypothesis-generating analysis to identify novel metabolites and hypothesis-testing analysis to confirm the previously reported associations between metabolites and AF. Mean age was 55.1 +/- 9.9 years, and 53% were women. Incident AF developed in 156 participants (6.3%) in 10 years of follow-up. A total of 217 metabolites were examined, consisting of 54 positively charged metabolites, 59 negatively charged metabolites, and 104 lipids. None of the 217 metabolites met our a priori specified Bonferroni corrected level of significance in the multivariate analyses. We were unable to replicate previous results demonstrating associations between metabolites that we had measured and AF. In conclusion, in our metabolomics approach, none of the metabolites we tested were significantly associated with the risk of future AF.

Serum brain-derived neurotrophic factor and risk of atrial fibrillation

Wed, 05/31/2017 - 11:44pm

Brain-derived neurotrophic factor (BDNF) is expressed by endothelial cells and can affect cardiovascular function. We examined if serum BDNF was associated with risk of incident atrial fibrillation (AF) in the Framingham Heart Study.

METHODS: We studied individuals without an AF diagnosis at baseline from the Framingham original and offspring cohorts. We used age- and sex-adjusted, and multivariable-adjusted Cox proportional hazards regression models to examine the association of serum BDNF concentrations with 10-year risk of incident AF.

RESULTS: We studied 3,457 participants (mean age 65+/-11years, 58% women). During follow-up, 395 participants developed AF. In unadjusted analysis, higher mean serum BDNF concentration was associated with lower incidence of AF (hazard ratio 0.89 per SD, 95% CI 0.80-0.99). In multivariable-adjusted analyses, serum BDNF concentration was not significantly associated with incident AF (hazard ratio 0.98 per SD, 95% CI 0.88-1.09). Compared with the lowest quartile, BDNF levels in the other quartiles were not associated with risk of AF in multivariable-adjusted analyses. No interactions between sex or age with serum BDNF concentrations and risk of AF were found.

CONCLUSIONS: In our prospective, community-based sample, we did not find a statistically significant association of serum BDNF levels with risk of incident AF.

Gut-liver axis and sterile signals in the development of alcoholic liver disease

Wed, 05/31/2017 - 11:44pm

Background: Innate immunity plays a critical role in the development of alcohol-induced liver inflammation. Understanding the inter-relationship of signals from within and outside of the liver that trigger liver inflammation is pivotal for development of novel therapeutic targets of alcoholic liver disease (ALD).

Aim: The aim of this paper is to review recent advances in the field of alcohol-induced liver inflammation.

Methods: A detailed literature review was performed using the PubMed database published between January 1980 and December 2016.

Results: We provide an update on the role of intestinal microbiome, metabolome and the gut-liver axis in ALD, discuss the growing body of evidence on the diversity of liver macrophages and their differential contribution to alcohol-induced liver inflammation, and highlight the crucial role of inflammasomes in integration of inflammatory signals in ALD. Studies to date have identified a multitude of new therapeutic targets, some of which are currently being tested in patients with severe alcoholic hepatitis. These treatments aim to strengthen the intestinal barrier, ameliorate liver inflammation and augment hepatocyte regeneration.

Conclusion: Given the complexity of inflammation in ALD, multiple pathobiological mechanisms may need to be targeted at the same time as it seems unlikely that there is a single dominant pathogenic pathway in ALD that would be easily targeted using a single target drug approach.

Short summary: Here, we focus on recent advances in immunopathogenesis of alcoholic liver disease (ALD), including gut-liver axis, hepatic macrophage activation, sterile inflammation and synergy between bacterial and sterile signals. We propose a multiple parallel hit model of inflammation in ALD and discuss its implications for clinical trials in alcoholic hepatitis.

Prescription contraception use and adherence by women with substance use disorders

Wed, 05/31/2017 - 11:44pm

BACKGROUND AND AIMS: Unintended pregnancy rates are high among women with substance use disorders (SUDs), which could be explained partly by lower use of and adherence to contraception. We aimed to test: (1) the association of SUD with prescription contraceptive use, contraceptive method selection and adherence; (2) whether practices participating in the Patient-Centered Medical Home Initiative (PCMHI) had better contraceptive use and adherence for patients with SUD; and (3) for differences in the association of SUD with adherence by type of contraceptive used.

DESIGN: Retrospective cohort analysis of claims and encounter data.

SETTING: Massachusetts, USA. PARTICIPANTS: A total of 47 902 women aged 16-45 years enrolled in Medicaid or Commonwealth Care in Massachusetts between 2010 and 2014.

MEASUREMENTS: We examined three dependent variables: (1) use of a reversible prescription contraceptive during 2012; (2) the contraceptive methods used; and (3) the proportion of days covered by a prescription contraceptive in the year following the first prescription contraceptive claim. The primary predictor was diagnosed SUD, defined as at least one claim for an alcohol or drug use disorder.

FINDINGS: SUD was associated with lower rates of prescription contraceptive use during 2012 [19.2 versus 23.9%; adjusted odds ratio (aOR) = 0.79, P < 0.001]. SUD was associated with decreased selection of long-acting reversible contraception (LARC) compared with short-acting contraception (SARC) (42.8 versus 44.5%; aOR = 0.83, P = 0.011). There was no significant association between SUD and adherence (aOR = 0.84, P = 0.068). PCMHI enrollment did not alter the relationship between SUD and contraceptive use or adherence. Contraceptive method did not impact the relationship between SUD and adherence.

CONCLUSION: Women with substance use disorders are less likely to use prescription contraceptives, especially long-acting methods, but are not significantly less likely to adhere to them once prescribed than women without substance use disorders.

Gender differences in risk factors for cigarette smoking initiation in childhood

Wed, 05/31/2017 - 11:44pm

INTRODUCTION: We investigated whether established risk factors for initiating cigarette smoking during adolescence (parents, siblings, friends smoke; home smoking rules, smokers at home, exposure to smoking in cars, academic performance, susceptibility to smoking, depressive symptoms, self-esteem, school connectedness, use of other tobacco products) are associated with initiation in preadolescents, and whether the effects of these factors differ by gender.

METHODS: In spring 2005, baseline data were collected in self-report questionnaires from 1801 5th grade students including 1553 never-smokers (mean age=10.7years), in the longitudinal AdoQuest I Study in Montreal, Canada. Follow-up data were collected in the fall and spring of 6th grade (2005-2006). Poisson regression analyses with robust variance estimated the effects of each risk factor on initiation and additive interactions with gender were computed to assess the excess risk of each risk factor in girls compared to boys.

RESULTS: 101 of 1399 participants in the analytic sample (6.7% of boys; 7.7% of girls) initiated smoking during follow-up. After adjustment for age, gender and maternal education, all risk factors except academic performance and school connectedness were statistically significantly associated with initiation. Paternal and sibling smoking were associated with initiation in girls only, and girls with lower self-esteem had a significant excess risk of initiating smoking in 6th grade.

CONCLUSIONS: Risk factors for smoking initiation in preadolescents mirror those in adolescents; their effects do not differ markedly by gender. Preventive programs targeting children should focus on reducing smoking in the social environment and the dangers of poly-tobacco use.

Shape Recovery with Concomitant Mechanical Strengthening of Amphiphilic Shape Memory Polymers in Warm Water

Wed, 05/31/2017 - 11:44pm

Maintaining adequate or enhancing mechanical properties of shape memory polymers (SMPs) after shape recovery in an aqueous environment are greatly desired for biomedical applications of SMPs as self-fitting tissue scaffolds or minimally invasive surgical implants. Here we report stable temporary shape fixing and facile shape recovery of biodegradable triblock amphiphilic SMPs containing a poly(ethylene glycol) (PEG) center block and flanking poly(lactic acid) or poly(lactic-co-glycolic acid) blocks in warm water, accompanied by concomitant enhanced mechanical strengths. Differential scanning calorimetry (DSC), wide-angle X-ray diffraction (WXRD), and small-angle X-ray scattering (SAXS) analyses revealed that the unique stiffening of the amphiphilic SMPs upon hydration was due to hydration-driven microphase separation and PEG crystallization. We further demonstrated that the chemical composition of degradable blocks in these SMPs could be tailored to affect the persistence of hydration-induced stiffening upon subsequent dehydration. These properties combined open new horizons for these amphiphilic SMPs for smart weight-bearing in vivo applications (e.g., as self-fitting intervertebral discs). This study also provides a new material design strategy to strengthen polymers in aqueous environment in general.

The Case for the Patient-Centered Medical Home in Correctional Healthcare

Tue, 05/30/2017 - 5:31pm

The patient-centered medical home model of care should be applied to incarcerated populations, who have complex medical, behavioral, and substance abuse issues that demand integrated care. A blog post on The Huffington Post about the positive impact PCMH can have on correctional health care from Julie White of the Health and Criminal Justice Program.

President Obama’s Legacy of Criminal Justice Reform: Reducing Disparity and Increasing Opportunity

Tue, 05/30/2017 - 5:30pm

As President Donald J. Trump begins his term and his administration takes shape, it is important for us to reflect on all of the criminal justice reforms of the past eight years under President Barack Obama. A post on The Huffington Post outlining those reforms from Julie White of the Health and Criminal Justice Program.

Mapping Your Route To Patient-centered Medical Home Recognition

Tue, 05/30/2017 - 5:30pm

Many primary care practices wish to become patient-centered medical homes, but the transformation process can be daunting. Here, three experts offer some professional advice.

This is a blog post to Primary Care Progress Notes.

Implementation of an opioid management initiative by a state Medicaid program

Tue, 05/30/2017 - 5:29pm

BACKGROUND: The utilization of prescription opioids has increased over the last 2 decades. Associated with this is the misuse of prescription opioids for nonmedical purposes. Medicaid programs have struggled with developing strategies that balance best practice models, appropriate utilization, and reduction in costs associated with the opioid medication class.

OBJECTIVE: To examine the impact of a 2-year stepwise initiative to reduce utilization and therapy costs of long-acting opioid analgesics (LAOA) by addressing issues of high dose, daily dose, and preferred therapeutic alternatives.

METHODS: Utilization data from the Massachusetts Medicaid pharmacy program for LAOAs were reviewed and compared for 2 time periods. The calendar year prior to the initiative, 2002, was used as a base year and represents a time period when there were no restrictions in place for members to obtain long-acting opioids. The calendar year 2005 was the comparison year representing a time period after the multiple steps of the initiative had been implemented. A retrospective claims-based analysis was performed to determine the impact of restrictions on LAOAs, defined as brand and generic versions of oxycodone ER, morphine ER, methadone, and fentanyl transdermal system. The primary measure was the percentage of change of unique utilizers, paid claims, and average daily dose for each LAOA following the implementation of the opioid management initiative. Secondary measures included a cost analysis.

RESULTS: Compared with 2002, the overall number of LAOA unique utilizers declined 17.8% (P < 0.0001), and the overall number of claims declined by 4.1% (P < 0.0001), while Medicaid pharmacy benefit member enrollment remained relatively stable. Average daily dose declined in methadone and morphine ER and increased in oxycodone ER and fentanyl transdermal system. The 2005 overall cost of LAOAs decreased 8.0% compared with the overall cost in 2002. The per-member-per-month (PMPM) cost for opioid users in 2002 was $110.57 ($120.04 when adjusted to 2005 dollars) compared with $123.75 in 2005. In comparison, the overall PMPM for all members in 2002 was $3.52 ($3.82 when adjusted to 2005 dollars) compared with $3.59 in 2005.

CONCLUSIONS: Our study successfully demonstrated that a state Medicaid program initiative can result in a significant overall decrease in opioid class utilization specifically for the targeted, more costly agents. This was achieved via the implementation of a Therapeutic Class Management multidisciplinary workgroup that established a prior authorization process implementing limits on dose, as well as identified preferred less costly agents. It further facilitated the direct opportunity for pharmacy-prescriber collaboration for LAOA medication management.

State fiscal considerations and research opportunities emerging from the Affordable Care Act's Medicaid expansion

Tue, 05/30/2017 - 5:29pm

This article discusses the economic impacts of Medicaid expansion under the Affordable Care Act and was based upon a panel presentation given by the authors on January 24, 2014 at a Boston University School of Law symposium: "Improved Health at a Reduced Cost? Economic Perspectives on the Patient Protection & Affordable Care Act."

Hepatitis C Virus-Induced Monocyte Differentiation Into Polarized M2 Macrophages Promotes Stellate Cell Activation via TGF-beta

Tue, 05/30/2017 - 12:13pm

BACKGROUND and AIMS: Monocyte and macrophage (MPhi) activation contributes to the pathogenesis of chronic hepatitis C virus (HCV) infection. Disease pathogenesis is regulated by both liver-resident MPhis and monocytes recruited as precursors of MPhis into the damaged liver. Monocytes differentiate into M1 (classic/proinflammatory) or M2 (alternative/anti-inflammatory) polarized MPhis in response to tissue microenvironment. We hypothesized that HCV-infected hepatoma cells (infected with Japanese fulminant hepatitis-1 [Huh7.5/JFH-1]) induce monocyte differentiation into polarized MPhis.

METHODS: Healthy human monocytes were co-cultured with Huh7.5/JFH-1 cells or cell-free virus for 7 days and analyzed for MPhi markers and cytokine levels. A similar analysis was performed on circulating monocytes and liver MPhis from HCV-infected patients and controls.

RESULTS: Huh7.5/JFH-1 cells induced monocytes to differentiate into MPhis with increased expression of CD14 and CD68. HCV-MPhis showed M2 surface markers (CD206, CD163, and Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN)) and produced both proinflammatory and anti-inflammatory cytokines. HCV-induced early interleukin 1beta production promoted transforming growth factor (TGF)beta production and MPhi polarization to an M2 phenotype. TGF-beta secreted by M2-MPhi led to hepatic stellate cell activation indicated by increased expression of collagen, tissue inhibitor of metalloproteinase 1, and alpha-smooth muscle actin. In vivo, we observed a significant increase in M2 marker (CD206) expression on circulating monocytes and in the liver of chronic HCV-infected patients. Furthermore, we observed the presence of a unique collagen-expressing CD14+CD206+ monocyte population in HCV patients that correlated with liver fibrosis.

CONCLUSIONS: We show an important role for HCV in induction of monocyte differentiation into MPhis with a mixed M1/M2 cytokine profile and M2 surface phenotype that promote stellate cell activation via TGF-beta. We also identified circulating monocytes expressing M2 marker and collagen in chronic HCV infection that can be explored as a biomarker.

Molecular Basis and Targeted Inhibition of CBFbeta-SMMHC Acute Myeloid Leukemia

Tue, 05/30/2017 - 12:13pm

Acute myeloid leukemia (AML) is characterized by recurrent chromosomal rearrangements that encode for fusion proteins which drive leukemia initiation and maintenance. The inv(16) (p13q22) rearrangement is a founding mutation and the associated CBFbeta-SMMHC fusion protein is essential for the survival of inv(16) AML cells. This Chapter will discuss our understanding of the function of this fusion protein in disrupting hematopoietic homeostasis and creating pre-leukemic blasts, in its cooperation with other co-occurring mutations during leukemia initiation, and in leukemia maintenance. In addition, this chapter will discuss the current approaches used for the treatment of inv(16) AML and the recent development of AI-10-49, a selective targeted inhibitor of CBFbeta-SMMHC/RUNX1 binding, the first candidate targeted therapy for inv(16) AML.

Amplification of Adipogenic Commitment by VSTM2A

Tue, 05/30/2017 - 12:13pm

Despite progress in our comprehension of the mechanisms regulating adipose tissue development, the nature of the factors that functionally characterize adipose precursors is still elusive. Defining the early steps regulating adipocyte development is needed for the generation of tools to control adipose tissue size and function. Here, we report the discovery of V-set and transmembrane domain containing 2A (VSTM2A) as a protein expressed and secreted by committed preadipocytes. VSTM2A expression is elevated in the early phases of adipogenesis in vitro and adipose tissue development in vivo. We show that VSTM2A-producing cells associate with the vasculature and express the common surface markers of adipocyte progenitors. Overexpression of VSTM2A induces adipogenesis, whereas its depletion impairs this process. VSTM2A controls preadipocyte determination at least in part by modulating BMP signaling and PPARgamma2 activation. We propose a model in which VSTM2A is produced to preserve and amplify the adipogenic capability of adipose precursors.

Central Role of IL-23 and IL-17 Producing Eosinophils as Immunomodulatory Effector Cells in Acute Pulmonary Aspergillosis and Allergic Asthma

Tue, 05/30/2017 - 12:13pm

Aspergillus fumigatus causes invasive pulmonary disease in immunocompromised hosts and allergic asthma in atopic individuals. We studied the contribution of lung eosinophils to these fungal diseases. By in vivo intracellular cytokine staining and confocal microscopy, we observed that eosinophils act as local sources of IL-23 and IL-17. Remarkably, mice lacking eosinophils had a >95% reduction in the percentage of lung IL-23p19+ cells as well as markedly reduced IL-23 heterodimer in lung lavage fluid. Eosinophils killed A. fumigatus conidia in vivo. Eosinopenic mice had higher mortality rates, decreased recruitment of inflammatory monocytes, and decreased expansion of lung macrophages after challenge with conidia. All of these functions underscore a potential protective role for eosinophils in acute aspergillosis. Given the postulated role for IL-17 in asthma pathogenesis, we assessed whether eosinophils could act as sources of IL-23 and IL-17 in models where mice were sensitized to either A. fumigatus antigens or ovalbumin (OVA). We found IL-23p19+ IL-17AF+ eosinophils in both allergic models. Moreover, close to 95% of IL-23p19+ cells and >90% of IL-17AF+ cells were identified as eosinophils. These data establish a new paradigm in acute and allergic aspergillosis whereby eosinophils act not only as effector cells but also as immunomodulatory cells driving the IL-23/IL-17 axis and contributing to inflammatory cell recruitment.