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1.  Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections 
mBio  2016;7(5):e01653-16.
Gram-positive bacteria in the genus Enterococcus are a frequent cause of catheter-associated urinary tract infection (CAUTI), a disease whose treatment is increasingly challenged by multiantibiotic-resistant strains. We have recently shown that E. faecalis uses the Ebp pilus, a heteropolymeric surface fiber, to bind the host protein fibrinogen as a critical step in CAUTI pathogenesis. Fibrinogen is deposited on catheters due to catheter-induced inflammation and is recognized by the N-terminal domain of EbpA (EbpANTD), the Ebp pilus’s adhesin. In a murine model, vaccination with EbpANTD confers significant protection against CAUTI. Here, we explored the mechanism of protection using passive transfer of immune sera to show that antisera blocking EbpANTD-fibrinogen interactions not only is prophylactic but also can act therapeutically to reduce bacterial titers of an existing infection. Analysis of 55 clinical CAUTI, bloodstream, and gastrointestinal isolates, including E. faecalis, E. faecium, and vancomycin-resistant enterococci (VRE), revealed a diversity of levels of EbpA expression and fibrinogen-binding efficiency in vitro. Strikingly, analysis of 10 strains representative of fibrinogen-binding diversity demonstrated that, irrespective of EbpA levels, EbpANTD antibodies were universally protective. The results indicate that, despite diversity in levels of fibrinogen binding, strategies that target the disruption of EbpANTD-fibrinogen interactions have considerable promise for treatment of CAUTI.
Urinary catheterization is a routine medical procedure, and it has been estimated that 30 million Foley catheters are used annually in the United States. Importantly, placement of a urinary catheter renders the patient susceptible to developing a catheter-associated urinary tract infection, accounting for 1 million cases per year. Additionally, these infections can lead to serious complications, including bloodstream infection and death. Enterococcus strains are a common cause of these infections, and management of enterococcal infections has been more difficult in recent years due to the development of antibiotic resistance and the ability of strains to disseminate, resulting in a major threat in hospital settings. In this study, we developed an antibiotic-sparing treatment that is effective against diverse enterococcal isolates, including vancomycin-resistant enterococci, during catheter-associated urinary tract infections.
PMCID: PMC5080383  PMID: 27795399
2.  The association of low complement with disease activity in systemic sclerosis: a prospective cohort study 
In some rheumatic diseases such as systemic lupus erythematosus (SLE), low serum complement (‘hypocomplementaemia’) is a feature of active disease. However, the role of hypocomplementaemia in systemic sclerosis (SSc) is unknown. We sought to determine the frequency, clinical associations and relationship to disease activity of hypocomplementaemia in SSc.
The study included 1140 patients fulfilling the 2013 American College of Rheumatology criteria for SSc. Demographic, serological and clinical data, obtained prospectively through annual review, were analysed using univariable methods. Linear and logistic regression, together with generalised estimating equations, were used to determine the independent correlates of hypocomplementaemia ever, and at each visit, respectively.
At least one episode of hypocomplementaemia (low C3 and/or low C4) occurred in 24.1 % of patients over 1893 visits; these patients were more likely to be seropositive for anti-ribonucleoprotein (OR = 3.8, p = 0.002), anti-Ro (OR = 2.2, p = 0.002), anti-Smith (OR = 6.3, p = 0.035) and anti-phospholipid antibodies (OR = 1.4, p = 0.021) and were more likely to display features of overlap connective tissue disease, in particular polymyositis (OR = 16.0, p = 0.012). However, no association was found between hypocomplementaemia and either the European Scleroderma Study Group disease activity score or any of its component variables (including erythrocyte sedimentation rate) in univariate analysis. Among patients with SSc overlap disease features, those who were hypocomplementaemic were more likely to have digital ulcers (OR = 1.6, p = 0.034), tendon friction rubs (OR = 2.4, p = 0.037), forced vital capacity <80 % predicted (OR = 2.9, p = 0.008) and lower body mass index (BMI) (OR for BMI = 0.9, p < 0.0005) at that visit, all of which are features associated with SSc disease activity and/or severity.
While hypocomplementaemia is not associated with disease activity in patients with non-overlap SSc, it is associated with some features of increased SSc disease activity in patients with overlap disease features.
PMCID: PMC5075219  PMID: 27770830
Systemic sclerosis; Complement; Disease activity
3.  The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity 
Cell  2016;166(5):1215-1230.e20.
Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models reveal that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.
Graphical Abstract
•Mutation of OTULIN causes OTULIN-related autoinflammatory syndrome (ORAS) in humans•Anti-TNF treatment reverses inflammation in ORAS patient and OTULIN-deficient mice•OTULIN deficiency deregulates M1-polyUb signaling and causes sterile inflammation•Loss of OTULIN has cell-type-specific effects on LUBAC abundance and signaling
A homozygous hypomorphic mutation in the deubiquitinase OTULIN causes a potentially fatal autoinflammatory disorder, which is reconciled in mouse models.
PMCID: PMC5002269  PMID: 27523608
4.  A Tale of Two Trails: Exploring Different Paths to Success 
This comparative case study investigates 2 successful community trail initiatives, using the Active Living By Design (ALBD) Community Action Model as an analytical framework. The model includes 5 strategies: preparation, promotion, programs, policy, and physical projects.
Key stakeholders at 2 sites participated in in-depth interviews (N = 14). Data were analyzed for content using Atlas Ti and grouped according to the 5 strategies.
Securing trail resources was challenging, but shared responsibilities facilitated trail development.
The initiatives demonstrated minimal physical activity encouragement strategies.
Community stakeholders did not coordinate programmatic opportunities for routine physical activity.
Trails’ inclusion in regional greenway master plans contributed to trail funding and development. Policies that were formally institutionalized and enforced led to more consistent trail construction and safer conditions for users.
Physical Projects
Consistent standards for way finding signage and design safety features enhanced trail usability and safety.
Communities with different levels of government support contributed unique lessons to inform best practices of trail initiatives. This study revealed a disparity between trail development and use-encouragement strategies, which may limit trails’ impact on physical activity. The ALBD Community Action Model provided a viable framework to structure cross-disciplinary community trail initiatives.
PMCID: PMC4955391  PMID: 21597125
bicycling; environment; physical activity; policy; qualitative research; walking
5.  Blood and Intestine eQTLs from an Anti-TNF-Resistant Crohn's Disease Cohort Inform IBD Genetic Association Loci 
Genome-wide association studies (GWAS) have identified loci reproducibly associated with inflammatory bowel disease (IBD) and other immune-mediated diseases; however, the molecular mechanisms underlying most of genetic susceptibility remain undefined. Expressional quantitative trait loci (eQTL) of disease-relevant tissue can be employed in order to elucidate the genes and pathways affected by disease-specific genetic variance.
In this study, we derived eQTLs for human whole blood and intestine tissues of anti-tumor necrosis factor-resistant Crohn's disease (CD) patients. We interpreted these eQTLs in the context of published IBD GWAS hits to inform on the disease process.
At 10% false discovery rate, we discovered that 5,174 genes in blood and 2,063 genes in the intestine were controlled by a nearby single-nucleotide polymorphism (SNP) (i.e., cis-eQTL), among which 1,360 were shared between the two tissues. A large fraction of the identified eQTLs were supported by the regulomeDB database, showing that the eQTLs reside in regulatory elements (odds ratio; OR=3.44 and 3.24 for blood and intestine eQTLs, respectively) as opposed to protein-coding regions. Published IBD GWAS hits as a whole were enriched for blood and intestine eQTLs (OR=2.88 and 2.05; and P value=2.51E-9 and 0.013, respectively), thereby linking genetic susceptibility to control of gene expression in these tissues. Through a systematic search, we used eQTL data to inform 109 out of 372 IBD GWAS SNPs documented in National Human Genome Research Institute catalog, and we categorized the genes influenced by eQTLs according to their functions. Many of these genes have experimentally validated roles in specific cell types contributing to intestinal inflammation.
The blood and intestine eQTLs described in this study represent a powerful tool to link GWAS loci to a regulatory function and thus elucidate the mechanisms underlying the genetic loci associated with IBD and related conditions. Overall, our eQTL discovery approach empirically identifies the disease-associated variants including their impact on the direction and extent of expression changes in the context of disease-relevant cellular pathways in order to infer the functional outcome of this aspect of genetic susceptibility.
PMCID: PMC4931595  PMID: 27336838
6.  Urinary tract infections: epidemiology, mechanisms of infection and treatment options 
Nature reviews. Microbiology  2015;13(5):269-284.
Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis and Staphylococcus saprophyticus. High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the molecular details of the crosstalk that occurs at the host–pathogen interface, as well as the consequences of these interactions for the pathophysiology of UTIs. We also describe current efforts to translate this knowledge into new clinical treatments for UTIs.
PMCID: PMC4457377  PMID: 25853778
7.  Inflammation-induced formation of fat-associated lymphoid clusters 
Nature immunology  2015;16(8):819-828.
Fat-associated lymphoid clusters (FALCs) are a recently discovered type of lymphoid tissue associated with visceral fat. Here we show that distribution of FALCs was heterogeneous with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 B cells in the peritoneal cavity through high expression of the chemokine CXCL13 and supported B cell proliferation and germinal center differentiation during peritoneal immune challenges. FALC formation was induced by inflammation, which triggered recruitment of myeloid cells that express tumor necrosis factor (TNF) necessary for TNF receptor-signaling in stromal cells. CD1d-restricted Natural killer T (NKT) cells were likewise required for inducible formation of FALCs. Thus, FALCs support and coordinate innate B and T cell activation during serosal immune responses.
PMCID: PMC4512620  PMID: 26147686
8.  Bcl11b is essential for group 2 innate lymphoid cell development 
Walker et al. demonstrate that the transcription factor Bcl11b is expressed in mouse lymphoid ILC2 precursors in the bone marrow and is required for their development. Mice deficient in Bcl11b exhibit a lack of ILC2 development and an expansion of RORγt+ ILC3s and are unable to clear Nippostrongylus brasiliensis worm infection, but can clear Citrobacter rodentium.
Group 2 innate lymphoid cells (ILC2s) are often found associated with mucosal surfaces where they contribute to protective immunity, inappropriate allergic responses, and tissue repair. Although we know they develop from a common lymphoid progenitor in the bone marrow (BM), the specific lineage path and transcriptional regulators that are involved are only starting to emerge. After ILC2 gene expression analysis we investigated the role of Bcl11b, a factor previously linked to T cell commitment, in ILC2 development. Using combined Bcl11b-tom and Id2-gfp reporter mice, we show that Bcl11b is expressed in ILC2 precursors in the BM and maintained in mature ILC2s. In vivo deletion of Bcl11b, by conditional tamoxifen-induced depletion or by Bcl11b−/− fetal liver chimera reconstitution, demonstrates that ILC2s are wholly dependent on Bcl11b for their development. Notably, in the absence of Bcl11b there is a concomitant expansion of the RORγt+ ILC3 population, suggesting that Bcl11b may negatively regulate this lineage. Using Nippostrongylus brasiliensis infection, we reveal that the absence of Bcl11b leads to impaired worm expulsion, caused by a deficit in ILC2s, whereas Citrobacter rodentium infection is cleared efficiently. These data clearly establish Bcl11b as a new factor in the differentiation of ILC2s.
PMCID: PMC4451131  PMID: 25964370
9.  Measured outcomes of chronic care programs for older adults: a systematic review 
BMC Geriatrics  2015;15:139.
Wagner’s Chronic Care Model (CCM), as well as the expanded version (ECCM) developed by Barr and colleagues, have been widely adopted as frameworks for prevention and management of chronic disease. Given the high prevalence of chronic illness in older persons, these frameworks can play a valuable role in reorienting the health care system to better serve the needs of seniors. We aimed to identify and assess the measured goals of E/CCM interventions in older populations. In particular, our objective was to determine the extent to which published E/CCM initiatives were evaluated based on population, community, system and individual-level outcomes (including clinical, functional and quality of life measures).
We conducted a systematic search of the Science Citation Index Web of Knowledge search tool to gather articles published between January 2003 and July 2014. We included published CCM interventions that cited at least one of the fundamental papers that introduced and described the CCM and ECCM. Studies retained for review reported evaluations of senior-focused E/CCM initiatives in community-based settings, with the topic of “older adults” OR senior* OR elder* OR geriatric OR aged. The resulting 619 published articles were independently reviewed for inclusion by two researchers. We excluded the following: systematic reviews, meta-analyses, descriptions of proposed programs, and studies whose populations did not focus on seniors.
We identified 14 articles that met inclusion criteria. Studies used a wide range of measures, with little consensus between studies. All of the included studies used the original CCM. While a range of system-level and individual patient outcomes have been used to evaluate CCM interventions, no studies employed measures of population or community health outcomes.
Future efforts to test E/CCM interventions with seniors would be aided by more consistent outcome measures, greater attention to outcomes for the caregivers of older persons with chronic illness, and a greater focus on population and community impacts.
PMCID: PMC4621859  PMID: 26503159
Chronic care model; Expanded chronic care model; Chronic illness; Seniors
10.  Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer’s Disease: Impacts on Cognitive Decline 
Nutrients  2015;7(9):7332-7357.
In the past few decades, the prevalence of obesity and type 2 diabetes mellitus (T2DM), as well as older individuals at risk for Alzheimer’s disease (AD), has increased. While the consumption of diets high in fat (total and saturated) have been linked to increased risk of AD, diets rich in antioxidants, polyunsaturated fats, and omega-3 fatty acids are associated with decreased risk. Additionally, AD patients are at increased risk for developing T2DM. Recent research suggests that there are stronger similarities between AD and T2DM than have previously been considered. Here we review the neurocognitive and inflammatory effects of high-fat diet consumption, its relationship to AD, and the treatment potential of dietary interventions that may decrease risk of cognitive decline and other associated neuropathological changes, such as insulin resistance, oxidative stress, and chronic inflammatory processes.
PMCID: PMC4586536  PMID: 26340637
Alzheimer’s disease; type 2 diabetes mellitus; high fat diets; obesity; insulin resistance; inflammation; diet reversal; animal models; humans; cognition
11.  Guidelines for the use of survivorship care plans: a systematic quality appraisal using the AGREE II instrument 
Survivorship care plans (SCPs) are written treatment summaries and follow-up care plans that are intended to facilitate communication and coordination of care among survivors, cancer care providers, and primary care providers. A growing number of guidelines for the use of SCPs exist, yet SCP use in the United States remains limited. Limited use of SCPs may be due to poor quality of these guidelines. The purpose of the study was to evaluate the quality of guidelines for SCP use, tools that are intended to promote evidence-based medicine.
We conducted a comprehensive search of the literature using MEDLINE/PubMed, EMBASE (Excerpta Medica Database), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) published through April 2014, in addition to grey literature sources and bibliographic and expert reviews. Guideline quality was assessed using the AGREE II instrument (Appraisal of Guidelines for Research and Evaluation, 2nd edition), a tool developed by an international group of scientists to advance the quality of clinical practice guidelines. To promote consistency with extant studies using the AGREE II instrument and to clearly and unambiguously identify potentially useful guidelines for SCP use, we also summarized AGREE II scores by strongly recommending, recommending, or not recommending the guidelines that we evaluated.
Of 128 documents screened, we included 16 guidelines for evaluation. We did not strongly recommend any of the 16 guidelines that we evaluated; we recommended 5 and we did not recommend 11. Overall, guidelines scored highest on clarity of presentation (i.e., guideline language, structure, and format): Guidelines were generally unambiguous in their recommendations that SCPs should be used. Guidelines scored lowest on applicability (i.e., barriers and facilitators to implementation, implementation strategies, and resource implications of applying the guideline): Few guidelines discussed facilitators and barriers to guideline application; advice and tools for implementing guidelines were vague; and none explicitly discussed resource implications of implementing the guidelines.
Guidelines often advocated survivorship care plan use without justification or suggestions for implementation. Improved guideline quality may promote survivorship care plan use.
Electronic supplementary material
The online version of this article (doi:10.1186/s13012-015-0254-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4425878  PMID: 25935752
Survivorship care plan; Guidelines; Dissemination; Quality appraisal
12.  Distribution and mixing of old and new nonstructural carbon in two temperate trees 
The New Phytologist  2015;206(2):590-597.
We know surprisingly little about whole-tree nonstructural carbon (NSC; primarily sugars and starch) budgets. Even less well understood is the mixing between recent photosynthetic assimilates (new NSC) and previously stored reserves. And, NSC turnover times are poorly constrained. We characterized the distribution of NSC in the stemwood, branches, and roots of two temperate trees, and we used the continuous label offered by the radiocarbon (carbon-14, 14C) bomb spike to estimate the mean age of NSC in different tissues. NSC in branches and the outermost stemwood growth rings had the 14C signature of the current growing season. However, NSC in older aboveground and belowground tissues was enriched in 14C, indicating that it was produced from older assimilates. Radial patterns of 14C in stemwood NSC showed strong mixing of NSC across the youngest growth rings, with limited ‘mixing in’ of younger NSC to older rings. Sugars in the outermost five growth rings, accounting for two-thirds of the stemwood pool, had a mean age < 1 yr, whereas sugars in older growth rings had a mean age > 5 yr. Our results are thus consistent with a previously-hypothesized two-pool (‘fast’ and ‘slow’ cycling NSC) model structure. These pools appear to be physically distinct.
PMCID: PMC4405048  PMID: 25558814
carbohydrates; carbon allocation; Harvard Forest; radiocarbon (14C); storage; tree rings; wood
13.  Mutations in Tetratricopeptide Repeat Domain 7A Result in a Severe Form of Very Early Onset Inflammatory Bowel Disease 
Gastroenterology  2014;146(4):1028-1039.
Background & Aims
Very early onset inflammatory bowel diseases (VEOIBD), including infant disorders, are a diverse group of diseases found in children less than 6 years of age. They have been associated with several gene variants. We aimed to identify genes that cause VEOIBD.
We performed whole-exome sequencing of DNA from 1 infants with severe enterocolitis and her parents. Candidate gene mutations were validated in 40 pediatric patients and functional studies were carried out using intestinal samples and human intestinal cell lines.
We identified compound heterozygote mutations in the tetratricopeptide repeat domain 7 (TTC7A) gene in an infant from non-consanguineous parents with severe exfoliative apoptotic enterocolitis; we also detected the mutations in 2 unrelated families, each with 2 affected siblings. TTC7A interacts with EFR3 homolog B (EFR3B) to regulate phosphatidylinositol 4-kinase (PI4KA) at the plasma membrane. Functional studies demonstrated that TTC7A is expressed in human enterocytes. The mutations we identified in TTC7A result in either mislocalization or reduced expression of TTC7A. PI4KA was found to co-immunoprecipitate with TTC7A; the identified TTC7A mutations reduced this binding. Knockdown of TTC7A in human intestinal-like cell lines reduced their adhesion, increased apoptosis, and decreased production of phosphatidylinositol 4-phosphate.
In a genetic analysis, we identified loss of function mutations in TTC7A in 5 infants with VEOIBD. Functional studies demonstrated that the mutations cause defects in enterocytes and T cells that lead to severe apoptotic enterocolitis. Defects in the PI4KA–TTC7A–EFR3B pathway are involved in the pathogenesis of VEOIBD.
PMCID: PMC4002656  PMID: 24417819
IBD; intestinal atresia; autoimmunity; intestine
14.  Life Events, Chronic Stressors, and Depressive Symptoms in Low-Income Urban Mothers With Asthmatic Children 
The purpose of this secondary data analysis was to examine the relationship of individual sociodemographic variables, life events, chronic stressors including asthma control and management and environmental stressors to maternal depression.
Cross sectional descriptive design study consisting of baseline data from participants enrolled in a randomized clinical trial of an asthma communication educational intervention.
Two hundred and one mothers of children with asthma (ages 6-12) recruited from community pediatric practices and pediatric emergency departments of two urban university hospitals. Measurement: Subjects responded to a questionnaire that included sociodemographic characteristics, life events, and chronic stressors. Depressive symptoms were assessed with the CESD.
Close to 25% of the mothers had a score of 16 or greater on the CESD. Significant bivariate relationships between low education, unemployment, feeling unsafe, and the use of quick relief asthma drugs with high depressive symptoms were found. In the multiple logistic regression models, education or unemployment (in separate models) and the use of quick relief medications for asthma were positively associated with depressive symptoms.
Implications for practice include the need to assess for the presence of maternal depression particularly in mothers of children with a chronic illness such as asthma.
PMCID: PMC4334657  PMID: 19573208
asthma; depressive symptoms; mothers; chronic illness
15.  A comparison of the predictive accuracy of three screening models for pulmonary arterial hypertension in systemic sclerosis 
There is evidence that early screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. We compared the predictive accuracy of two recently published screening algorithms (DETECT 2013 and Australian Scleroderma Interest Group (ASIG) 2012) for SSc-associated PAH (SSc-PAH) with the commonly used European Society of Cardiology/European Respiratory Society (ESC/ERS 2009) guidelines.
We included 73 consecutive SSc patients with suspected PAH undergoing right heart catheterization (RHC). The three screening models were applied to each patient. For each model, contingency table analysis was used to determine sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for PAH. These properties were also evaluated in an ‘alternate scenario analysis’ in which the prevalence of PAH was set at 10%.
RHC revealed PAH in 27 (36.9%) patients. DETECT and ASIG algorithms performed equally in predicting PAH with sensitivity and NPV of 100%. The ESC/ERS guidelines had sensitivity of 96.3% and NPV of only 91%, missing one case of PAH; these guidelines could not be applied to three patients who had absent tricuspid regurgitant (TR) jet. The ASIG algorithm had the highest specificity (54.5%). With PAH prevalence set at 10%, the NPV of the models was unchanged, but the PPV dropped to less than 20%.
In this cohort, the DETECT and ASIG algorithms out-perform the ESC/ERS guidelines, detecting all patients with PAH. The ESC/ERS guidelines have limitations in the absence of a TR jet. Ultimately, the choice of SSc-PAH screening algorithm will also depend on cost and ease of application.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0517-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4332896  PMID: 25596924
16.  Challenges in Promoting Joint Use Agreements: Experiences From Community Transformation Grant Awardees in North Carolina, Illinois, and Wisconsin, 2011–2014 
Community Transformation Grant awardees in North Carolina, Illinois, and Wisconsin promoted joint use agreements (formal agreements between 2 parties for the shared use of land or facilities) as a strategy to increase access to physical activity in their states. However, awardees experienced significant barriers to establishing joint use agreements, including 1) confusion about terminology and an aversion to complex legal contracts, 2) lack of applicability to single organizations with open use policies, and 3) questionable value in nonurban areas where open lands for physical activity are often available and where the need is instead for physical activity programs and infrastructure. Furthermore, promotion of formal agreements may unintentionally reduce access by raising concerns regarding legal risks and costs associated with existing shared use of land. Thus, joint use agreements have practical limitations that should be considered when selecting among strategies to promote physical activity participation.
PMCID: PMC4415413  PMID: 25880770
17.  Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis 
Immunity  2013;39(2):357-371.
Liver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix-components, ultimately leading to fibrosis and liver-failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33’s pro-fibrotic effects related to activation and expansion of liver resident innate lymphoid cells (ILC2). We identified ILC2-derived IL-13, acting through type-II IL-4 receptor-dependent signaling via the transcription factor STAT6 and hepatic stellate-cell activation, as a critical downstream cytokine of IL-33-dependent pathologic tissue remodeling and fibrosis. Our data reveal key immunological networks implicated in hepatic fibrosis and support the concept of modulation of IL-33 bioactivity for therapeutic purposes.
PMCID: PMC4172965  PMID: 23954132
18.  MHCII-Mediated Dialog between Group 2 Innate Lymphoid Cells and CD4+ T Cells Potentiates Type 2 Immunity and Promotes Parasitic Helminth Expulsion 
Immunity  2014;41(2):283-295.
Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity.
Graphical Abstract
•Genetic ablation of ILC2s impairs type-2 immunity•MHCII-expressing ILC2s potentiate Th2 responses•IL-2 from T cells promotes ILC2 proliferation and expression of type-2 cytokines•MHCII and IL-13 expression by ILC2s is important for N. brasiliensis expulsion
Type-2 innate lymphoid cells proliferate and release interleukin-13 during protective immunity to helminth infection and detrimentally during allergy and asthma. McKenzie and colleagues establish that these activities are potentiated through an MHC class II-mediated dialogue with T cells.
PMCID: PMC4148706  PMID: 25088770
19.  T-bet is essential for NKp46+ innate lymphocyte development through the Notch pathway 
Nature immunology  2013;14(4):389-395.
Innate lymphoid cells (ILCs) including lymphoid tissue-inducer (LTi) cells, IL-22-producing NKp46+ innate cells and IL-13-producing nuocytes play important roles in regulating intestinal microbiota, defence against pathogens and formation of lymphoid tissue1-4. Their development is dependent on Id2 and Rorγt or Rorα5-7. Lineage tracing experiments have shown that the common lymphoid precursor gives rise to nuocytes, LTi cells and NKp46+ ILCs6,8,9, but these studies have not deciphered the discrete steps and transcription factors that specify ILC subset development, activation and maintenance. Whether NKp46+ ILCs arise directly from LTi cells, or rather represent a separate lineage that diverges earlier in development, remains controversial10-12. We investigated the requirement for the transcriptional master regulator T-bet (encoded by Tbx21) which is critical for the development of both T cells and NK cells13,14, in driving differentiation of ILC populations. Here we report that T-bet played an essential role for the development of NKp46+ ILCs, but was dispensable for LTi cells or nuocytes. Tbx21+/+ LTi cells adopted an NKp46+ phenotype in vitro and in vivo but not in the absence of Tbx21. Decrease of T-bet expression coordinately reduced Notch1 and Notch2 and we show Notch signaling is necessary for the transition of LTi cells into NKp46+ ILCs. In addition, Tbx21−/− mice have an accumulation in CD4− LTi cells and differentiation into NKp46+ ILCs came solely from this population. Our results pinpoint T-bet as the critical regulator of NKp46+ ILC differentiation by regulation of Notch2 signaling. NKp46+ cells are an important element of the protective intestinal mucosal cellular arsenal, and here, we uncover the distinct molecular pathways that guide the development of NKp46+ ILCs.
PMCID: PMC4076532  PMID: 23455676
Lymphoid tissue inducer cells; innate lymphoid cells; nuocytes; NKp46; GFP reporter mouse
20.  Mcl-1 is essential for the survival of plasma cells 
Nature immunology  2013;14(3):290-297.
The long-term survival of plasma cells is entirely dependent on signals derived from their environment. These extrinsic factors presumably induce and sustain the expression of antiapoptotic proteins of the Bcl-2 family. It is uncertain whether there is specificity among Bcl-2 family members in the survival of plasma cells and whether their expression is linked to specific extrinsic factors. We found here that deletion of the gene encoding the antiapoptotic protein Mcl-1 in plasma cells resulted in rapid depletion of this population in vivo. Furthermore, we found that the receptor BCMA was needed to establish high expression of Mcl-1 in bone marrow but not spleen plasma cells and that establishing this survival pathway preceded the component of plasma cell differentiation that depends on the transcriptional repressor Blimp-1. Our results identify a critical role for Mcl-1 in the maintenance of plasma cells.
PMCID: PMC4041127  PMID: 23377201
21.  Stress and Quality of Life in Caregivers of Inner-city Minority Children with Poorly Controlled Asthma 
Caregiver quality of life (QOL) is known to influence asthma management behaviors. Risk factors for low caregiver QOL in families of inner-city children with asthma remain unclear. This study evaluated the interrelationships of asthma control, stress, and caregiver QOL.
Data were analyzed from a home-based behavioral intervention for children with persistent asthma post asthma emergency department treatment. Caregivers reported on baseline demographics, asthma control, asthma management stress, life stress, and QOL. Hierarchical regression analysis examined the contributions of socio-demographic factors, asthma control, asthma management stress, and life stress in explaining caregiver QOL.
Children (N=300) were primarily African-American (96%) and young (Mean age of 5.5 years). Caregivers were predominantly the biological mother (92%), single (70%), and unemployed (54%). Poor QOL was associated with higher caregiver education and number of children in the home, low asthma control, and increased asthma management stress and life stress. The model accounted for 28% of variance in caregiver QOL.
Findings underscore the need for multi-faceted interventions to provide caregivers of children with asthma tools to cope with asthma management demands and contemporary life stressors.
PMCID: PMC3575578  PMID: 23414978
asthma; caregiver; stress; quality of life
22.  The Staphylococcus aureus ArlRS Two-Component System Is a Novel Regulator of Agglutination and Pathogenesis 
PLoS Pathogens  2013;9(12):e1003819.
Staphylococcus aureus is a prominent bacterial pathogen that is known to agglutinate in the presence of human plasma to form stable clumps. There is increasing evidence that agglutination aids S. aureus pathogenesis, but the mechanisms of this process remain to be fully elucidated. To better define this process, we developed both tube based and flow cytometry methods to monitor clumping in the presence of extracellular matrix proteins. We discovered that the ArlRS two-component system regulates the agglutination mechanism during exposure to human plasma or fibrinogen. Using divergent S. aureus strains, we demonstrated that arlRS mutants are unable to agglutinate, and this phenotype can be complemented. We found that the ebh gene, encoding the Giant Staphylococcal Surface Protein (GSSP), was up-regulated in an arlRS mutant. By introducing an ebh complete deletion into an arlRS mutant, agglutination was restored. To assess whether GSSP is the primary effector, a constitutive promoter was inserted upstream of the ebh gene on the chromosome in a wildtype strain, which prevented clump formation and demonstrated that GSSP has a negative impact on the agglutination mechanism. Due to the parallels of agglutination with infective endocarditis development, we assessed the phenotype of an arlRS mutant in a rabbit combined model of sepsis and endocarditis. In this model the arlRS mutant displayed a large defect in vegetation formation and pathogenesis, and this phenotype was partially restored by removing GSSP. Altogether, we have discovered that the ArlRS system controls a novel mechanism through which S. aureus regulates agglutination and pathogenesis.
Author Summary
Staphylococcus aureus is a bacterial pathogen that is responsible for causing significant disease in humans. The development of antibiotic resistant strains has made these infections more difficult to treat, and an improved understanding of how this pathogen causes infections will facilitate the development of new tools for treatment. It has long been recognized that S. aureus can bind human matrix proteins to form stable clumps in a process called agglutination, but the importance of agglutination during infection is only just becoming understood. In this work, we developed several techniques to investigate the S. aureus agglutination mechanism. We discovered that the ArlRS two-component regulatory system controls agglutination by regulating the expression of the ebh gene, which encodes the Giant Staphylococcal Surface Protein (GSSP). When ArlRS is non-functional, S. aureus agglutination is prevented through the action of GSSP. These phenotypes were confirmed in a rabbit model of sepsis and infective endocarditis, demonstrating that ArlRS is an important regulator of virulence. Taken together, the identification of ArlRS as a regulator of S. aureus agglutination and pathogenesis may lead to innovative directions for therapeutic development.
PMCID: PMC3868527  PMID: 24367264
23.  The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study 
Arthritis Research & Therapy  2013;15(6):R193.
Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) (‘proposed’ algorithm) in a screening algorithm for SSc-PAH.
We evaluated our proposed algorithm (PFT with NT-proBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).
Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8%, respectively.
The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive, screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies.
PMCID: PMC3978999  PMID: 24246100
24.  Selective Inhibition of Matrix Metalloproteinase-9 Attenuates Secondary Damage Resulting from Severe Traumatic Brain Injury 
PLoS ONE  2013;8(10):e76904.
Traumatic brain injury (TBI) is a leading cause of death and long-term disability. Following the initial insult, severe TBI progresses to a secondary injury phase associated with biochemical and cellular changes. The secondary injury is thought to be responsible for the development of many of the neurological deficits observed after TBI and also provides a window of opportunity for therapeutic intervention. Matrix metalloproteinase-9 (MMP-9 or gelatinase B) expression is elevated in neurological diseases and its activation is an important factor in detrimental outcomes including excitotoxicity, mitochondrial dysfunction and apoptosis, and increases in inflammatory responses and astrogliosis. In this study, we used an experimental mouse model of TBI to examine the role of MMP-9 and the therapeutic potential of SB-3CT, a mechanism-based gelatinase selective inhibitor, in ameliorating the secondary injury. We observed that activation of MMP-9 occurred within one day following TBI, and remained elevated for 7 days after the initial insult. SB-3CT effectively attenuated MMP-9 activity, reduced brain lesion volumes and prevented neuronal loss and dendritic degeneration. Pharmacokinetic studies revealed that SB-3CT and its active metabolite, p-OH SB-3CT, were rapidly absorbed and distributed to the brain. Moreover, SB-3CT treatment mitigated microglial activation and astrogliosis after TBI. Importantly, SB-3CT treatment improved long-term neurobehavioral outcomes, including sensorimotor function, and hippocampus-associated spatial learning and memory. These results demonstrate that MMP-9 is a key target for therapy to attenuate secondary injury cascades and that this class of mechanism-based gelatinase inhibitor–with such desirable pharmacokinetic properties–holds considerable promise as a potential pharmacological treatment of TBI.
PMCID: PMC3806745  PMID: 24194849
25.  Factors Associated with Completion of a Behavioral Intervention for Caregivers of Urban Children with Asthma 
Rates of preventive follow-up asthma care after an acute emergency department (ED) visit are low among inner-city children. We implemented a novel behavioral asthma intervention, Pediatric Asthma Alert (PAAL) intervention, to improve outpatient follow-up and preventive care for urban children with a recent ED visit for asthma.
The objective of this article is to describe the PAAL intervention and examine factors associated with intervention completers and noncompleters.
Children with persistent asthma and recurrent ED visits (N = 300) were enrolled in a randomized controlled trial of the PAAL intervention that included two home visits and a facilitated follow-up visit with the child’s primary care provider (PCP). Children were categorized as intervention completers, that is, completed home and PCP visits compared with noncompleters, who completed at least one home visit but did not complete the PCP visit. Using chi-square test of independence, analysis of variance, and multiple logistic regression, the intervention completion status was examined by several sociodemographic, health, and caregiver psychological variables.
Children were African-American (95%), Medicaid insured (91%), and young (aged 3–5 years, 56%). Overall, 71% of children randomized to the intervention successfully completed all home and PCP visits (completers). Factors significantly associated with completing the intervention included younger age (age 3–5 years: completers, 65.4%; noncompleters, 34.1%; p < .001) and having an asthma action plan in the home at baseline (completers: 40%; noncompleters: 21%; p = .02). In a logistic regression model, younger child age, having an asthma action plan, and lower caregiver daily asthma stress were significantly associated with successful completion of the intervention.
The majority of caregivers of high-risk children with asthma were successfully engaged in this home and PCP-based intervention. Caregivers of older children with asthma and those with high stress may need additional support for program completion. Further, the lack of an asthma action plan may be a marker of preexisting barriers to preventive care.
PMCID: PMC3773483  PMID: 22991952
asthma; children; controller medications; inner city; preventive care

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