Citizen-centered health promotion: Building collaboration to facilitate healthy living

Unhealthy behaviors, notably tobacco use; unhealthy diets; and inadequate physical activity are major contributors to chronic disease in the U.S. and are more prevalent among socioeconomically disadvantaged groups. Differences in the prevalence of unhealthy behaviors among communities with different physical, social, and economic resources suggest that contextual environmental factors play an important causal role. Yet health promotion interventions often are undertaken in isolation and with inadequate attention to these holistic social and economic influences on lifestyle. For example, clinicians\u27 advice to patients to stop smoking or lose weight can help motivate people to change behaviors, but their ability to take subsequent action can benefit from coordination with community-based and public health programs that offer intensive counseling services, and from modified environmental conditions to facilitate behavior change where people live, work, learn, and play. Reshaping these environmental conditions to support healthier living is the subject of six recommendations from the Robert Wood Johnson Foundation Commission to Build a Healthier America. Changing the conditions of daily life to make them conducive to healthy behaviors--what is here called citizen-centered health promotion--requires a concerted effort by clinical, educational, business, civic and governmental partners within communities. Linkages among clinical practices and community-based programs have been demonstrated to be effective, but moving from demonstration projects to sustainable community collaborations nationwide will require a proactive effort to establish the necessary infrastructure and financing

Eosinophils Are Recruited in Response to Chitin Exposure and Enhance Th2-Mediated Immune Pathology in Aspergillus fumigatus Infection

In patients infected with the fungus Aspergillus fumigatus, Th1 responses are considered protective, while Th2 responses are associated with increased morbidity and mortality. How host-pathogen interactions influence the development of these protective or detrimental immune responses is not clear. We compared lung immune responses to conidia from two fungal isolates that expressed different levels of the fungal cell wall component chitin. We observed that repeated aspirations of the high-chitin-expressing isolate Af5517 induced increased airway eosinophilia in the lungs of recipient mice compared to the level of eosinophilia induced by isolate Af293. CD4+ T cells in the bronchoalveolar lavage fluid (BALF) of Af5517-aspirated mice displayed decreased gamma interferon secretion and increased interleukin-4 transcription. In addition, repeated aspirations of Af5517 induced lung transcription of the Th2-associated chemokines CCL11 (eotaxin-1) and CCL22 (macrophage-derived chemokine). Eosinophil recruitment in response to conidial aspiration was correlated with the level of chitin exposure during germination and was decreased by constitutive lung chitinase expression. Moreover, eosinophil-deficient mice subjected to multiple aspirations of Af5517 prior to neutrophil depletion and infection exhibited decreased morbidity and fungal burden compared to the levels of morbidity and fungal burden found in wild-type mice. These results suggest that exposure of chitin in germinating conidia promotes eosinophil recruitment and ultimately induces Th2-skewed immune responses after repeated aspiration. Furthermore, our results suggest that eosinophils should be examined as a potential therapeutic target in patients that mount poorly protective Th2 responses to A. fumigatus infection

Immunotherapy with Canarypox Vaccine and Interleukin-2 for HIV-1 Infection: Termination of a Randomized Trial

OBJECTIVES: To determine whether immunotherapy of chronic HIV-1 infection can prevent or attenuate viremia upon antiviral discontinuation. DESIGN: This was a Phase II randomized, partially double blinded, 2×2 factorial study of three steps of 12 wk/step. Step I involved four groups: (1) vaccine placebo, (2) vaccine (ALVAC, vCP1452), (3) placebo + interleukin 2 (IL-2), and (4) vaccine + IL-2. Step II involved a 12-wk diagnostic treatment interruption (DTI). Step III involved an extension of the DTI for an additional 12 wk. SETTING: The Weill-Cornell General Clinical Research Center. PARTICIPANTS: Chronically infected HIV-1 positive adults with undetectable HIV-1 levels and > 400 CD4(+) T cells/μl. INTERVENTIONS: An HIV canarypox vaccine (vCP1452) and vaccine placebo, administered every 4 wk for four doses, and low-dose IL-2 administered daily for 12–24 wk. OUTCOME MEASURES: Primary endpoints: (1) Proportion of participants with undetectable plasma HIV RNA during trial Step II, (2) mean log(10) HIV RNA copies/ml ([HIV]) from weeks 21–25, and (3) proportion of individuals eligible for trial Step III. RESULTS: 44 participants were randomized, but 16 withdrew or were withdrawn before completing Step II. As all participants underwent viral relapse in Step II, the study was terminated after 28 participants completed Step II. Among the four groups, there was no difference in mean [HIV] or the proportion of individuals with < log(10) 4.48 HIV; no difference between the mean [HIV] of the two groups that received ALVAC (n = 17) versus placebo (n = 11); and no significant difference between the mean [HIV] of the two groups that received IL-2 (n = 11) versus placebo (n = 17). CONCLUSIONS: Neither ALVAC (vCP1452) nor low-dose daily IL-2 nor their combination prevented the relapse of viremia upon discontinuation of antiviral therapy

Long-term Efficacy and Tolerability of RPC4046 in an Open-Label Extension Trial of Patients With Eosinophilic Esophagitis

Background & Aims The short-term efficacy of RPC4046, a monoclonal antibody against interleukin-13, has been shown in patients with eosinophilic esophagitis (EoE). We investigated the long-term efficacy and safety of RPC4046 in an open-label, long-term extension (LTE) study in adults with EoE. Methods We analyzed data from 66 patients who completed the 16-week, double-blind, induction portion of a phase 2 study of RPC4046 (180 mg or 360 mg/wk) vs placebo and then completed a 52-week LTE, receiving open-label RPC4046 360 mg/wk. The study was conducted at 28 centers in 3 countries; patients were enrolled between September 2014 and January 2017. Outcomes were stratified by double-blind dose group and included esophageal eosinophil counts, EoE endoscopic reference score, EoE histologic scoring system score, symptom-based EoE activity index score, and safety. Results By week 12 of the LTE, esophageal eosinophil mean and peak counts, total EoE endoscopic reference scores, and EoE histologic scoring system grade and stage scores did not differ considerably between patients who originally received placebo vs RPC4046. Most patients maintained responses through week 52. Symptom remission (symptom-based EoE activity index score, ≤20) increased from 14% at LTE entry to 67% at LTE week 52 in placebo‒RPC4046 patients and from 30% to 54% in RPC4046‒RPC4046 (either dose) patients. Of the 28 patients who did not have a histologic response to RPC4046 during the double-blind induction phase, 10 patients (36%) achieved response during the LTE. The most common adverse events were upper respiratory tract infection (21%) and nasopharyngitis (14%). Conclusions One year of treatment with RPC4046 is generally well tolerated and results in continued improvement and/or maintenance of endoscopic, histologic, and clinical measures of EoE disease activity relative to baseline

Simultaneous Recruitment of Drug Users and Men Who Have Sex with Men in the United States and Russia Using Respondent-Driven Sampling: Sampling Methods and Implications

The Sexual Acquisition and Transmission of HIV Cooperative Agreement Program (SATHCAP) examined the role of drug use in the sexual transmission of the human immunodeficiency virus (HIV) from traditional high-risk groups, such as men who have sex with men (MSM) and drug users (DU), to lower risk groups in three US cities and in St. Petersburg, Russia. SATHCAP employed respondent-driven sampling (RDS) and a dual high-risk group sampling approach that relied on peer recruitment for a combined, overlapping sample of MSM and DU. The goal of the sampling approach was to recruit an RDS sample of MSM, DU, and individuals who were both MSM and DU (MSM/DU), as well as a sample of sex partners of MSM, DU, and MSM/DU and sex partners of sex partners. The approach efficiently yielded a sample of 8,355 participants, including sex partners, across all four sites. At the US sites—Los Angeles, Chicago, and Raleigh–Durham—the sample consisted of older (mean age = 41 years), primarily black MSM and DU (both injecting and non-injecting); in St. Petersburg, the sample consisted of primarily younger (mean age = 28 years) MSM and DU (injecting). The US sites recruited a large proportion of men who have sex with men and with women, an important group with high potential for establishing a generalized HIV epidemic involving women. The advantage of using the dual high-risk group approach and RDS was, for the most part, the large, efficiently recruited samples of MSM, DU, and MSM/DU. The disadvantages were a recruitment bias by race/ethnicity and income status (at the US sites) and under-enrollment of MSM samples because of short recruitment chains (at the Russian site)

Brain Tumor Cells in Circulation Are Enriched for Mesenchymal Gene Expression

Glioblastoma (GBM) is a highly aggressive brain cancer characterized by local invasion and angiogenic recruitment, yet metastatic dissemination is extremely rare. Here, we adapted a microfluidic device to deplete hematopoietic cells from blood specimens of patients with GBM, uncovering evidence of circulating brain tumor cells (CTCs). Staining and scoring criteria for GBM CTCs were first established using orthotopic patient-derived xenografts (PDX), and then applied clinically: CTCs were identified in at least one blood specimen from 13/33 patients (39%; 26/87 samples). Single GBM CTCs isolated from both patients and mouse PDX models demonstrated enrichment for mesenchymal over neural differentiation markers, compared with primary GBMs. Within primary GBMs, RNA-in-situ hybridization identifies a subpopulation of highly migratory mesenchymal tumor cells, and in a rare patient with disseminated GBM, systemic lesions were exclusively mesenchymal. Thus, a mesenchymal subset of GBM cells invades into the vasculature, and may proliferate outside the brain

CCR3 is a target for age-related macular degeneration diagnosis and therapy

Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and that despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation because it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor A (VEGF-A) neutralization, which is in clinical use at present, and, unlike VEGF-A blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition

STYLE AS EXEMPLIFICATIONAL ASPECT OF DISCOURSE

Goodmanova semiotika i teorija stila znatno utječu na suvremena promišljanja pojma stil i određivanja nadležnosti literarne stilistike, naročito u Francuskoj. Ključnim se u tome kontekstu pokazuje Goodmanov koncept egzemplifikacije kao specifične referencijalne funkcije. U ovome radu donosi se kritički pregled Goodmanovih teza i njegovih nastavljača, posebice G. Genettea.Goodman\u27s semiotics and the theory of style are highly influental in contemporary conteptualizations of style and in defining the scope of literary stylistics, particulary in France. The key concept in that context is exemplification – a specific referential function. This paper presents a critical summary of Nelson Goodman\u27s hypotheses as well as his successors\u27, namely Gérard Genette