Tox induces T cell IL-10 production in a BATF-dependent manner.

Tox is a member of the high mobility group (HMG)-Box transcription factors and plays important roles in thymic T cell development. Outside of the thymus, however, Tox is also highly expressed by CD8 and CD4 T cells in various states of activation and in settings of cancer and autoimmune disease. In CD4 T cells, Tox has been primarily studied in T follicular helper (TFH) cells where it, along with Tox2, promotes TFH differentiation by regulating key TFH-associated genes and suppressing CD4 cytotoxic T cell differentiation. However, the role of Tox in other T helper (Th) cell subtypes is less clear. Here, we show that Tox is expressed in several physiologically-activated Th subtypes and its ectopic expression enhances the in vitro differentiation of Th2 and T regulatory (Treg) cells. Tox overexpression in unpolarized Th cells also induced the expression of several genes involved in cell activation (Pdcd1), cellular trafficking (Ccl3, Ccl4, Xcl1) and suppressing inflammation (Il10) across multiple Th subtypes. We found that Tox binds the regulatory regions of these genes along with the transcription factors BATF, IRF4, and JunB and that Tox-induced expression of IL-10, but not PD-1, is BATF-dependent. Based on these data, we propose a model where Tox regulates Th cell chemotactic genes involved in facilitating dendritic cell-T cell interactions and aids in the resolution or prevention of inflammation through the production of IL-10.

Endoscopic Ultrasound-Guided Gastro-gastrostomy Using Lumen Apposing Metal Stent for Management of High-Grade Gastric Outlet Obstruction Secondary to Vertical Banded Gastroplasty.

Vertical banded gastroplasty (VBG) is associated with an increased risk of pouch stricture secondary to narrowing of the banded gastroplasty outlet. We describe a case of a 60-year-old male with stage 4 small cell lung cancer presenting with recurrent gastric outlet obstruction secondary to stenosis at the site of VBG. Given a prior history of failed standard endoscopic maneuvers including balloon dilation and steroid injection, the decision was made to create an endoscopic ultrasound-guided gastro-gastrostomy using lumen opposing metal stent. The patient did well post procedure and was able to tolerate a soft mechanical diet within 24 h. He was subsequently discharged to hospice for his advanced metastatic disease.

Definitive nonsurgical management of stump cholecystitis with EUS-guided lumen-apposing metal stent placement and electrohydraulic lithotripsy.

Video 1Definitive nonsurgical management of stump cholecystitis with EUS-guided lumen-apposing metal stent placement and electrohydraulic lithotripsy.

Operationalization of Intrinsic Capacity in Older People and Its Association With Subsequent Disability, Hospital Admission and Mortality: Results From The English Longitudinal Study of Ageing.

BACKGROUND: Intrinsic capacity (IC) is a new concept in the healthy aging field and has many operationalized definitions. In this study, we operationalized IC using item response theory in the English Longitudinal Study of Ageing (ELSA) and tested the predictive value of the scale using a subsequent functional ability, mortality, and hospital admission. METHODS: IC was measured at baseline (2004, Wave 2) using 14 dichotomous indicators: word recall, orientation in time, balance, chair rises, walking speed, upper mobility, lower mobility, eyesight, hearing, grip strength, body mass index, waist circumference, depressive symptoms, and life satisfaction. A 2-parameter item response theory model was used to generate a scale of IC at baseline. Logistic regression was used for the prediction of subsequent difficulties, measured by difficulties with ≥1 activities of daily living (ADLs) and ≥1 instrumental activities of daily living (IADLs) at 4 and 8 years after baseline. Competing risk and Cox regressions were employed to test the prediction of hospital admission and mortality, respectively, over a 14-year follow-up. RESULTS: IC scores were generated for 4 545 individuals aged on average 70.8 years (standard deviation [SD] 7.93). Better baseline IC scores were associated with reduced risk of subsequent difficulties with ADLs and IADLs, hospital admission (subdistribution hazard ratios [SHR] = 0.99, 95% confidence interval [CI] 0.98-0.99), and mortality (hazard ratios [HR] = 0.98, 95% CI 0.98-0.99), when adjusted for sociodemographic and health-related covariates. CONCLUSION: These results suggest the utility of this IC score as a measure of risk for future adverse outcomes in older people, potentially above that indicated by other sociodemographic and health-related factors.

IL-1ß promotes IL-9-producing Th cell differentiation in IL-2-limiting conditions through the inhibition of BCL6.

IL-9-producing CD4+ T helper cells, termed Th9 cells, differentiate from naïve precursor cells in response to a combination of cytokine and cell surface receptor signals that are elevated in inflamed tissues. After differentiation, Th9 cells accumulate in these tissues where they exacerbate allergic and intestinal disease or enhance anti-parasite and anti-tumor immunity. Previous work indicates that the differentiation of Th9 cells requires the inflammatory cytokines IL-4 and TGF-ß and is also dependent of the T cell growth factor IL-2. While the roles of IL-4 and TGF-ß-mediated signaling are relatively well understood, how IL-2 signaling contributes to Th9 cell differentiation outside of directly inducing the Il9 locus remains less clear. We show here that murine Th9 cells that differentiate in IL-2-limiting conditions exhibit reduced IL-9 production, diminished NF-kB activation and a reduced NF-kB-associated transcriptional signature, suggesting that IL-2 signaling is required for optimal NF-kB activation in Th9 cells. Interestingly, both IL-9 production and the NF-kB transcriptional signature could be rescued by addition of the NF-kB-activating cytokine IL-1ß to IL-2-limiting cultures. IL-1ß was unique among NF-kB-activating factors in its ability to rescue Th9 differentiation as IL-2 deprived Th9 cells selectively induced IL-1R expression and IL-1ß/IL-1R1 signaling enhanced the sensitivity of Th9 cells to limiting amounts of IL-2 by suppressing expression of the Th9 inhibitory factor BCL6. These data shed new light on the intertwined nature of IL-2 and NF-kB signaling pathways in differentiating Th cells and elucidate the potential mechanisms that promote Th9 inflammatory function in IL-2-limiting conditions.

EUS-guided gastrojejunostomy for management of malignant gastric outlet obstruction in a patient with Roux-en-Y anatomy.

Video 1Endoscopic ultrasound-guided gastrojejunostomy.

Assessment of ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome): A Case Study for Health Care Providers.

INTRODUCTION: Over a million adults in the U.S. are affected by chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME). A debilitating illness, ME/CFS is accompanied by profound fatigue that is not relieved by rest and affects daily activities. Symptoms include postexertional malaise, cognitive problems, unrefreshing sleep, and pain. This course provides tools to teach medical, physician assistant, and nursing students to recognize, diagnose, and manage patients with ME/CFS. METHODS: The student is expected to view the provider-to-provider video and the PowerPoint slide curriculum, which describe the steps for evaluation. The video depicts two physicians conferring about ME/CFS and addresses the challenges of making a diagnosis. The slide curriculum shows the different ME/CFS symptoms and case definitions and how to apply them using a case study. Medical, physician assistant, and nursing students were recruited to evaluate the course and viewed it either online or in a campus education center. RESULTS: Results showed that students met learning objectives and showed increases from pre- to posttest evaluation in their understanding of the difficulties of diagnosing ME/CFS and managing the illness. In addition to knowledge, student attitudes towards ME/CFS changed, with more empathy towards patients and the awareness that ME/CFS requires frequent communication and reevaluation of patients' symptoms. DISCUSSION: Strategies of how to manage ME/CFS for the patient and manage time constraints during visits with ME/CFS patients are discussed.

Skin cancer knowledge and prevention counseling among Arizona pharmacists.

Skin cancer is particularly prevalent in Arizona, with incidence rates ranking number 2 worldwide. This study assessed pharmacists' knowledge of skin cancer and factors that impacted skin cancer prevention patient counseling. Participants were recruited using a listserv of pharmacists that were members of the Arizona Pharmacy Alliance (AzPA) or preceptors of the University of Arizona College of Pharmacy. Subjects completed an online questionnaire consisting of knowledge-based questions, questions about patient counseling preferences, and subject demographics. The mean correct score on the Skin Cancer and Sun Exposure Knowledge Indicator was 5.8 ± 1.9. Pharmacists living in Arizona for longer duration were more likely to know the minimum recommended sunscreen sun protection factor (SPF) for adults when outdoors (P = .003) and factors associated with malignant melanoma prognosis/survival (P = .004) but were less likely to know the definition of ABCD acronym (P = .027). Having a family or friend diagnosed with any form of skin cancer or precancerous skin condition led to more pharmacists knowing the risk factors for developing melanoma (P = .046) and knowing how often to apply water resistant sunscreen (P = .035). In conclusion, the length of pharmacy practice in Arizona and having a family member or close friend affected by skin cancer significantly impacted a pharmacists' knowledge of skin cancer.

Exhaled breath condensate biomarkers in asbestos-related lung disorders.

OBJECTIVES: Asbestos induces generation of reactive oxygen and nitrogen species in laboratory studies. Several such species can be measured non-invasively in humans in exhaled breath condensate (EBC) but few have been evaluated. This study aimed to assess oxidative stress and lung inflammation in vivo. METHODS: Eighty six men were studied: sixty subjects with asbestos-related disorders (asbestosis: 18, diffuse pleural thickening (DPT): 16, pleural plaques (PPs): 26) and twenty six age- and gender-matched normal individuals. RESULTS: Subjects with asbestosis had raised EBC markers of oxidative stress compared with normal controls [8-isoprostane (geometric mean (95% CI) 0.51 (0.17-1.51) vs 0.07 (0.04-0.13) ng/ml, p<0.01); hydrogen peroxide (13.68 (8.63-21.68) vs 5.89 (3.99-8.69) microM, p<0.05), as well as increased EBC total protein (17.27 (10.57-28.23) vs 7.62 (5.13-11.34) microg/ml, p<0.05), and fractional exhaled nitric oxide (mean+/-SD) (9.67+/-3.26 vs 7.57+/-1.89ppb; p<0.05). EBC pH was lower in subjects with asbestosis compared with subjects with DPT (7.26+/-0.31 vs 7.53+/-0.24; p<0.05). There were no significant differences in exhaled carbon monoxide, EBC total nitrogen oxides and 3-nitrotyrosine between any of the asbestos-related disorders, or between these and controls. CONCLUSION: In asbestos-related disorders, markers of inflammation and oxidative stress are significantly elevated in subjects with asbestosis compared with healthy individuals but not in pleural diseases.

Occupational sensitization to lupin in the workplace: occupational asthma, rhinitis, and work-aggravated asthma.

BACKGROUND: Lupin is a legume. Its seed can be ground into flour and incorporated into food as a protein source. Cases of rhinitis, urticaria, and anaphylaxis from ingestion of lupin have been reported as well as asthma. OBJECTIVE: To present a cross-sectional study of workers in a food processing company who were exposed to lupin and developed occupational allergy secondary to inhaling lupin products. METHODS: Subjects were interviewed using a standardized questionnaire, including demographics and current and past symptoms. They underwent skin prick tests (SPTs) to common aeroallergens and lupin products, spirometry, and off-line exhaled nitric oxide measurement. Symptomatic subjects, sensitized to lupin on SPT, underwent methacholine bronchial provocation challenge. Those with bronchial hyperresponsiveness had specific bronchial provocation challenge to lupin. RESULTS: A total of 53/54 subjects completed testing (98%). Overall, 21% (11/53) had positive SPT results to lupin. The lupin-sensitive group had a trend toward atopy (P = .06). Seven of 11 (64%) subjects in this group were symptomatic; all had rhinitis, and 2 had wheeze. Two subjects had positive methacholine challenges, and 1 had a positive specific bronchial provocation challenge to lupin with both an early-phase and a late-phase response. CONCLUSION: Allergy to inhaled lupin occurs in the workplace. A high sensitization rate on SPT was found, which correlated with symptoms. The clinical significance of cross-reactivity between legumes on SPT is unclear. CLINICAL IMPLICATIONS: Sensitization to the legume, lupin, can occur from exposure at work and carries a high prevalence of clinical symptoms, which in some cases leads to occupational rhinitis and asthma.

Comparison of biomarkers in exhaled breath condensate and bronchoalveolar lavage.

RATIONALE: Exhaled breath condensate (EBC) is increasingly studied as a noninvasive research method of sampling the lungs, measuring several biomarkers. The exact site of origin of substances measured in EBC is unknown, as is the clinical applicability of the technique. Special techniques might be needed to measure EBC biomarkers. OBJECTIVES: To assess biomarker concentrations in clinical disease and investigate the site of origin of EBC, we compared EBC and bronchoalveolar lavage (BAL) biomarkers in 49 patients undergoing bronchoscopy for clinical indications. MEASUREMENTS: We measured exhaled nitric oxide, 8-isoprostane, hydrogen peroxide, total nitrogen oxides, pH, total protein, and phospholipid (n = 33) and keratin (n = 15) to assess alveolar and mucinous compartments, respectively. EBC was collected over 10 min using a refrigerated condenser according to European Respiratory Society/American Thoracic Society recommendations, and BAL performed immediately thereafter. RESULTS: 8-Isoprostane, nitrogen oxides, and pH were significantly higher in EBC than in BAL (3.845 vs. 0.027 ng/ml, 28.4 vs. 3.8 microM, and 7.35 vs. 6.4, respectively; p < 0.001). Hydrogen peroxide showed no difference between EBC and BAL (17.5 vs. 20.6 microM, p = not significant), whereas protein was significantly higher in BAL (33.8 vs. 183.2 microg/ml, p < 0.001). Total phospholipid was also higher in EBC, but keratin showed no difference. No significant correlation was found between EBC and BAL for any of the biomarkers evaluated either before or after correction for dilution. CONCLUSIONS: In clinical disease, markers of inflammation and oxidative stress are easily measurable in EBC using standard laboratory techniques and EBC is readily obtained. However, EBC and BAL markers do not correlate.