Citations

Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal disorder resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor (TGF)-β has a well-established role in lung fibrosis, clinical experience with neutralizing antibodies to TGF-β has been disappointing, and strategies to directly suppress TGF-β1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in TGF-β1 regulation and to validate the role of miR-326 in pulmonary fibrosis.We show that hsa-miR-326 regulates TGF-β1 expression and that hsa-miR-326 levels are inversely correlated to TGF-β1 protein levels in multiple human cell lines. The increase in TGF-β1 expression during the progression of bleomycin-induced lung fibrosis in mice was associated with loss of mmu-miR-326. Restoration of mmu-miR-326 levels by intranasal delivery of miR-326 mimics was sufficient to inhibit TGF-β1 expression and attenuate the fibrotic response. Moreover, human IPF lung specimens had markedly diminished miR-326 expression as compared with nonfibrotic lungs. Additional targets of miR-326 controlling TGF-β signaling and fibrosis-related pathways were identified, and miR-326 was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that miR-326 plays a key role in regulating TGF-β1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating lung fibrosis.

Summary Objective We aimed to assess the prevalence of impulse control disorders ( ICD s) in patients with prolactin‐secreting adenomas treated with dopamine agonists ( DA s), to identify associated factors and to compare it with a group of patients with nonfunctioning pituitary adenoma. Subjects, Design and Measurement In a postal survey, 77 patients from Group A (patients with prolactinomas and present or past use of DA s) and 70 patients from Group B (patients with nonfunctioning pituitary adenoma and no history of DA therapy) responded to a questionnaire on compulsive shopping, pathologic gambling, hypersexuality and punding. Associated clinical information was obtained through the survey and review of medical electronic records. Results The total ICD prevalence was 24·68% in Group A and 17·1% in Group B ( P = 0·31). Group A had an increased rate of hypersexuality ( P = 0·03). Subgroup analysis revealed that men in Group A had a significantly increased frequency of total ICD s when compared with men in Group B (27·7 vs 3·7%, P = 0·01). No differences in rates of total ICD s were found between women of Groups A and B (20 vs 25·6%, P = 0·78). No association with type, dose or duration of treatment with DA was noted. Conclusions Males with prolactinomas treated with DA s were 9·9 times more likely to develop an ICD than their counterparts with nonfunctioning pituitary adenomas. Until prospective studies on the relationship of DA use in patients with prolactinoma and ICD s are available, the authors propose that patients with prolactinoma be forewarned of possible ICD development with DA therapy.

Background Dabigatran is a novel oral anticoagulant approved for thromboprophylaxis in atrial fibrillation. Adoption patterns of this new agent in community practice are unknown. Methods and Results We studied patterns of dabigatran use among patients enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT‐AF) Registry between June 2010 and August 2011 and followed for 12 months. Among 9974 atrial fibrillation patients included, 1217 (12%) were treated with dabigatran during the study. Overall, patients receiving dabigatran were younger (median age 72 versus 75 years, P <0.0001), more likely to be white (92% versus 89%, P =0.005), more likely to have private insurance (33% versus 25%, P <0.0001), and less likely to have prior cardiovascular disease (4% versus 33%, P <0.0001). They had more new‐onset atrial fibrillation (8.8% versus 4.1%, P <0.0001), lower CHADS 2 scores (estimated risk based on the presence of congestive heart failure, hypertension, aged ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack; mean 2.0 versus 2.3, P <0.0001), and lower Anticoagulation and Risk Factors in Atrial Fibrillation scores (mean 2.4 versus 2.8, P <0.0001). More than half (n=14/25, 56%) of patients with severe kidney disease were not prescribed reduced dosing, whereas 10% (n=91/920) with preserved renal function received lower dosing. Among patients not on dabigatran at baseline, 8% had dabigatran initiated during follow‐up. Patient education was significantly associated with switching from warfarin to dabigatran (adjusted odds ratio for postgraduate 1.73, P =0.007), whereas antiarrhythmic drug use significantly correlated with de novo adoption of dabigatran (adjusted odds ratio 2.4, P <0.0001). Conclusions Patients receiving dabigatran were younger and at a lower risk of stroke and bleeding. Patients appeared to drive switching from warfarin, whereas clinical characteristics influenced de novo start of dabigatran. These data suggest cautious early uptake of dabigatran, and more careful attention to dosing adjustments is warranted. Clinical Trial Registration URL : Clinicaltrials.gov. Unique identifier: NCT 01165710.

Key Points Imatinib improves outcomes for adults with Ph+ ALL at least in part by facilitating allogeneic stem cell transplant. Allogeneic hematopoietic stem cell transplant is not dispensible in Ph+ ALL in the imatinib era.

Key Points Heme, released from hemoglobin, elicits vaso-occlusion in transgenic sickle mice via endothelial TLR4 signaling. Heme/TLR4 signaling activates NF-κB and triggers vaso-occlusion through Weibel-Palade body degranulation and adhesion molecule expression.

Background Limited information is available on the frequency of pulmonary embolism ( PE ) in patients with an acute ischemic stroke ( AIS ). We evaluated clinical characteristics, predisposing factors, and outcomes in AIS patients with PE . Methods and Results We included all AIS patients admitted to participating institutions in the R egistry of the C anadian S troke N etwork. Clinically PE was documented by a physician and confirmed by computed tomography pulmonary angiography within 30 days of the stroke case index. The primary outcome was death or disability at discharge. Secondary outcomes included disposition, length of hospital stay, mortality at 3 months and 1 year. Among 11 287 patients with AIS , PE was found in 89 (0.78%) patients. History of cancer, deep vein thrombosis ( DVT )/ PE , and DVT during the hospitalization were associated with PE . PE was associated with higher risk of death at 30 days (25.8% versus 13.6%; P <0.001), at 1 year (47.2% versus 24.6%; P <0.001), and disability at discharge (85.4% versus 63.6%; P <0.001). Mean length of stay was longer in stroke patients with PE (36 versus 16 days; P =0.001). After adjusting for age, sex, and stroke severity, PE remained associated with lower survival at 30 days and 1 year, and death or disability at discharge ( OR 3.02; 95% CI 1.56 to 5.83). Conclusions In this large cohort study, PE occurred in nearly 1% of AIS patients. PE was more common in patients with severe stroke, history of cancer, previous DVT / PE or acute DVT and associated with lower short‐ and long‐term survival, greater disability, and longer length of stay.