tbuckley/cabot-search huggingface dataset:
Long-term exposure to tobacco smoke on alveolar macrophages phenotype with regard to genetic and age predisposition
Authors: Svetlana Lyamina, Timofey Vedenikin, Igor Malyshev
Journal: European Respiratory Journal (2012)

Core role of tobacco smoke as a risk factor in chronic obstructive pulmonary disease (COPD) is proved, but COPD develops not in every smoker.  Objective :to estimate the effect of long-term tobacco smoke on a functional phenotype of alveolar macrophages (A;M) with regard to genetically determined macrophages phenotype while aging.  Methods : Experimental COPD (eCOPD) was simulated in vivo in two genetic mice strains:C57/BL6 (n=40)-predominant M1 phenotype,and Balb/c (n=40)-M2 phenotype. ECOPD groups included 30 mice, control–10 mice. Tobacco smoking lasted for 6 months-2 cigarettes t.i.d. COPD was verified histologically. AM functional phenotype was assessed by nitric oxide production (NO) spectrophometrically.  Results .COPD was confirmed histologically in both eCOPD groups, changes were more expressed in C57/BL6. There was no significant difference in basal NO production (bNO) in eCOPD groups, but induced NO production (iNO) significantly decreased during 6 months and was much lower in C57/BL6 than in BALB/c: 3.80±0.21 vs 5.53±0.29 mkM (p Conclusions .We elicited genetic predisposition to COPD risk factor - tobacco smoke, associated with M1 macrophages phenotype and age-related transformation of AM phenotype towards antiinflammatory M2, increasing with long-term inhalation of tobacco smoke and more expressed in M1 phenotype.
Impaired Hedgehog signalling-induced endothelial dysfunction is sufficient to induce neuropathy: implication in diabetes
Authors: Candice Chapouly, Qinyu Yao, Soizic Vandierdonck, Frederic Larrieu-Lahargue, John N. Mariani, Alain-Pierre Gadeau, Marie-Ange Renault
Journal: Cardiovascular Research (2015)

Microangiopathy, i.e. endothelial dysfunction, has long been suggested to contribute to the development of diabetic neuropathy, although this has never been fully verified. In the present paper, we have identified the role of Hedgehog (Hh) signalling in endoneurial microvessel integrity and evaluated the impact of impaired Hh signalling in endothelial cells (ECs) on nerve function.By using Desert Hedgehog (Dhh)-deficient mice, we have revealed, that in the absence of Dhh, endoneurial capillaries are abnormally dense and permeable. Furthermore, Smoothened (Smo) conditional KO mice clarified that this increased vessel permeability is specifically due to impaired Hh signalling in ECs and is associated with a down-regulation of Claudin5 (Cldn5). Moreover, impairment of Hh signalling in ECs was sufficient to induce hypoalgesia and neuropathic pain. Finally in Lepr(db/db) type 2 diabetic mice, the loss of Dhh expression observed in the nerve was shown to be associated with increased endoneurial capillary permeability and decreased Cldn5 expression. Conversely, systemic administration of the Smo agonist SAG increased Cldn5 expression, decreased endoneurial capillary permeability, and restored thermal algesia to diabetic mice, demonstrating that loss of Dhh expression is crucial in the development of diabetic neuropathy.The present work demonstrates the critical role of Dhh in maintaining blood nerve barrier integrity and demonstrates for the first time that endothelial dysfunction is sufficient to induce neuropathy.
Evolution of the Leukemic State Group Report
Authors: O. N. Witte, J. P. Allison, M. Essex, P. J. Fialkow, N. Haran-Ghera, J. C. Howard, W. Ostertag, V. Schirrmacher, H. J. Seidel, I. L. Weissman
Journal: Leukemia (1985)
Mithramycin Depletes Specificity Protein 1 and Activates p53 to Mediate Senescence and Apoptosis of Malignant Pleural Mesothelioma Cells
Authors: Mahadev Rao, Scott M. Atay, Vivek Shukla, Young Hong, Trevor Upham, R. Taylor Ripley, Julie A. Hong, Mary Zhang, Emily Reardon, Patricia Fetsch, Markku Miettinen, Xinmin Li, Cody J. Peer, Tristan Sissung, William D. Figg, Assunta De Rienzo, Raphael Bueno, David S. Schrump
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Specificity protein 1 (SP1) is an oncogenic transcription factor overexpressed in various human malignancies. This study sought to examine SP1 expression in malignant pleural mesotheliomas (MPM) and ascertain the potential efficacy of targeting SP1 in these neoplasms. Experimental Design: qRT-PCR, immunoblotting, and immunohistochemical techniques were used to evaluate SP1 expression in cultured MPM cells and MPM specimens and normal mesothelial cells/pleura. MTS, chemotaxis, soft agar, β-galactosidase, and Apo-BrdUrd techniques were used to assess proliferation, migration, clonogenicity, senescence, and apoptosis in MPM cells following SP1 knockdown, p53 overexpression, or mithramycin treatment. Murine subcutaneous and intraperitoneal xenograft models were used to examine effects of mithramycin on MPM growth in vivo. Microarray, qRT-PCR, immunoblotting, and chromatin immunoprecipitation techniques were used to examine gene expression profiles mediated by mithramycin and combined SP1 knockdown/p53 overexpression and correlate these changes with SP1 and p53 levels within target gene promoters. Results: MPM cells and tumors exhibited higher SP1 mRNA and protein levels relative to control cells/tissues. SP1 knockdown significantly inhibited proliferation, migration, and clonogenicity of MPM cells. Mithramycin depleted SP1 and activated p53, dramatically inhibiting proliferation and clonogenicity of MPM cells. Intraperitoneal mithramycin significantly inhibited growth of subcutaneous MPM xenografts and completely eradicated mesothelioma carcinomatosis in 75% of mice. Mithramycin modulated genes mediating oncogene signaling, cell-cycle regulation, senescence, and apoptosis in vitro and in vivo. The growth-inhibitory effects of mithramycin in MPM cells were recapitulated by combined SP1 knockdown/p53 overexpression. Conclusions: These findings provide preclinical rationale for phase II evaluation of mithramycin in patients with mesothelioma. Clin Cancer Res; 22(5); 1197–210. ©2015 AACR.
Inadequate neurology services undermine patient care in the UK
Authors: P. K. Morrish
Journal: BMJ (2015)

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Potassium and Its Discontents
Authors: David H Ellison, Andrew S Terker, Gerardo Gamba
Journal: Journal of the American Society of Nephrology (2015)

Hyperkalemia is common in patients with impaired kidney function or who take drugs that inhibit the renin-angiotensin-aldosterone axis. During the past decade, substantial advances in understanding how the body controls potassium excretion have been made, which may lead to improved standard of care for these patients. Renal potassium disposition is primarily handled by a short segment of the nephron, comprising part of the distal convoluted tubule and the connecting tubule, and regulation results from the interplay between aldosterone and plasma potassium. When dietary potassium intake and plasma potassium are low, the electroneutral sodium chloride cotransporter is activated, leading to salt retention. This effect limits sodium delivery to potassium secretory segments, limiting potassium losses. In contrast, when dietary potassium intake is high, aldosterone is stimulated. Simultaneously, potassium inhibits the sodium chloride cotransporter. Because more sodium is then delivered to potassium secretory segments, primed by aldosterone, kaliuresis results. When these processes are disrupted, hyperkalemia results. Recently, new agents capable of removing potassium from the body and treating hyperkalemia have been tested in clinical trials. This development suggests that more effective and safer approaches to the prevention and treatment of hyperkalemia may be on the horizon.
NK-Cells In Dasatinib-Treated Chronic Myeloid Leukemia Patients Display a Unique Phenotype Associated With Cytotoxic Potential
Authors: Beatriz Colom Fernandez, Anna Kreutzman, Valentin Garcia, Maria José Requena Rodríguez, Raúl Córdoba Mascuñano, Begoña Maestro Gutiérrez, Juan Luis Steegmann, Cecilia Muñoz Calleja
Journal: Blood (2013)
Abstract 15088: Scar Pattern in Chagas Heart Disease
Authors: Mahmoud I Traina, Mariam Thomas, Jason Bradfield, Salvador Hernandez, Alvaro J Altamirano Ufion, Daniel R Sanchez, Sheba K Meymandi
Journal: Circulation (2014)

Introduction: Scar in Chagas heart disease (CHD) is thought to be predominantly epicardial and requires epicardial access for ventricular tachycardia (VT) ablation. However, little data exists on scar patterns in this population. We evaluated the patterns of scar in patients who underwent magnetic resonance imaging (MRI) with delayed enhancement (DE). Methods: 19 patients were enrolled who had evidence of DE by MRI: 4 (21.0%) patients with normal electrocardiogram (ECG) and normal echocardiogram (echo) (group 1); 3 (15.8%) patients with abnormal ECG and normal echo (group 2); and 12 (63.2%) patients with abnormal ECG and echo (group 3). Results: In the 19 patients, there were 110 segments (34.1%) with DE identified using a 17-segment model. Pattern of involvement is as follows: endocardial 30 (27.3%), mid-myocardial 22 (20.0%), epicardial 2 (1.8%) and transmural 56 (50.9%). Most common territories of involvement are as follows (% of patients with segment involved): Basal inferolateral (78.9%), basal anterolateral (68.4%), mid inferolateral (63.2%), mid anterolateral (52.6%), apical lateral (52.6%) and apex (42.1%). The pattern of involvement also varied by group. In group 1, mid-myocardial 7 (50%), endocardial 6 (42.9%), transmural 1 (7.1%). In group 2, mid-myocardial 2 (18.2%), endocardial 6 (54.5%), transmural 3 (27.3%). In group 3, mid-myocardial 13 (15.3%), endocardial 18 (21.2%), transmural 52 (61.2%), epicardial 2 (2.4%). Conclusion: DE tends to occur most commonly in the basal and mid lateral segments. At earlier stages of disease, myocardial scar pattern tends to involve mid-myocardium and endocardium, and progress to transmural in later stages. Isolated epicardial scar was rare in this patient population, which is has potential implications for VT ablation strategies.
Contribution of angiotensin II to renal hemodynamic and excretory responses to nitric oxide synthesis inhibition in the rat.
Authors: T Takenaka, K D Mitchell, L G Navar
Journal: Journal of the American Society of Nephrology (1993)

This study was performed to evaluate the contribution of angiotensin II to the effects of nitric oxide (NO) synthesis inhibition on renal hemodynamics and excretory function in rats. Intravenous infusion of N omega-nitro-L-arginine (NLA; 20 micrograms/100 g.min) increased renal arterial pressure (RAP) from 128 +/- 2 to 143 +/- 3 mm Hg (P < 0.05; N = 6) and decreased RBF by 64 +/- 3% (P < 0.01) and GFR by 41 +/- 5% (P < 0.05). In response to reduction of RAP to control levels (127 +/- 2 mm Hg) by means of an adjustable clamp (CL) placed on the suprarenal aorta, RBF and GFR exhibited efficient autoregulation and were not altered. In rats (N = 6) pretreated with the AT1 angiotensin II receptor antagonist losartan (10 mg/kg iv), the infusion of NLA increased RAP (from 114 +/- 1 to 135 +/- 2 mm Hg; P < 0.05) and decreased RBF by 42 +/- 3% (P < 0.05). However, NLA did not decrease GFR in the losartan-treated rats. As in the control rats, the reduction of RAP to 113 +/- 1 mm Hg elicited autoregulatory responses that maintained RBF and GFR. In the untreated rats, at similar RAP (128 +/- 2 (control) versus 127 +/- 2 mm Hg (NLA+CL)). NO synthesis inhibition decreased urine flow and sodium excretion (P < 0.05, in both cases). However, during blockade of AT1 receptors, NLA infusion failed to decrease urine flow and sodium excretion, even when RAP was controlled (114 +/- 1 (control) versus 113 +/- 1 mm Hg (NLA+CL)).(ABSTRACT TRUNCATED AT 250 WORDS)
Structured and Modular Training Pathway for Robot-assisted Radical Prostatectomy (RARP): Validation of the RARP Assessment Score and Learning Curve Assessment
Authors: Catherine Lovegrove, Giacomo Novara, Alex Mottrie, Khurshid A. Guru, Matthew Brown, Ben Challacombe, Richard Popert, Johar Raza, Henk Van der Poel, James Peabody, Prokar Dasgupta, Kamran Ahmed
Journal: European Urology (2015)
Knowledge, attitude, and practices and influencing factors related to seasonal influenza vaccination among health-care workers in Qingdao, China, 2013–14: a prospective cohort study
Authors: Xiaoning Hao, Tao Bo, Zhi Liu, Shutao Pang, Fachun Jiang, Jianchun Liu, Tianyang Liu, Linghan Bu, None Tana
Journal: The Lancet (2015)
Genomic Rearrangements in Unusual and Atypical Melanocytic Neoplasms
Authors: Thomas Wiesner
Journal: JAMA Dermatology (2015)

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Abstract 19768: Does Frailty Predispose Patients to Increased Adverse Events after Left Ventricular Assist Device Implantation for Destination Therapy?
Authors: John M Stulak, Simon Maltais, John A Schirger, Richard C Daly, David L Joyce, Lyle D Joyce, Shannon Dunlay
Journal: Circulation (2014)

Introduction: Frailty has recently been shown to be associated with increased risk of death after continuous-flow left ventricular assist device (CF-LVAD) implantation as destination therapy (DT), but no data exists specifically analyzing its association with specific early and late adverse events. Methods: Between February 2007 and May 2014, 251 patients (205 male) underwent primary implantation of CF-LVAD at our institution; 157 (63%) were implanted as DT and preoperative frailty assessment was available in 96 pt. Frailty was identified in 58/96 (60%) patients according to the deficit index (31 impairments, disabilities and comorbidities) and defined as &gt; 25% deficits. Age (67 vs. 64 years, p=0.12), male sex (79% vs. 87%, 0.63), chronic kidney disease (64% vs. 63%, p=0.74), creatinine (1.7 vs. 1.5, p=0.1), hemoglobin (11.6 vs. 11.5, p=0.98), and albumin levels (3.7 vs. 3.8, p=0.53) were similar between frail and non-frail pt, while diabetes (59% vs. 13%, p&lt;0.001), ischemic etiology (64% vs. 45%, p=0.04), and preop balloon pump (50% vs. 26%, p=0.01) were significantly different. Results: All patients underwent CF-LVAD implantation and cardiopulmonary bypass time was similar between groups (102 vs. 111 min., p=0.3). There were no significant differences in early adverse events between frail and non-frail pt, including inotrope duration (120 vs. 96 hr., p=0.11), right ventricular failure (19% vs. 13%, p=0.44), respiratory failure (26% vs. 18%, p=0.34), acute renal failure (16% vs. 13%, p=0.69), and hepatic dysfunction (16% vs. 13%, p=0.69). Median length of stay (20 vs. 16 days, p=0.25) and early mortality (12% vs. 8%, p=0.48) were also similar. During a median follow up of 2 years with 224 patient/years of support, any GI bleed (43% vs. 42%, p=0.79), any thromboembolic event (34% vs. 39%, p=0.74), and driveline infection (10% vs. 26%, p=0.052). Conclusions: In this select cohort of patients, frailty did not portend higher risk of adverse events after CF-LVAD implantation for DT despite prior observation that late survival is reduced in these patients. These findings are extremely important in patient selection and counseling of patients prior to LVAD implantation.
The Moral Agency of Physician Organizations: Meeting Obligations to Advocate for Patients and the Public
Authors: David A. Fleming
Journal: Annals of Internal Medicine (2015)

The close of the American College of Physician's (ACP) centennial year is an opportune time to reflect on the organization's important role in professional development and advocating for sound health policy. Organized medicine provides a professional home where members can participate in scholarly activities and access guidance that will help them to be better doctors. Professional organizations also serve patients by improving physicians' knowledge and skill, being a public repository of health-related information, and advocating for improvement of public health. High-functioning medical professional organizations, such as ACP, also function intentionally as moral agents through well-designed efforts to advocate for patients and the public.
Systemic genome screening identifies the outcome associated focal loss of long noncoding RNA PRAL in hepatocellular carcinoma
Authors: Chuan‐chuan Zhou, Fu Yang, Sheng‐xian Yuan, Jin‐zhao Ma, Feng Liu, Ji‐hang Yuan, Feng‐rui Bi, Kong‐ying Lin, Jian‐hua Yin, Guang‐wen Cao, Wei‐ping Zhou, Fang Wang, Shu‐han Sun
Journal: Hepatology (2015)

Systemic analyses using large-scale genomic profiles have successfully identified cancer-driving somatic copy number variations (SCNVs) loci. However, functions of vast focal SCNVs in "protein-coding gene desert" regions are largely unknown. The integrative analysis of long noncoding RNA (lncRNA) expression profiles with SCNVs in hepatocellular carcinoma (HCC) led us to identify the recurrent deletion of lncRNA-PRAL (p53 regulation-associated lncRNA) on chromosome 17p13.1, whose genomic alterations were significantly associated with reduced survival of HCC patients. We found that lncRNA-PRAL could inhibit HCC growth and induce apoptosis in vivo and in vitro through p53. Subsequent investigations indicated that the three stem-loop motifs at the 5' end of lncRNA-PRAL facilitated the combination of HSP90 and p53 and thus competitively inhibited MDM2-dependent p53 ubiquitination, resulting in enhanced p53 stability. Additionally, in vivo lncRNA-PRAL delivery efficiently reduced intrinsic tumors, indicating its potential therapeutic application.lncRNA-PRAL, one of the key cancer-driving SCNVs, is a crucial stimulus for HCC growth and may serve as a potential target for antitumor therapy.
The burden of hepatitis C to the United States Medicare system in 2009: Descriptive and economic characteristics
Authors: David B. Rein, Joshua Borton, Danielle K. Liffmann, John S. Wittenborn
Journal: Hepatology (2015)

The aim of this work was to estimate and describe the Medicare beneficiaries diagnosed with hepatitis C virus (HCV) in 2009, incremental annual costs by disease stage, incremental total Medicare HCV payments in 2009 using the Surveillance, Epidemiology, and End Results (SEER)‐Medicare linked data covering the years 2002 to 2009. We weighted the 2009 SEER‐Medicare data to create estimates of the number of patients with an HCV diagnosis, used an inverse probability‐weighted two‐part, probit, and generalized linear model to estimate incremental per patient per month costs, and used simulation to estimate annual 2009 Medicare burden, presented in 2014 dollars. We summarized patient characteristics, diagnoses, and costs from SEER‐Medicare files into a person‐year panel data set. We estimated there were 407,786 patients with diagnosed HCV in 2009, of whom 61.4% had one or more comorbidities defined by the study. In 2009, 68% of patients were diagnosed with chronic HCV only, 9% with cirrhosis, 12% with decompensated cirrhosis (DCC), 2% with liver cancer, 2% with a history of transplant, and 8% who died. Annual costs for patients with chronic infection only and DCC were higher than the values used in many previous cost‐effectiveness studies, and treatment of DCC accounted for 63.9% of total Medicare's HCV expenditures. Medicare paid $2.7 billion (credible interval: $0.7‐$4.6 billion) in incremental costs for HCV in 2009. Conclusions: The costs of HCV to Medicare in 2009 were substantial and expected to increase over the next decade. Annual costs for patients with chronic infection only and DCC were higher than values used in many cost‐effectiveness analyses. (H epatology 2016;63:1135–1144)
Abstract 15451: The Novel Mechanistic and Diagnostic Role of Tie-2+cd14+ Monocytes in Patients with a Thoracic Aortic Aneurysm
Authors: Seyedhossein Aharinejad, Mohamed Salama, Jonathan Grzybeck, Trevor Lucas, Gunther Laufer, Florian Schonhoff, Thierry Carrel, Martin Czerny
Journal: Circulation (2012)

Thoracic aortic aneurysm (TAA) is a dangerous disease with high mortality, and is associated with extracellular matrix (ECM) remodeling and increased matrix metalloprotease activity (MMP) in the ao...
Abstract 13181: Characteristics of Diurnal Change of Pulse Rate in Resistant Hypertension
Authors: Hiroaki Watanabe, Tomoyuki Kabutoya, Satoshi Hoshide, Kazuo Eguchi, Kazuomi Kario
Journal: Circulation (2014)

Introduction: Sympathetic hyperactivity is one of the most important causes of resistant hypertension. Ambulatory blood pressure monitoring (ABPM) allows measurement of blood pressure (BP) and pulse rate (PR) throughout the day, as well as measurement of diurnal variations in BP and PR, which are controlled by the autonomic nervous system. Hypothesis: We hypothesized that abnormal diurnal change of BP and PR are associated with resistant hypertension. Methods: We evaluated 1003 patients with hypertension who were enrolled in the Japan Morning Surge Home Blood Pressure Study and were using ABPM. Resistant hypertension was defined as clinic BP≧140/90 mmHg despite the use of optimal doses of 3 classes of antihypertensive drugs, including a diuretic. BP or PR dipper status was defined as (awake systolic BP (SBP) or PR-sleep SBP or PR)/awake SBP or PR ≧0.1. BP or PR nondipper status was defined as (awake SBP or PR-sleep SBP or PR)/awake SBP or PR &lt;0.1 and ≧0. BP and PR riser status were defined as awake SBP or PR &lt; sleep SBP or PR. Results: The numbers of PR nondippers and PR risers in the resistant hypertensive groups were significantly greater than those in the non-resistant hypertensive groups (x2=9.35, p=0.009), but there were no significant differences in the diurnal variation of BP between the resistant hypertensive and non-resistant hypertensive groups (x2=3.10, p=0.21). In the resistant hypertensive groups, the proportion of PR risers was approximately three-fold greater than that in the non-resistant hypertensive groups after adjustment for age, gender, 24-h BP, PR, and BP variation (Hazard ratio 2.94, 95%Cl 1.25-6.91, p=0.013), but there were no significant differences in the proportion of PR nondippers (Hazard ratio 1.36, 95%Cl 0.82-2.26, p=0.23). Conclusions: A riser pattern of PR was associated with resistant hypertension. ABPM may be useful to identify resistant hypertensive patients who have autonomic nervous system dysfunction.