tbuckley/cabot-search huggingface dataset:
Abstract 4461: Rho-kinase Pathway Plays an Important Role in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stent
Authors: Takashi Shiroto, Satoshi Yasuda, Ryuji Tsuburaya, Yoshitaka Ito, Hatsue Ishibashi-Ueda, Kenta Ito, Jun Takahashi, Hiroaki Shimokawa
Journal: Circulation (2008)

It has recently been reported that coronary vasoconstricting responses are enhanced at the edge of coronary segment implanted with drug-eluting stent (DES) as compared with bare-metal stent (BMS) in humans. We have previously demonstrated in animal models and humans that activation of Rho-kinase plays a key role in the molecular mechanism of coronary vasospasm. In this study, we thus examined whether Rho-kinase pathway also is involved in the DES-induced coronary hyperconstriction in vitro and in vivo. In cultured human coronary vascular smooth muscle cells, paclitaxel (10 –1000 nM, comparable tissue concentrations in humans, 24 hours) concentration-dependently up-regulated Rho-kinase expression (n=9) and increased Rho-kinase activity (10 nM, n=6). In a porcine model in vivo, DES (Taxus ™ ) and BMS (Express ™ ) were randomly implanted in the left anterior descending and circumflex coronary arteries (n=5). Four weeks after the implantation, coronary vasoconstricting responses to serotonin (5-HT, 50 and 100 μg/kg, IC) were significantly enhanced at the DES site compared with the BMS site (DES −52±4 vs. BMS −31±5%, P&lt;0.01), and the enhanced responses were prevented by hydroxyfasudil (HF, 90 and 300 μg/kg, IC), a selective Rho-kinase inhibitor ( Figure A ). The same in vivo findings also were noted in another comparison between DES (Cypher ™ ) and BMS (Velocity ™ ) (DES −62±3% vs. BMS −41±3%, n=6, P&lt;0.01) ( Figure B ). Histological analysis showed microthrombus formation only at the DES site. These results suggest that Rho-kinase pathway also plays an important pathogenetic role in the DES-induced coronary hyperconstricting responses.
BRCA1 regulates the expression of cell cycle proteins via the proteosome
Authors: Dana Berneman, Moshe Z. Papa, Ronit I. Yarden
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1300 

Germline mutations in the breast and ovarian tumor suppressor gene, BRCA1 , predispose women to breast and ovarian cancers. The gene product, BRCA1, is a protein of 1863 amino acids with two conserved domains. The BRCT domain at the carboxyl terminus is a motif found in many proteins involved in DNA repair and maintenance of genomic stability. The RING domain at the amino terminus is found in proteins involved in ubiquitylation. In response to DNA damage, BRCA1 becomes hyperphosphorylated and relocalizes to sites of DNA double strand breaks. We and others demonstrated that BRCA1 is involved in relaying the DNA damage signal. We established that in response to ionizing radiation (IR) BRCA1 activates the G2/M cell cycle checkpoint by regulating the expression, activity and cellular localization of key cell cycle proteins. Wild type full length BRCA1 expression in HCC1937 breast cancer cells, deficient for BRCA1, resulted in down regulation of cyclin B and Cdc25C while an increase in Wee1 and 14-3-3 proteins. Studies demonstrated that cancer predisposing mutations in the RING domain of BRCA1 prevent the activation of the G2/M checkpoint in response to DNA damage. Here we report that BRCA1 regulates the expression of checkpoint proteins via the proteosome. BRCA1 deficient and proficient breast cancer cells were treated with the proteosome inhibitors: calpain inhibitor (AL’L’N) and MG132 . we observed significant increase in the protein levels of Cdc25 and cyclin B in BRCA1 proficient cells treated with 5 μM of ALLN. Furthermore, ex-vivo ubiquitylation assays suggested that BRCA1 may tag cell cycle proteins with ubiquitin. We are currently investigating the role of BRCA1 in proteosome-mediated degradation of cell cycle proteins following DNA damage.
Risk is highest during first months of use
Authors: H B M Reijnen, W J Atsma
Journal: BMJ (1995)

using the pill early because they had had a thrombo- embolic event).The users of products containing levonorgestrel and norethisterone might then comprise, in effect, a population of survivors who are less at risk of the condition under study.I understand that further analyses are in progress to test this hypothesis in various ways.The same model, however, has important implications for prescribers now.A first time user could
Confidentiality
Authors: Julius Bourke, Simon Wessely
Journal: BMJ (2008)

Confidentiality in the medical setting refers to "the principle of keeping secure and secret from others, information given by or about an individual in the course of a professional relationship,"1 and it is the right of every patient, even after death.2 Breaches of confidentiality are common, albeit usually accidental.2 Around a third of the calls received by the Medical Protection Society from doctors are related to confidentiality, particularly in general practice.3 It is the most common reason for doctors, at any stage of their training, to seek advice from their indemnity unions. Confidentiality lies at the heart of the relationship between doctor and patient, and one survey suggests that the public view any breaches of this as the most important reason for striking doctors off the medical register.4 Maintaining confidentiality is part of the "good faith" that exists between doctor and patient.5 Ignoring patients' rights to confidentiality would lose their trust, and might prevent people from seeking help when needed. Confidentiality preserves individual dignity, prevents information misuse, and protects autonomous decision making by the patient.6 #### Key points
食品、饮料、睡眠以及电视与成人体重逐步增加有关
Authors: 徐静（译）
Journal: BMJ (2011)

即使体重指数正常的健康成年人也会随着时间的流逝而逐渐变胖。近期的一个分析表明在3个长期的队列研究中，从中选择的美国健康专家亚组平均每年体重增加近1磅（0．45kg）。这是为什么呢？仔细看看他们食谱的变化与体重变化的关系，就能分析出其常见的原因。更多油炸薯条、薯片、土豆泥、肉以及含糖饮料的摄入都与明显的体重增加相关。
Abstract B09: Targeting macrophages to degrade fibrosis in pancreatic ductal adenocarcinoma
Authors: Kristen B. Long, Santiago L. Luque, Gregory L. Beatty
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDA) is commonly resistant to chemotherapy due to extensive stromal fibrosis and poor vascularity which combine to inhibit chemotherapy diffusion into tumor tissue. Strategies that target tumor-associated fibrosis have shown promise in preclinical and early clinical trials. We have previously shown that treatment with an agonist CD40 monoclonal antibody (mAb) can induce macrophages to facilitate degradation of tumor-associated fibrosis in PDA, resulting in tumor regressions. Here, we investigated the mechanism by which macrophages facilitate stromal degradation using the KrasG12D; Trp53R172H; Pdx-1 Cre (KPC) genetically engineered mouse model of PDA. By immunofluorescence imaging, we first characterized the extracellular matrix that surrounds PDA tumors in the KPC model. We found high levels of fibronectin, hyaluronic acid and type I collagen present within the surrounding PDA stroma. Treatment with a CD40 mAb resulted in macrophage dependent degradation of both fibronectin and type I collagen, but had no effect on hyaluronic acid. To examine the ability of macrophages to degrade type I collagen, we developed an in vitro colorimetric collagen degradation assay. We found that neither CD40 activation nor classical activation with IFN-γ and LPS were sufficient to induce macrophages to degrade type I collagen. In contrast, classical activation of macrophages in the presence of tumor cells led to &amp;gt;50% collagen degradation in vitro. This effect was correlated with the ability of classically activated macrophages to eliminate tumor cells. Our findings suggest that macrophages acquire the capacity to degrade tumor-associated stromal fibrosis only after activation and successful elimination of tumor cells. This finding has important implications for the design of novel strategies that exploit the anti-fibrotic potential of macrophages for potentially improving drug delivery in PDA. Citation Format: Kristen B. Long, Santiago L. Luque, Gregory L. Beatty. Targeting macrophages to degrade fibrosis in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B09.
Abstract 15622: Cost-Effectiveness of Pediatric Heart Transplantation Across a Positive Crossmatch
Authors: Brian Feingold, Steven A Webber, Cindy L Bryce, Heather E Tomko, Seo Y Park, William T Mahle, Kenneth J Smith
Journal: Circulation (2014)

Introduction: Allosensitized children listed with a requirement for a negative prospective crossmatch (XM) have a high risk of death awaiting heart transplantation (HTx). Previously we found that acceptance of the first suitable organ offer for these patients, regardless of the possibility of a +XM, results in a survival benefit at all times after listing, including post-HTx. The cost-effectiveness of this strategy is unknown. Methods: We used a Markov-state transition model with a 10 yr time horizon to compare survival, costs, and utility (i.e. quality of life) for 2 waitlist strategies for sensitized candidates: requiring a negative prospective XM (WAIT) vs. accepting the first suitable organ offer (TAKE). Model data were derived from OPTN status 1A pediatric HTx listings from 1999-2009, the PHTS and HCUP KIDS databases, and other published sources. We assumed no possibility of a +XM in the wait strategy and that the probability of a +XM in the take strategy was equal to the pre-transplant PRA. Results: At base case, TAKE was dominant; it cost less ($122,856) and gained more (1.04) quality-adjusted life-years (QALYs) than WAIT. In sensitivity analyses varying all model parameters individually over clinically plausible ranges, TAKE remained dominant or favored (using a $100,000/QALY cost-effectiveness threshold) except when the probability of HTx for TAKE was &lt;55% over 2 years (base case value 67%). After adjustment of the model so that waitlist probabilities of death and delisting were equal in both strategies (while maintaining the lower probability of HTx associated with WAIT), TAKE remained dominant. WAIT was no longer dominated if mortality after HTx across a +XM was &gt;30%/year (equivalent to median post-HTx survival of &lt;3 yrs); yet even at the extreme assumption of 100% 1-year mortality after HTx across a +XM for TAKE, the wait strategy was not cost effective ($350,097/QALY). CONCLUSIONS: Among sensitized status 1A pediatric HTx candidates, we found that taking the first suitable organ offer is less costly and results in greater survival than awaiting HTx across a negative prospective XM. This suggests that HTx should not be denied based on sensitization status alone.
A prognostic score at diagnosis for Ewing tumor patients with metastatic disease at extrapulmonary sites
Authors: R. Ladenstein, U. Pötschger, M. Le Deley, J. Whelan, M. Paulussen, O. Oberlin, H. van der Berg, U. Dirksen, A. Craft, H. Jürgens
Journal: Journal of Clinical Oncology (2009)

10544 Background: To assess prognostic factors at diagnosis in prospectively treated patients with primary extra-pulmonary metastatic Ewing tumors (EPM-ET) of the EURO-E.W.I.N.G. 99 Study. Methods: From 1999 to 2005, 281 patients were enrolled. Median age was 16.2 years (0.4–49). Primary site was extremity in 84 patients and axial in 197 (115 pelvic sites), with a tumor volume &gt;200ml in 171 patients. Treatment consisted of 6 VIDE cycles, one VAI/VAC cycle, local treatment (surgery and/or radiotherapy), and high-dose busulfan-melphalan followed by peripheral stem cell transplantation (HDT/SCT). Results: After a median follow up of 3.8 years, event-free survival (EFS) and overall survival (OS) at 3 years for all 281 patients were 27%±3% and 34%±4%. Six VIDE cycles were completed by 250 patients (89%); 169 (60%) received HDT/SCT. Cox regression analyses demonstrated increased risk for patients with more than two bone metastatic sites (hazard ratio: HR 2.0), a primary tumor volume &gt;200ml (HR 1.8), bone marrow metastases (HR 1.6), age &gt;14 years (HR 1.6), and additional lung metastases (HR 1.5). A risk score based on these HR identified three risk groups with EFS rates of 50% for scores &lt;_3 (82 patients), 25% for scores &gt;3 to &lt;5 (102 patients), and 10% for scores &gt;_5 (70 patients), p&lt; 0.0001. Conclusions: A proportion of EPM-ET patients may survive with intensive multimodal therapy. Age, tumor volume, and extent of metastatic spread are relevant risk factors. A score based on these factors identifies EPMD-ET patients with a more favorable outlook at diagnosis and may facilitate risk adapted treatment approaches. No significant financial relationships to disclose.
Abstract 13148: Timing, Not Magnitude, of Peak Systolic Strain is Similar Across Speckle Tracking Platforms: A Comparison of 2D Strain with Velocity Vector Imaging
Authors: Jill B Whelan, Gerard P Aurigemma, Jeffrey C Hill, Amir Shaikh, Dennis A Tighe
Journal: Circulation (2011)

Background: Speckle tracking echocardiography (STE) provides novel insight into both global and regional systolic and diastolic function. There are both vendor-dependent (2D strain-GE Healthcare-2D...
In memoriam
Authors: Theodore Dalrymple
Journal: BMJ (2007)

Am I morbid when I say that there comes a time in life when you wonder what people will say about you when you're gone? The answer, of course, is that they won't think at all about you, at least for much or most of the time. Life itself dictates that it must go on even without our help: we are as pebbles dropped into a pond, causing a few ripples at most.
Ineffectiveness of clonidine in the treatment of the benzodiazepine withdrawal syndrome: report of three cases
Authors: W K Goodman, D S Charney, L H Price, S W Woods, G R Heninger
Journal: American Journal of Psychiatry (1986)

The effectiveness of clonidine hydrochloride in the treatment of abrupt withdrawal from long-term, therapeutic doses of benzodiazepines was studied in three patients under double-blind, placebo-controlled conditions. The intensity, severity, and duration of the abstinence syndrome were not altered by clonidine at a dose sufficient to markedly reduce blood pressure and plasma free 3-methoxy-4-hydroxyphenylglycol. These results contrast with the established efficacy of clonidine in the opiate withdrawal syndrome and suggest that many of the symptoms of benzodiazepine withdrawal may not be caused by hyperactivity of the noradrenergic system.
Abstract 16403: Occurrence of Autophagy and Bridging of the Autophagic Process to Apoptotic and Necrotic Cell Death in the Human Heart With End-Stage Heart Failure
Authors: Carol Chen-Scarabelli, Giuseppe Faggian, David Lanfear, Mitali Shah, Louis Saravolatz, Samuel Saravolatz, Gabriele Scarabelli, Kadija Abounit, Maddalena Tessari, Zhaokan Yuan, Giovanni Corsetti, Alessandro Mazzucco, Tiziano M Scarabelli
Journal: Circulation (2010)

Objectives:  Although originally described as a survival mechanism against stressful events, such as starvation, whether and to what extent autophagy is implicated in the terminal stages of heart failure is unknown. Hence, we studied magnitude and evolution of autophagy in patients with intractable heart failure.   Methods:  Myocardial samples were obtained from 19 patients with ischemic cardiomyopathy (n=11) and idiopathic dilated cardiomyopathy (n=8), who underwent cardiac transplantation. Hearts from 11 subjects deceased from noncardiac causes were used as controls. Autophagy was evaluated by immunostaining with a monoclonal LC3 antibody, while its relationship with apoptosis and necrosis was assessed by double staining with TUNEL assay and complement 9 (C9) immunological staining, respectively.   Results:  Heart failure hearts showed levels of myocyte autophagy over 7 fold greater than control hearts. Myocyte autophagy, revealed by staining with a monoclonal LC3 antibody, was detected in 8.7±1.6% of the entire myocyte population from heart failure heart and in 1.2±0.3% of cardiac myocytes from control hearts. LC3 positive vacuoles formation was observed to start at one nuclear pole, before becoming bipolar and involving the cytosol. Subsequently, the autophagic process extended also to the nuclei, which, in the final stages, underwent a progressive vacuolization and disintegration, assuming a peculiar “strawberry like aspect”. Interestingly, cardiac cells in which the autophagic vacuoles covered less than 50% of their surface, nuclear disintegration was not observed. Consensually, this cell population never showed colocalization of LC3 and C9 staining (to demonstrate colocalization of autophagy and necrosis) or TUNEL reagents (to demonstrate colocalization of autophagy and apoptosis). On the contrary, myocytes in which the autophagic vacuoles covered more than 50% of the cellular body, exhibited nuclear degeneration, which was associated with TUNEL and C9 positive staining.   Conclusions:  Autophagy was extensively detected in end-stage heart failure and progression of the process, causing broad cytosolic destruction and nuclear disintegration, finally resulted in cell death by apoptosis and necrosis.
Meta-analysis Spurious precision? Meta-analysis of observational studies
Authors: M. Egger, M. Schneider, G. D. Smith
Journal: BMJ (1998)

In previous articles we have focused on the potentials, principles, and pitfalls of meta-analysis of randomised controlled trials.1 2 3 4 5 Meta-analysis of observational data is, however, also becoming common. In a Medline search we identified 566 articles (excluding those published as letters) published in 1995 and indexed with the medical subject heading (MeSH) term “meta-analysis.” We randomly selected 100 of these articles and examined them further. Sixty articles reported on actual meta-analyses, and 40 were methodological papers, editorials, and traditional reviews (1). Among the meta-analyses, about half were based on observational studies, mainly cohort and case-control studies of medical interventions or aetiological associations.

View this table:

Characteristics of 100 articles randomly selected from articles published in 1995 and indexed in Medline with keyword “meta-analysis”



The randomised controlled trial is the principal research design in the evaluation of medical interventions. However, aetiological hypotheses—for example, those relating common exposures to the occurrence of disease—cannot generally be tested in randomised experiments. Does breathing other people's tobacco smoke cause lung cancer, drinking coffee cause coronary heart disease, and eating a diet rich in saturated fat cause breast cancer? Studies of such “menaces of daily life”6 use observational designs or examine the presumed biological mechanisms in the laboratory. In these situations the risks involved are generally small, but once a large proportion of the population is exposed, the potential public health implications of these associations—if they are causal—can be striking.

Analyses of observational data also have a role in medical effectiveness research.7 The evidence available from clinical trials will rarely answer all the important questions. Most trials are conducted to establish efficacy and safety of a single agent in a specific clinical situation. Owing to the limited size of such trials, less common adverse effects of drugs may only be detected in case-control …
Abstract 3182: Real-Time 3D Transesophageal Echocardiographic Mitral Valve Measurements: Comparison with Transthoracic Imaging
Authors: Sonal Chandra, Lynn Weinert, Martin Hyca, Berthold Klas, Roberto M Lang, Lissa Sugeng
Journal: Circulation (2007)

Although mitral annular (MA) geometry has been assessed using transthoracic real-time 3D echocardiography (TT RT3DE), it is unknown whether these images are of sufficient quality to provide similar data to that obtained from the transesophageal (TEE) approach. We compared MV annular measurements derived from images obtained using the new matrix array RT3DE TEE (mTEE) transducer with those obtained from TT RT3DE images. Method : Ten patients undergoing TEE evaluation were studied (iE33, Philips). ECG-gated, wide-angled acquisitions of the LV including the mitral valve were obtained using the mTEE probe and the TT RT3DE transducer (X3). Both TT and mTEE images were analyzed off-line using a semi-automated MA assessment software (TomTec), that yielded: anterior-posterior (AP), anterolateral-posteromedial (AL-PM) and commissural (CC) diameters, sphericity index (SI), and annular circumference (AC). For each mTEE and TT RT3DE images, inter- and intra-observer variability were calculated. Results : All 10 patients had adequate mTEE and TT RT3DE image quality for analysis. Although there were no significant differences between TT RT3DE and mTEE measurements, the latter had lower inter- and intra-observer variability (Table). Conclusion: MA measurements obtained with the mTEE are similar to TT RT3DE data, but more reproducible. Accordingly, studies involving quantitative 3D evaluation of the mitral valve from mTEE images are likely to reach statistical significance with a smaller number of subjects.
Ipilimumab-Induced Adrenalitis
Authors: Sara Bacanovic, Irene A. Burger, Paul Stolzmann, Jürg Hafner, Martin W. Huellner
Journal: Clinical Nuclear Medicine (2015)

Ipilimumab is a monoclonal antibody against the inhibitory CTLA-4 receptor expressed on T cells. It provokes an upregulation of the immune system. This substance was approved by the US Food and Drug Administration in 2011 and is since increasingly used as a targeted therapeutic approach for metastasized melanoma. Ipilimumab is known to cause neuroendocrine disorders, such as hypophysitis and adrenal insufficiency. Our case of a 79-year-old patient represents an important imaging pitfall. Imaging findings of newly symmetrically and smoothly enlarged, hypermetabolic adrenal glands in the setting of previous ipilimumab therapy represent drug-induced adrenalitis and not metastatic disease.