tbuckley/cabot-search huggingface dataset:
Abstract 3620: Cellular Pcsk9 Autocatalytic Activity Measured in Hepatocytes
Authors: Sanae Kourimate, Florent Lalanne, Philippe Costet
Journal: Circulation (2008)

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a natural inhibitor of the Low density lipoprotein receptor (LDLr). Its autocatalytic cleavage is necessary to its processing within the cell and the targeting of the LDLr. Therefore identifying molecules that would modulate this activity is an important challenge. The possibility of measuring this activity has been debated. Using whole hepatocytes lysates and optimized conditions, we showed that the cleavage of a fluorogenic peptide corresponding to proPCSK9 cleavage site is specific to this proprotein convertase. Indeed, the fluorogenic activity was virtually absent in primary hepatocytes from PCSK9 knockout mice compared with wild type hepatocytes. In human immortalized hepatocytes (IHH), a reduction of PCSK9 expression by 40 to 60% using SiRNA technology reproducibly decreased PCSK9 activity in a range of similar magnitude. Maldi-Toff analysis of the cell lysate following the the experiment showed that the fluorogenic peptide is cleaved at the right site LVFAQ152. In IHH cells exposed to the Liver X agonist T0901317 1 microM or fenofibric acid 250microM, or to both drugs concomitantly for 48h, PCSK9 protein content was respectively increased by 60% (p&lt;0.5), decreased by 70% (p&lt;0.01) or decreased by 30% (p&lt;0.01). We observed similar variations of the fluorogenic activity of these cell lysates. We also observed that PCSK9 autocatalytic activity was increased in cells accumulating PCSK9 upon exposure to pravastatin 10microM for 48h, and that the repressive effect of fenofibric acid 250microM overcame the induction by pravastatin, in agreement with our previous works on PCSK9 transcriptional regulation. We also analysed the catalytic activity of PCSK9 gain of function variants. Altogether, these results show that PCSK9 endogenous autocatalytic activity can be measured in cellulo. Futhermore, the catalytic activity reflects PCSK9 protein abundance. We suggest that this test could also be used to identify postraductional modulators of PCSK9 activity.
Abstract 635: Inhibiting Reactive Apoptosis by Cardiac-specific Nix Ablation Prevents Decompensation of Pathological Hypertrophy
Authors: Abhinav Diwan, Janaka Wansapura, Scot Matkovich, Faisal Syed, Hairong Li, Yehia Marreez, Gerald W Dorn
Journal: Circulation (2007)

Background : Compensated pathological hypertrophy will inevitably remodel, leading to functional decompensation. Postulated mechanisms include cardiomyocyte dropout, changes in myocardial matrix, and altered cardiac metabolism. Transcriptional modulation of apoptosis-regulating Bcl2 family members is associated with myocardial hypertrophy, but a role for programmed cardiomyocyte death in left ventricular (LV) remodeling has not been established. Methods and Results : Proapoptotic Nix, which is transcriptionally upregulated in pressure overload and Gαq-dependent hypertrophies, was subjected to germ-line or cardiac-specific gene targeting (KO) using Cre-lox technology and conditional cardiac-specific overexpression (TG) using tetracycline suppressible bitransgenic system in mice. Conditional forced Nix expression in neonatal and adult hearts was well tolerated, but acted synergistically with the pro-hypertrophic Gαq transgene to increase cardiomyocyte apoptosis (TUNEL %: 0.8±0.1 in Gαq TG vs 7.8±0.6 in Gαq+Nix TG) and caused lethal cardiomyopathy with LV dilation (LVEDD mm: 3.7±0.2 vs 4.6±0.2) and depressed systolic function (% fractional shortening (%FS): 39±4 vs 23±4). Nix KO combined with Gαq TG significantly reduced cardiomyocyte apoptosis (TUNEL %: 4.8±0.2 in GαqTG+ Nix KO vs 8.4±0.5 in GαqTG), improved systolic function (LV%FS: 43±3 vs 27±3), attenuated LV remodeling (r/h:2.4±0.1 vs 4.0±0.6), and largely prevented lethality of the Gαq peripartum model of apoptotic cardiomyopathy. Cardiac-specific (Nkx2.5-Cre) Nix KO mice were subjected to transverse aortic constriction (TAC) (gradients: 89±4 vs 83±5 mmHg in controls, n=12 each, P =NS). In cardiac Nix KO, serial echocardiograms and terminal invasive hemodynamic studies at 9 weeks after TAC revealed significantly less LV dilation (LVEDD mm: 3.3±0.1 vs 3.8±0.2), maintained concentric remodeling (r/h:1.8±0.1 vs 2.3±0.3), and preserved function (%FS: 63±3 vs 51±4; +dP/dt40 mmHg/s: 11519±1211 vs 8499±399) as compared with controls. Conclusions : Nix-induced cardiomyocyte apoptosis is a major determinant of adverse remodeling in pathological hypertrophies, and suggests therapeutic value for apoptosis inhibition to prevent cardiomyopathic decompensation.
Guidelines for the management of patients with pancreatic cancer periampullary and ampullary carcinomas
Journal: Gut (2005)

N Resection in the presence of preoperative detection of portal vein encasement is rarely justified (grade C).N Percutaneous biliary drainage prior to resection in jaundiced patients does not improve surgical outcome and may increase the risk of infective complications (grade A).N Left sided resection (with splenectomy) is appropriate for localised carcinomas of the body and tail of the pancreas.Involvement of the splenic vein or artery is not in itself a contraindication to such resection.(grade B) Palliative surgeryN Duodenal bypass should be used during palliative surgery (grade B).N Biliary bypass should be constructed with the bile duct in preference to the gall bladder (grade B). Non-surgical therapiesN Adjuvant or neoadjuvant therapies in conjunction with surgery should only be given in the context of a clinical trial (grade A).N If chemotherapy is used for palliation, gemcitabine single agent treatment is recommended (grade A).N Therapy with novel treatments should only be offered to patients within clinical trials (grade C). v2
Abstract 1634: Validation of 64-Slice Multi-Detector Computed Tomography Coronary Angiography Against Invasive Hemodynamic Measurements of Fractional Flow Reserve in the Detection of Non-Flow-Limiting Coronary Stenoses
Authors: Kamran Akram, Robert O’Donnell, Jennifer LaCorte, Charles Brown, Szilard Voros
Journal: Circulation (2007)

Introduction. Multi-detector CT coronary angiography (CorCTA) has been introduced for coronary artery disease (CAD) detection and been validated against invasive angiography (XRA) and intravascular ultrasound (IVUS). However, the diagnostic accuracy of CorCTA-derived area stenosis (%AS), diameter stenosis (%DS), minimal lumen area (MLA) and minimal lumen diameter (MLD) have not been previously validated against fractional flow reserve (FFR). Methods. Twenty consecutive patients enrolled in a study of non-obstructive CAD underwent CorCTA and invasive FFR measurements within 2 weeks. Patients without prior CAD with visual intermediate stenoses (40–70%) by either XRA or CorCTA were eligible. CorCTA was performed on a 64-slice scanner. %AS, %DS, MLA and MLD were measured quantitatively with commercial software (SurePlaque; Vital Images). FFR was determined by averaging 3 independent measurements after intracoronary injection of adenosine. Statistical analysis was done using Analyse-It software. Results. CorCTA-derived values (mean±SD) in the group were as follows: %AS=43.8±21.3%, %DS=58.9±21.4%, MLA=3.9±3.0mm 2 , MLD=1.4±0.8mm, FFR=0.89±0.09. Two patients had flow-limiting stenoses by FFR. Table shows the area under the curve (AUC), optimal cutpoint, sensitivity, specificity, PPV and NPV for the parameters to predict non-flow-limiting FFR. All parameters performed well in predicting non-flow-limiting FFR as expressed by the AUC; these were highly significant. Values below stenosis cutpoints (%AS&lt;60%, %DS&lt;77%) and MLA&gt;3.0 mm 2 , MLD&gt;0.89 mm reliably excluded flow-limiting stenoses. Cutpoints were higher for %DS vs %AS (77% vs. 60%). Conclusions. To our knowledge, this is the first study to compare CorCTA to FFR. %AS, %DS, MLA and MLD performed very well in excluding hemodynamically significant stenoses. While%DS and MLD by CorCTA tend to overestimate the significance of stenosis, %AS and MLA correlate well to similar values derived from IVUS. Accuracy of CorCTA in Excluding Flow Limiting Stenoses As Measured by FFR
Abstract 14529: Characteristics of Patients with Cardiac Sarcoidosis Presenting Primarily with Ventricular Arrhythmias
Authors: Mohamed A Abdel-Shafee, Koji Fukuda, Yuji Wakayama, Makoto Nakano, Yuhi Hasebe, Masateru Kondo, Hiroaki Shimokawa
Journal: Circulation (2011)

Background:  Cardiac involvement is an important prognostic factor of sarcoidosis and ventricular tachycardia (VT) is a common presentation of patients with cardiac sarcoidosis (CS). In this study, we aimed to elucidate the predictors of developing such serious arrhythmias in CS patients.   Methods:  We examined 61 consecutive patients with CS who were admitted to our Hospital from January 2004 until March 2011. The diagnosis of CS was made based on the guidelines by the Japanese Ministry of Health and Welfare. We analyzed various demographic and clinical data, including delayed enhancement on cardiac magnetic resonance imaging (DE-MRI), with a special reference to their association with ventricular arrhythmias as a primary presentation of CS.   Results:  The CS patients were mostly middle-aged (58±12 years), females (62%) and mostly with grossly normal heart structure (60%), with a dilated cardiomyopathy-like phenotype as the only observed structural abnormality (40%) and ventricular arrhythmias as the most encountered electrical abnormality (47%). Of the parameters studied, no significant association with a primary presentation of ventricular arrhythmias was noted for age, gender or the presence of extra-cardiac sarcoidosis (P=0.63, 0.42 and 0.58 respectively). In contrast, a significant association with a primary presentation of ventricular arrhythmias was noted for compromised LV function at admission, including a worse NYHA class (P=0.041) and a lower LVEF (P=0.007). Importantly, the presence of DE-MRI was the most significant parameter associated with ventricular arrhythmia presentation (P=0.047, r =0.426) and the absence of DE-MRI carried a 100% negative predictive value for this presentation.   Conclusions:  These results indicate that compromised LV function and more importantly, DE-MRI, are significant clinical characteristics associated with ventricular arrhythmias as a primary presentation of CS.
Chronic brain disease: an overview
Authors: C E Wells
Journal: American Journal of Psychiatry (1978)

The author discusses the current state of clinical and pathological knowledge regarding chronic brain disease, focusing particularly on the dementias. His review of clinical studies deals with diagnostic issues and methods, etiology, and treatment. More basic research on brain alterations with aging, their relation to clinical manifestations of dementia, and studies of specific disorders are also reviewed. These disorders have been receiving increasing attention from psychiatrists, who are becoming more aware of the importance of organic cerebral factors in their patients' complaints. The need to understand the chronic brain diseases and their appropriate diagnosis and treatment will continue to grow as the proportion of older individuals in our society increases.
Tardive dyskinesia and other clinical consequences of neuroleptic treatment in children and adolescents
Authors: C T Gualtieri, D Quade, R E Hicks, J P Mayo, S R Schroeder
Journal: American Journal of Psychiatry (1984)

Of 41 children, adolescents, and young adults who were withdrawn from chronic neuroleptic treatment, 18 developed tardive dyskinesia, withdrawal dyskinesia, nondyskinetic withdrawal symptoms, or transient behavior deterioration. Development of neuroleptic-related problems seemed to be associated with cumulative neuroleptic dose and possibly with the sex of the subject. Only 12 of the 41 subjects required resumption of neuroleptic treatment after a prolonged trial withdrawal period.
Editorial misconduct
Authors: R. Smith
Journal: BMJ (2003)

As with members of any group—be they doctors, politicians, or cardinals—some editors misbehave. Managing their misbehaviour is complicated by widespread devotion to the principle of editorial freedom, a devotion that is energetically promoted by editors. When an organisation takes the nuclear option of firing its editor—as the American Medical Association did in 1999—the roof falls in.1 2 How can the circle of editorial independence and the need to discipline erring editors, of whom there are many, be squared? The answer may be self regulation, some sort of general medical journalists council.

Regular readers of the BMJ will imagine that it is my own misbehaviour that prompts me to meditate on the theme of editorial misconduct. My sins in the past two months include publishing an obituary seen by many as a hatchet job,3 4 publishing research funded by the tobacco industry that implied that passive smoking did not kill,5 carrying an offensive cover on the journal that depicted doctors as pigs, drug company representatives as lizards, and a bemused patient as a guinea pig, and publishing a study highly sceptical of the private finance initiative in the run up to the Scottish parliamentary elections.6 The obituary sin has been referred to the Press Complaints Commission, a body that provides self regulation for the …
Abstract 14056: Reducing to Practice the Concept of a Biological Pacemaker: Efficacy of Percutaneous, Right-Sided Gene Delivery in the Bundle of His versus Open-Chest Ventricular Wall Injection in a Porcine Model of Complete Heart Block
Authors: Eugenio Cingolani, Kristine Yee, Michael Shehata, Sumeet S Chugh, Eduardo Marban, Hee Cheol Cho
Journal: Circulation (2011)

Introduction: Present therapy for symptomatic bradycardia relies on electronic pacemakers. Complications may arise from device implantation, malfunction or infection. Biological pacemakers may, in ...
Abstract 3760: Atherogenic Affects Of Arsenic: Role Of Endoplasmic Reticulum Stress And Unfolded Protein Response
Authors: Petra Haberzettl, Elena Vladykovskaya, Oleg Barski, Srinivas Sithu, Stanley D’Souza, Christopher States, Sanjay Srivastava
Journal: Circulation (2008)

Arsenic is a global water contaminant and EPA has listed arsenic as a high priority hazardous substance in the United States. Epidemiological studies suggest that chronic arsenic ingestion increases cardiovascular disease in humans, particularly, carotid atherosclerosis. However, mechanisms of arsenic-induced atherogenesis are unknown. We examined the effect of arsenic exposure on early lesion formation in apoE-null mice maintained on water supplemented with (0, 1, 5 and 50 ppm; 3–16 weeks of age) sodium arsenite. Arsenic, did not affect plasma cholesterol but decreased the triglycerides by 18±4 % (P&lt;0.05). NMR analysis of the lipoproteins showed a significant decrease in the abundance of large VLDL particle (&gt;60 nm diameter). Despite a significant decrease in plasma triglyceride, atherosclerotic lesion formation was significantly increased (2– 4 fold; P&lt;0.05 for all doses) in the aortic sinus and the aortic arch of the arsenic-fed mice in a dose dependent manner. Immunohistochemical analysis showed significant increase in the accumulation of macrophages, expression of MCP-1 and unfolded protein response (UPR) dependent activating transcription factor (ATF)-4 and ATF3, in the lesions of arsenic (1ppm) exposed mice. In vitro , arsenic (5–25 μM), significantly increased the expression of ICAM-1, transmigration of differentiated monocytes and expression of the pro-inflammatory cytokine IL-8 in vascular endothelial cells (vEC). Arsenic, also increased the expression of ER-chaperones Grp 78, HERP and calnexin (2– 6 fold; P&lt;0.01). Examination of the effect of arsenic on UPR showed that arsenic, induced the splicing of IRE-1 dependent, bZIP transcription factor XBP-1(alarm phase) and increased the phosphorylation of eIF2α (PERK mediated adaptive phase) by 3 fold (P&lt;0.01) in vEC. Arsenic also induced the expression of the downstream effecter proteins of eIF2α-ATF3 (8 fold; P&lt;0.01) and pro-apoptotic protein CHOP (4 fold; P&lt;0.01) in vEC. Chemical chaperone, phenyl butyric acid (PBA), attenuated the arsenic-induced expression of ATF3 (&gt;90%; P&lt;0.001) and CHOP (&gt;90%; P&lt;0.001). These data suggest that ER-stress and UPR could exacerbate arsenic-induced vascular inflammation and promote atherogenesis.
Psychomotor function in affective disorders: an overview of new monitoring techniques
Authors: Greden Jf, Carroll Bj
Journal: American Journal of Psychiatry (1981)

Clinicians and researchers lack accuracy in assessing psychomotor functions of patients. Several objective monitoring techniques have recently been proposed with the goal of compiling accurate determinations. These include electromyographic determinations of facial expressions of emotion, measurement of speech phonation and pause times, and use of movement-activated recording monitors to quantify motility. Objective psychomotor assessments may improve classification, longitudinal monitoring, treatment selection, and prediction of outcome for patients with depression and mania.
Abstract 14282: A Prospective Randomized Trial Using Optical Coherence Tomography to Compare the Xience V Everolimus-Eluting Stent with a Bare Metal Stent Postdilated with a Paclitaxel-Eluting Balloon (OCTOPUS Trial)
Authors: Tudor C Poerner, Sylvia Otto, Florian Janiak, Johannes Gassdorf, Kristina Nitsche, Christian Jung, Bjoern Goebel, Hans R Figulla
Journal: Circulation (2012)

Background: We evaluated the Xience V® everolimus eluting stent (DES; Abbott Vascular) against the bare metal stent Coroflex Blue® postdilated with the paclitaxel-eluting balloon Sequent Please® (B...
Abstract 15782: The Embryonic Heart Contains Resident C-Kit-Positive Cardiac Stem Cells
Authors: Alex Matsuda, Barbara Ogorek, Joao Ferreira-Martins, Donato Cappetta, Sergio Signore, Domenico D'Amario, Claudia Fiorini, James Kostyla, Noriko Ide-Iwata, Virginia Caballero, Fumihiro Sanada, Toru Hosoda, Piero Anversa, Annarosa Leri, Marcello Rota, Jan Kajstura
Journal: Circulation (2011)

C-kit-positive cardiac stem cells (CSCs) are present in the adult heart, but whether these cells are nested within the embryonic organ and contribute to myocardial development remains unclear. Here, we tested whether CSCs are nested in the maturing embryo, participating in the formation of the adult cardiac phenotype. For this purpose, we studied mice in which EGFP is driven by the c-kit promoter. C-kit positive cells were identified in the cardiogenic mesoderm at E6.5, cardiac crescent at E7.5 and at later stages of the fetal heart. Time-lapse two-photon microscopy was employed to document that EGFP-positive CSCs undergo morphogenetic movements within the developing heart and do not translocate to the myocardium from extracardiac regions. EGFP-positive CSCs were negative for markers of hematopoietic cell lineages, excluding their origin from primitive sites of hematopoiesis. The number of CSCs increased linearly from E7.5 to E19, resulting in a 5.6-fold expansion of the stem cell compartment in the heart; 21 CSCs were found at E7.5 and 120 at E19. The growth of the cardiac mass was paralleled by an increase in CSCs; CSCs divided symmetrically and asymmetrically. In the latter case, the commitment to the myocyte lineage in vivo was shown by the non-uniform localization of the cell fate determinant, α-adaptin, in the dividing cell, together with the expression of Nkx2.5, MEF2C, α-sarcomeric actin, troponin I and α-cardiac actinin in one of the two daughter cells. In vitro, EGFP-positive c-kit positive CSCs at E12-E19 were self-renewing, clonogenic and multipotent, all critical determinants of stem cell function. C-kit positive cells differentiated into myocytes and vascular smooth muscle cells (SMCs) and endothelial cells (ECs). The inherent ability of embryonic CSCs to form myocytes was confirmed by fate mapping in vivo. CSCs were obtained at E18 from mice in which EGFP is under the control of the α-MHC promoter. Single cell CSC clones were generated and these cells were delivered to the infarcted LV of wild-type mice. This protocol rescued the infarcted heart resulting in the formation of EGFP-positive myocytes and EGFP-negative vascular SMCs and ECs. In conclusion, lineage negative c-kit-positive cells in the embryonic-fetal heart correspond to bona fide CSCs.
Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B
Authors: Jin Su, Liqing Zhu, Alexandra Sherman, Xiaomei Wang, Shina Lin, Aditya Kamesh, Joey H. Norikane, Stephen J. Streatfield, Roland W. Herzog, Henry Daniell
Journal: Biomaterials (2015)

Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ∼2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP+ regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ∼870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft2 per annum yielding 24,000–36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs.