tbuckley/cabot-search huggingface dataset:
Abstract 12646: Oxidation-Dependent Phosphomimetic Effect of a Human Heart Failure Mutation of Phospholamban
Authors: Neha Abrol, Pieter P de Tombe, Seth L Robia
Journal: Circulation (2014)

Rationale: A naturally-occurring, missense Arg9-to-Cys (R9C) mutation of phospholamban (PLB) triggers cardiomyopathy and premature death in humans. However, the fundamental molecular mechanism underlying the cardiotoxic role of R9C-PLB in sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) regulation and cardiomyocyte Ca 2+ handling is not clear. Objective: The goal of this study was to investigate the acute physiological consequences of R9C-PLB mutation on cardiomyocyte Ca 2+ kinetics and contractility and identify the molecular mechanism underlying R9C pathology. Methods and Results: We measured the physiological consequences of R9C-PLB mutation on Ca 2+ transients and sarcomere shortening in adult cardiomyocytes at increasing pacing frequencies. In contrast to studies of chronic R9C-PLB expression in transgenic mice, we found that acute expression of R9C-PLB exerts a positively inotropic and lusitropic effect in cardiomyocytes. Importantly, R9C-PLB exhibited blunted sensitivity to frequency potentiation and β-adrenergic stimulation, two major physiological mechanisms for the regulation of cardiac performance. To identify the molecular mechanism of R9C pathology, we fused fluorescent protein tags to PLB and SERCA, and compared the effect of R9C and pentamer-destabilizing mutation (SSS) on PLB oligomerization and PLB-SERCA interaction. Fluorescence resonance energy transfer (FRET) measurements in live cells revealed that R9C exhibited an increased affinity of PLB oligomerization, and a decreased binding affinity to SERCA due to an oxidative modification which mimics phosphorylation. Real-time FRET analysis in cardiomyocytes revealed that R9C-PLB exhibits enhanced sensitivity to oxidative stress, which is a prevailing condition in heart failure. Conclusions: We conclude that the primary mechanism of R9C pathology is a phosphomimetic effect of PLB cysteine oxidation, manifested as increased oligomerization and a change in the structure of the PLB-SERCA regulatory complex.
Predicting survival in heart failure: validation of the <scp>MAGGIC</scp> heart failure risk score in 51 043 patients from the <scp>S</scp>wedish <scp>H</scp>eart <scp>F</scp>ailure <scp>R</scp>egistry
Authors: Ulrik Sartipy, Ulf Dahlström, Magnus Edner, Lars H. Lund
Journal: European Journal of Heart Failure (2013)
Genetics: Society and Clinical Practice Genetics: Society and Clinical Practice
Authors: T. Richards
Journal: BMJ (1998)

Peter S Harper, Angus J Clarke Bios Scientific Publishers, £19.95, pp 264 ISBN 1 85996 206

Public interest in how genes determine both what we are and what may happen to us is growing. Commercial concerns have promised that they will soon be able to provide us with compact disks containing our complete genetic blueprint. Those people who have pursued their interest down burgeoning websites may have an informed view, but most people (including many doctors) have only a sketchy knowledge of genetics, so any book that sheds a balanced light on current issues is welcome.

Genetics is just that. Coauthored by two experienced clinical geneticists the book is rooted …
The Molecular Basis of Blood Diseases.
Authors: George Stamatoyannopoulos
Journal: Annals of Internal Medicine (1987)

The recent application of the techniques of molecular biol- ogy to the study of human diseases has made it possible to obtain information unavailable-and, in some instances, unimaginable-a decade ago.Because of the rapidity with which developments have occurred, many clinicians and scientists may be unaware of them and of the insights they provide into the origin of diseases.To address the needs of this audience, four noted authorities in the field, George Stamatoyannopoulos, Arthur Nienhuis, Philip Leder, and Philip Majerus, have recruited 27 of their colleagues to describe what is currently known about the molecular basis of blood diseases.The first chapter introduces the reader to the methods of molecular cloning and analysis of gene structure that have generated much of the information pre- sented subsequently.Several chapters then describe gene structure, expression, and regulation, using the globin genes as a model.After this general introduction, specific groups of diseases are addressed.Each area of classic hematology-the red cell, the white cell (both normal and malignant), and the soluble and cellular components of the hemostatic system (including hemostasis, thrombosis, and fibrinolysis)-is taken up in turn.In addition, three chap- ters present immunological topics-immunoglobulin and T-cell receptor genes (as well as lymphocyte differentia- tion), enzyme deficiencies associated with immunological disorders, and molecular mechanisms of complement ac-
Development of two real-time multiplex PCR assays for the detection and quantification of eight key bacterial pathogens in lower respiratory tract infections
Authors: N.J. Gadsby, M.P. McHugh, C.D. Russell, H. Mark, A. Conway Morris, I.F. Laurenson, A.T. Hill, K.E. Templeton
Journal: Clinical Microbiology and Infection (2015)

The frequent lack of a positive and timely microbiological diagnosis in patients with lower respiratory tract infection (LRTI) is an important obstacle to antimicrobial stewardship. Patients are typically prescribed broad-spectrum empirical antibiotics while microbiology results are awaited, but, because these are often slow, negative, or inconclusive, de-escalation to narrow-spectrum agents rarely occurs in clinical practice. The aim of this study was to develop and evaluate two multiplex real-time PCR assays for the sensitive detection and accurate quantification of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. We found that all eight bacterial targets could be reliably quantified from sputum specimens down to a concentration of 100 CFUs/reaction (8333 CFUs/mL). Furthermore, all 249 positive control isolates were correctly detected with our assay, demonstrating effectiveness on both reference strains and local clinical isolates. The specificity was 98% on a panel of nearly 100 negative control isolates. Bacterial load was quantified accurately when three bacterial targets were present in mixtures of varying concentrations, mimicking likely clinical scenarios in LRTI. Concordance with culture was 100% for culture-positive sputum specimens, and 90% for bronchoalveolar lavage fluid specimens, and additional culture-negative bacterial infections were detected and quantified. In conclusion, a quantitative molecular test for eight key bacterial causes of LRTI has the potential to provide a more sensitive decision-making tool, closer to the time-point of patient admission than current standard methods. This should facilitate de-escalation from broad-spectrum to narrow-spectrum antibiotics, substantially improving patient management and supporting efforts to curtail inappropriate antibiotic use.
Functional DNA J domain is required for methylation-controlled J protein (MCJ/DNAJC15)-mediated chemosensitivity
Authors: Nelmary Hernandez Alvarado, Jeremy Chien, Viji Shridhar
Journal: Clinical Cancer Research (2006)

B67   Members of the DNAJ protein family stimulate Hsp70 ATPase activity and target its chaperone activity to participate in many complex biologic processes, such as cell cycle regulation, protein folding and translocation, exocytosis, tumor cell growth, DNA replication and apoptosis. We had previously identified Methylation Controlled J-protein (MCJ/DNAC15) as a downregulated gene in ovarian cancer and showed that clonal lines expressing wild-type MCJ are more sensitive to commonly used chemotherapeutic agents in ovarian cancer. However, the subcellular location or the function MCJ is currently unknown. Confocal microscopy of GFP tagged MCJ revealed that it localizes to mitochondria. In order to determine the contribution of MCJ-DNAJ domain in chemoresponse, we generated an inducible system in 293T HEK Flp IN T-Rex cells to express both the wild-type and the mutant MCJ (H124Q), with a mutation within the J domain that abrogates its activity. Cell survival and apoptosis were measured after treatment with cisplatin and paclitaxel in cells following induction. Cell survival analyses revealed that wild-type MCJ expression confers sensitivity to chemotherapeutic agents. Hoechst staining indicates that wild-type MCJ expression potentiates cisplatin and paclitaxel-induced apoptosis. In contrast, the H124Q mutation attenuates chemotherapy induced cytotoxicity. The highly conserved histidine residue within the signature tripeptide HPD has been shown to be important for J domain-mediated activation of Hsp70 proteins in other systems. However, MCJ expression does not affect cell cycle distribution. Based on these data, we hypothesize that the DNAJ domain of MCJ may play a role in chemotherapy-induced cytotoxicity. Identification of MCJ binding proteins may elucidate the mechanism by which MCJ confers chemosensitivity to agents commonly used to treat ovarian cancer patients.
SPLENIC INFARCTION ASSOCIATED WITH HIGH ALTITUDE FLYING AND SICKLE CELL TRAIT
Authors: A E STOCK
Journal: Annals of Internal Medicine (1956)

Case Reports1 March 1956SPLENIC INFARCTION ASSOCIATED WITH HIGH ALTITUDE FLYING AND SICKLE CELL TRAITALBERT E. STOCK, M.D.ALBERT E. STOCK, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-44-3-554 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptRecent articles have emphasized a clinical syndrome of splenic infarction associated with high altitude flying and sicklemia.1, 2, 3 These articles have recorded several Negro patients suffering from a syndrome previously thought to be rare. The military and economic implications of Negroes flying at high altitudes in unpressurized cabins have been discussed elsewhere. The question of splenectomy as the treatment of choice remains unanswered.It is the purpose of this paper to report one additional patient with sickle cell trait and a small splenic infarct in which conservative therapy was successful.CASE REPORTA 22 year old Negro male corporal...Bibliography1. CooleyPetersonEngelJernigan JCWLCEJP: Clinical triad of massive splenic infarction, sicklemia trait, and high altitude flying, J. A. M. A. 154: 111, 1954. CrossrefMedlineGoogle Scholar2. Motulsky AG: Sicklemia, J. A. M. A. 155: 388, 1954. CrossrefGoogle Scholar3. Conn HO: Sickle-cell trait and splenic infarction associated with high-altitude flying, New England J. Med. 251: 417, 1954. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Colorado Springs, Colorado*Received for publication January 7, 1955.From the Department of Medicine, Central Colorado Medical Center, Colorado Springs, Colorado. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byMassive splenic infarction and splenic venous thrombosis observed in a patient with acute splenic syndrome of sickle cell traits on contrast-enhanced thin-slice computed tomographyA Unique Cause of Intestinal and Splenic Infarction in a Sickle Cell Trait PatientSplenic Complications of Sickle Cell Anemia and the Role of SplenectomyMassive splenic infarction in Saudi patients with sickle cell anemia: A unique manifestationMultiple Renal and Splenic Infarctions in a Neonate Following Transfusion with Sickle Trait BloodSickle Cell Trait and AviationThe morbidity of sickle cell traitOcclusive pulmonary vascular disease associated with hemoglobin SC diseaseAbdominal crises associated with sicklemia and airplane flights 1 March 1956Volume 44, Issue 3Page: 554-556KeywordsArmed forcesHemoglobinHypoxiaInfarctionSplenectomy ePublished: 1 December 2008 Issue Published: 1 March 1956 PDF downloadLoading ...
Abstract 16804: Tideglusib, a Novel Allosteric Inhibitor of Glycogen Synthase Kinase-3-β Mimics Canonical Wnt Signaling
Authors: Jugajyoti Baruah, Kishore Wary
Journal: Circulation (2014)

Rationale: As Glycogen Synthase Kinase-3 (GSK-3)β enzyme regulates β-catenin stability, we addressed the ability of Tideglusib, a novel allosteric inhibitor of GSK-3β, to activate canonical Wnt signaling in microvascular endothelial cells (ECs). Methods and Results: The treatment of primary ECs with Wnt3a or Tideglusib stabilized β-catenin polypeptide species in a dose-dependent manner. A time-course analyses showed increased in phosphorylated form of GSK-3β-S9, thereby, increased stabilization of β-catenin within 3-4 hours in response to Tideglusib. The addition of Tideglusib induced robust expression of not only transcription factor Nanog, but also Cyclin-D1 and Vascular Endothelial Growth Factor Receptor-2 proteins. Microscopic analyses demonstrated disappearance of VE-cadherin from the adherens junctions, while increased accumulation of β-catenin in the nucleus. Moreover, Fluorescence-activated cell sorting (FACS) of Propidium iodide and Annexin-V labeled ECs previously treated with Tideglusib showed ...
The effect of continuous positive airway pressure therapy on endothelial function in obstructive sleep apnea: A systematic review and meta-alysis
Authors: Esther I. Schwarz, Christian Schlatzer, Milo A. Puhan, John R. Stradling, Malcolm Kohler
Journal: European Respiratory Journal (2014)

Background 

Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder associated with adverse cardiovascular outcome. Endothelial dysfunction is one of the proposed mechanistic links between OSA and the increased cardiovascular risk. Treatment with continuous positive airway pressure (CPAP) may reverse this detrimental pathophysiological consequence of OSA. Most studies on the effect of CPAP on endothelial function in OSA are limited by their low sample size. The objective of this systematic review was to assess the effect of CPAP therapy on endothelial function in patients with OSA.

Methods 

We conducted a systematic review and meta-analysis searching literature databases up to August 2013 for randomized controlled trials (RCTs) on the effect of CPAP on endothelial function in OSA, assessed by flow-mediated dilatation (FMD) and other validated techniques. The primary outcome for the meta-analysis (DerSimonian/Laird random-effects method) was the treatment effect on FMD.

Results 

Eight RCTs comparing the effects of therapeutic CPAP versus subtherapeutic CPAP (or no intervention) on endothelial function involving 245 OSA patients were included in the systematic review. The studies are consistent in effect direction, showing an improvement of endothelial function by CPAP. Four RCTs involving 150 patients could be used for the meta-analysis. Compared to the control group, CPAP therapy (range 2-24 weeks) significantly increased absolute % FMD by 3.87% (95%CI 1.93 to 5.80, p < 0.0001).

Conclusion 

In patients with OSA, CPAP therapy improves endothelial function significantly and to a clinically important extent.
Abstract 9412: The Significance of Aldehyde Dehydrogenase 2 Polymorphisms in Coronary Spastic Angina
Authors: Yuji Mizuno, Eisaku Harada, Sumio Morita, Yoshinobu Morikawa, Hitoshi Nakagawa, Daisuke Katoh, Yusuke Kashiwagi, Toyoaki Murohara, Michihiro Yoshimura, Yoshihiko Saito, Hirofumi Yasue
Journal: Circulation (2014)

Introduction: Coronary spasm plays an important role in the pathogenesis of coronary heart disease and coronary spastic angina (CSA) is prevalent in East Asia including Japan. Oxidative stress is thought to be one of important factors in pathogenesis of coronary spasm. Interestingly, East Asians have been shown to have a frequent mutation of the aldehyde dehydrogenase 2 (ALDH2) gene (ALDH2*2) that leads to reducing of anti-oxidative effect and intolerance to alcohol ingestion (alcohol flushing). Furthermore, we previously reported that coronary spasm could be induced by alcohol intake in CSA patients. Hypothesis: We herein examined whether CSA is associated with ALDH2 polymorphisms by using single nucleotide polymorphism (SNP) genotyping method. Methods: The study subjects consisted of 155 patients in whom intracoronary injection of acetylcholine were performed on suspicion of coronary spastic angina. They were divided into 95 CSA patients (67 men/ 28 women, mean age 67 ± 10) and 60 non-CSA patients (26 men/ 34 women, mean age 65 ± 13). SNP genotyping test for ALDH2 along with clinical data for CSA risk factors were investigated.[[Unable to Display Character: &amp;#8232;]] Results: Gender (male), uric acid and smoking were higher (P = 0.001, P = 0.0014 and P = 0.001, respectively) and HDL cholesterol level was lower (P = 0.0021) in the CSA patients than in the non-CSA patients. There was a significant difference on the rate of CSA between ALDH2*1/*1 (wild type) and ALDH2*1/*2 or ALDH2*2/*2 (non-activated genotype) (51.2% vs. 73.2%, P = 0.005). Multivariable logistic regression analysis including age, ALDH2 non-activated genotype, smoking, and HDL cholesterol as independent variables revealed that ALDH2 non-activated genotype, HDL cholesterol and smoking were significant predictors of CSA (P = 0.007, P = 0.030 and P = 0.016, respectively). Furthermore, this study showed that ALDH2*2/*2 is a significant risk factor for CSA (90.9%) and multi-vessel spasm (80%).[[Unable to Display Character: &amp;#8232;]] Conclusions: ALDH2 non-activated genotype as well as smoking and HDL cholesterol, was significantly associated with CSA in Japanese patients.
Sorting by Restricted-Length-Weighted Reversals
Authors: Thach Cam Nguyen, Hieu Trung Ngo, Nguyen Bao Nguyen
Journal: Genomics Proteomics & Bioinformatics (2005)

Abstract Classical sorting by reversals uses the unit-cost model, that is, each reversal consumes an equal cost. This model limits the biological meaning of sorting by reversal. Bender and his colleagues extended it by assigning a cost function f(l) = lα for all α ≥ 0, where l is the length of the reversed subsequence. In this paper, we extend their results by considering a model in which long reversals are prohibited. Using the same cost function above for permitted reversals, we present tight or nearly tight bounds for the worst-case cost of sorting by reversals. Then we develop algorithms to approximate the optimal cost to sort a given 0/1 sequence as well as a given permutation. Our proposed problems are more biologically meaningful and more algorithmically general and challenging than the problem considered by Bender et al. Furthermore, our bounds are tight and nearly tight, whereas our algorithms provide good approximation ratios compared to the optimal cost to sort 0/1 sequences or permutations by reversals.
Ethics Consultation in Pediatrics: Long-Term Experience From a Pediatric Oncology Center
Authors: Liza-Marie Johnson, Christopher L. Church, Monika Metzger, Justin N. Baker
Journal: The American Journal of Bioethics (2015)

There is little information about the content of ethics consultations (EC) in pediatrics. We sought to describe the reasons for consultation and ethical principles addressed during EC in pediatrics through retrospective review and directed content analysis of EC records (2000–2011) at St. Jude Children's Research Hospital. Patient-based EC were highly complex and often involved evaluation of parental decision making, particularly consideration of the risks and benefits of a proposed medical intervention, and the physician's fiduciary responsibility to the patient. Nonpatient consultations provided guidance in the development of institutional policies that would broadly affect patients and families. This is one of the few existing reviews of the content of pediatric EC and indicates that the distribution of ethical issues and reasons for moral distress are different than with adults. Pediatric EC often facilitates complex decision making among multiple stakeholders, and further prospective research is needed on the role of ethics consultation in pediatrics.
Stomatocytosis Is Absent in “Stomatin”-Deficient Murine Red Blood Cells
Authors: Yiwen Zhu, Chris Paszty, Tikva Turetsky, Susan Tsai, Frans A. Kuypers, Gloria Lee, Philip Cooper, Patrick G. Gallagher, Mary E. Stevens, Edward Rubin, Narla Mohandas, William C. Mentzer
Journal: Blood (1999)
Abstract 17388: Post-procedural Aortic Regurgitation in Patients Undergoing Transcatheter Aoritc Valve Implantation with Edwards SAPIEN Valve versus Medtronic CoreValve for Severe Aortic Stenosis: a Meta-analysis
Authors: Hemang B Panchal, Neil Barry, Samit Bhatheja, Kais Albalbissi, Vijay Ramu, Timir Paul
Journal: Circulation (2014)

Background: Transcatheter aortic valve implantation (TAVI) is performed using an Edwards SAPIEN valve (EV) or Medtronic CoreValve (CV) in patients with severe aortic stenosis who are not a candidate for surgical aortic valve replacement. The objective of this meta-analysis is to compare post-procedural aortic regurgitation (AR) in patients who underwent TAVI using EV and CV. Methods: PubMed and the Cochrane Center Register of Controlled Trials were searched through May 2014. Twelve studies (n=3245) comparing TAVI procedure that used EV (n=1490) and CV (n=1755) were included. End point was post-procedural aortic valve regurgitation. The odds ratio (OR) with 95% confidence interval (CI) was computed and p<0.05 was considered as a level of significance. Results: The studies were homogeneous. AR grade 2 or more (moderate to severe) was significantly higher in CV group compared to EV group (OR: 2.25, CI: 1.72-2.95, p<0.00001) (Figure). AR grade 3 or more (severe) was not significantly different between two gro...