tbuckley/cabot-search huggingface dataset:
Neurological channelopathies
Authors: M. R Rose
Journal: BMJ (1998)

Disorders of ion channels (channelopathies) are increasingly being identified, making this a rapidly expanding area of neurology. Ion channel function may be controlled by changes in voltage (voltage gated), chemical interaction (ligand gated), or by mechanical perturbation. The first disorders recognised as channelopathies were the voltage gated channelopathies causing inherited muscle diseases: the non-dystrophic myotonias and familial periodic paralyses. Paramyotonia congenita is due to mutations in the gene coding for the α1 subunit of the sodium channel, while Thomsen's disease (autosomal dominant myotonia congenita) and Becker's disease (autosomal recessive myotonia congenita) are allelic disorders associated with mutations in a gene coding for skeletal muscle chloride channel. Familial hyperkalaemic periodic paralysis is due to mutations in the same sodium channel gene as that affected in paramyotonia congenita, while familial hypokalaemic periodic paralysis results from mutations in the gene coding for the α1 subunit of a skeletal muscle calcium channel.1

The first demonstration that channelopathies could affect nerves as well as muscles …
A double-blind randomised control trial of peripheral blood eosinophils to direct prednisolone use in COPD exacerbations
Authors: Mona Bafadhel, Susan McKenna, Sarah Terry, Vijay Mistry, Mitesh Pancholi, David Lomas, Per Venge, Mike Barer, Seb Johnston, Ian Pavord, Chris Brightling
Journal: European Respiratory Journal (2011)

Introduction: COPD exacerbations and treatment responses are heterogeneous. Prednisolone therapy is associated with adverse events. Identifying steroid responsive subgroups maybe beneficial

Aims: To compare biomarker-directed prednisolone therapy to current standard treatment during COPD exacerbations

Methods: Patients with COPD exacerbations were randomised to receive standard therapy (ST) or a biomarker directed therapy (BT). BT patients were given prednisolone when the blood eosinophil count was >2% (biomarker positive) and placebo when ≤ 2% (biomarker negative) (see figure).

![Figure][1] 



Results: From 109 patients; 86 exacerbations were treated in the BT group and 80 in the ST group. Prednisolone prescription was reduced by 49% (95% CI 38 to 59, p<0.001) in the BT compared to ST group. There was no difference between groups in health status or FEV1 after 14 days treatment. Placebo administration did not result in excess treatment failure (hospitalisation or readmission) which occurred in 15% and 2% of biomarker negative patients in ST and BT groups (p=0.04). Improvements in health status after 14 days were greater in placebo treated patients compared to those in the ST group who were biomarker negative (mean change 1.01 vs. 0.56; mean difference 0.45; 95% CI 0.01 to 0.90; p=0.04)

Conclusions: A phenotype-specific biomarker approach can safely and effectively be applied to prednisolone therapy during exacerbations.

 [1]: pending:yes
Abstract 3947: Radiation treatment solubilizes membrane receptors in meningioma cells
Authors: Venkateswara Rao Gogineni, Dilip R. Maddirela, Chandramu Chetty, Jasti S. Rao
Journal: Cancer Research (2014)

Abstract In our earlier studies we reported that radio-resistance was associated with soluble uPAR and uPARAP in meningioma cells. In the present study we show solubilization of a broad range of membrane-bound receptors induced by radiation treatment. Although the increase in radiation dosage beyond 10Gy increased the release of receptors, cell proliferation was adversely affected. Further, fractionated dosages (5Gy+5Gy) or a single dose (10Gy) radiation showed a significant surge in soluble receptors after 36 hours of treatment. Correspondingly, an initial lag in proliferation with G2-M arrest and subsequent recovery was seen in irradiated cells. Pretreatment of meningioma cells with N-acetyl cysteine before radiation treatment significantly quenched the solubilization of receptors. Conditioned media collected from irradiated cells promoted invasiveness and migration of meningioma cells compared to the controls. Later, screening for cell-free receptors in the brain sections of tumor-bearing mice also showed an increased incidence in irradiated groups. In conclusion, our study reveals an additional niche of receptor functioning in meningioma. Citation Format: Venkateswara Rao Gogineni, Dilip R. Maddirela, Chandramu Chetty, Jasti S. Rao. Radiation treatment solubilizes membrane receptors in meningioma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3947. doi:10.1158/1538-7445.AM2014-3947
Enrichment of total serum IgG4 in patients with pemphigus
Authors: T. Funakoshi, L. Lunardon, C.T. Ellebrecht, A.R. Nagler, C.E. O’Leary, A.S. Payne
Journal: British Journal of Dermatology (2012)

Background Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially fatal blistering diseases caused by autoantibodies targeting desmoglein (Dsg) adhesion proteins. Previous studies have shown an IgG4 > IgG1 predominance of anti-Dsg antibodies in pemphigus; however, no studies have examined total serum IgG4 levels in pemphigus. IgG4 is induced by chronic antigen stimulation, which could occur with persistent skin blistering and potentially elevate the total serum IgG4 relative to other IgG subclasses in patients with pemphigus. Objectives The primary aim of the study was to quantitate total and Dsg-specific IgG subclasses in patients with pemphigus. Methods IgG subclasses and Dsg-specific IgG1 and IgG4 were quantitated in patients with PV and PF, and in sera from age-matched controls using a subclass enzyme-linked immunosorbent assay. The effectiveness of IgG4 depletion in blocking IgG pathogenicity in PV was determined using a keratinocyte dissociation assay. Results Dsg-specific antibodies comprised a median of 7·1% and 4·2% of total IgG4 in patients with PV and PF, respectively, with eightfold and fourfold enrichment in IgG4 vs. IgG1. Total serum IgG4, but not other IgG subclasses, was enriched in patients with PV and PF compared with age-matched controls (P = 0·004 and P = 0·005, respectively). IgG4 depletion of PV sera reduced pathogenicity in a keratinocyte dissociation assay and showed that affinity-purified IgG4 is more pathogenic than other serum IgG fractions. Conclusions Dsg-specific autoantibodies are significantly enriched in IgG4, which may explain the enrichment of total serum IgG4 in some patients with pemphigus. By preferentially targeting autoimmune rather than beneficial immune antibodies, IgG4-targeted therapies may offer safer treatment options for pemphigus.
Abstract 12438: Novel 4-Dimensional Optical Technique to Elucidate Hemodynamic Shear Forces and Initiation of Trabeculation During Cardiac Morphogenesis
Authors: Juhyun Lee, Peng Fei, Nelson Jen, Tyler Beebe, Chih-ming Ho, Alison Marsden, Neil Chi, Tzung Hsiai
Journal: Circulation (2014)

Hemodynamic shear forces are intimately linked with cardiac development. However, the mechano-transduction mechanisms underlying this morphological event remain elusive. Trabeculation develops after cardiac looping, which is visualized in zebrafish embryos starting at 70 hours post-fertilization (hpf). We hypothesized that endocardial wall shear stress (WSS) up-regulates Notch signaling to initiate trabeculation. We developed a novel fast z-axis imaging acquisition system to reconstruct time-dependent 3-dimensional WSS in live zebrafish using single plane illuminating microscopy (SPIM). To assess the link between shear stress and trabeculation, we lowered the WSS by micro-injection of (1) gata1a-morpholino oligonucleotides (MO) at 2-cell stage to reduce erythropoiesis and viscosity by 70%, (2) tnnt2a-MO injection to inhibit cardiac contraction, and (3) use of weak atrium(wea) mutant to inhibit atrial contraction. To determine mechano-signal transduction underlying WSS and trabeculation, we assessed Notch signaling by in situ hybridization of NRG1 and notch1b. At 70 hpf, the control fish showed formation of trabeculation, whereas gata1 MO injected fish revealed a decrease in trabeculation in response to a reduction in shear stress by 90 %. Both wea mutant and tnnt2a MO injected fish exhibited smooth endocardial surfaces without trabecular networking. In situ hybridization of NRG1 and Notch 1b further showed a decrease in fluorescent intensity in the gata1 MO, wea mutant, and tnnt2a MO groups by 2.33±0.87-fold, 4.21±0.25-fold, and 4.96±0.17-fold, respectively (p &lt; 0.05 vs. control fish, n=10). Thus, our findings indicate that hemodynamic shear forces are implicated in the initiation of cardiac trabecualtion via Notch signaling pathway, with a translational implication to understanding congenital noncompacted cardiomyopathy.
The Tromsø Heart Study
Authors: Dag S. Thelle, Egil Arnesen, Olav H. Førde
Journal: New England Journal of Medicine (1983)

We examined the relation between coffee consumption and levels of serum total cholesterol, high-density-lipoprotein (HDL) cholesterol, and triglycerides in a population of 7213 women and 7368 men between the ages of 20 and 54 years. Coffee consumption was positively associated with levels of total cholesterol and triglycerides in both sexes and was inversely associated with levels of HDL cholesterol in women. The coffee-cholesterol relation remained strong and statistically significant (P<0.0001 in a covariance analysis) after adjustment for age, logarithm of body-mass index, physical activity in leisure time, cigarette smoking, and alcohol consumption. After adjustment for all covariates, the total cholesterol level was 5.56±0.05 mmol per liter (mean ±S.E.) in men drinking less than one cup of coffee a day, as compared with 6.23±0.03 mmol per liter in those consuming more than nine cups a day. The corresponding figures for women were 5.32±0.05 and 5.92±0.04 mmol per liter. None of the other variables considered could explain this relation. We conclude that coffee consumption is a major contributor to the variation in levels of total cholesterol. (N Engl J Med 1983; 308:1454–7.)
IPSS-R in 555 Taiwanese patients with primary MDS: Integration of monosomal karyotype can better risk-stratify the patients
Authors: Yi‐Tsung Yang, Hsin‐An Hou, Chieh‐Yu Liu, Chien‐Chin Lin, Wen‐Chien Chou, Fen‐Yu Lee, Ming‐Chih Liu, Chia‐Wen Liu, Jih‐Luh Tang, Ming Yao, Chi‐Cheng Li, Yuan‐Yeh Kuo, Shang‐Yi Huang, Bor‐Sheng Ko, Chien‐Yuan Chen, Szu‐Chun Hsu, Chien‐Ting Lin, Shang‐Ju Wu, Woei Tsay, Yao‐Chang Chen, Hwei‐Fang Tien
Journal: American Journal of Hematology (2014)

The revised International Prognostic Scoring System (IPSS‐R) was recently developed to better assess the clinical outcome of adult patients with myelodysplastic syndrome (MDS). In this study, we aimed to investigate the prognostic impact of this new risk model on 555 MDS patients in Taiwan. Generally, the IPSS‐R could discriminate MDS patients regarding risk of leukemia evolution and overall survival in our cohort and it further refined prognostic stratification in all IPSS risk categories. However, we could not find the inter‐group difference between IPSS‐R very low and low risk subgroups in both leukemia‐free survival (LFS) and overall survival (OS). IPSS‐R couldn't distinguish the prognosis between very good and good and between good and intermediate risk cytogenetic categories in OS, and between very good and good and between intermediate and poor cytogenetic‐risk categories in LFS, either. On the other hand, incorporation of monosomal karyotype (MK) into IPSS‐R could further stratify MDS patients with higher‐risk IPSS‐R (intermediate, high and very high risk) into four groups, rather than three groups, with different OS ( P &lt; 0.001). Intriguingly, patients receiving allogeneic hematopoietic stem cell transplantation had longer survival than those without in the IPSS‐R high and very high, but not other risk groups. Similarly, patients treated with hypomethylating agents had better survival than those not in the IPSS‐R very high risk group. In conclusion, IPSS‐R can risk‐stratify MDS patients in Taiwan but with some limitations, especially in very low risk category, and MK has additional prognostic value in discriminating MDS patients with higher‐risk IPSS‐R. Am. J. Hematol. 89:E142–E149, 2014. © 2014 Wiley Periodicals, Inc.
662. Adenovirus Targeting Via Leucine Zipper Peptide Ligand Attachment
Authors: Joel N. Glasgow, Abner Mhashilkar, David T. Curiel, Nikolay Korokhov
Journal: Molecular Therapy (2004)

Gene therapy vectors based on human adenovirus (Ad) serotypes 2 and 5 continue to show increasing promise as gene therapy delivery vehicles. Early gene therapy efforts, however, revealed that the clinical benefit of these gene delivery modalities was irrevocably linked to specific localization of the therapeutic agent. Hence, a fundamental requirement for somatic cell gene therapy is targetable gene delivery vectors. To this end, Ads incorporating genetic modifications have provided gains in vector efficiency; however, specific vector targeting to specific cell-surface molecules is still required. For cell-specific targeting, the use of antibodies or single chain antibody fragments (scFv) remains a very attractive concept made possible by the discovery of disease-specific membrane antigens and a wide selection of cognate antibody molecules. However, a barrier to the development of Ad vectors with genetically incorporated scFvs occurs when the antibody requires posttranslational modifications not available to Ad capsid proteins due to their cytoplasmic routing during virion assembly. To overcome this problem, we have developed a targeting strategy that uses a secreted scFv that undergoes the requisite posttranslational modification (disulfide bond formation) in the endoplasmic reticulum and is trafficked for secretion. Formation of the vector/ligand targeting complex occurs following cell lysis and is achieved via genetic tagging of the Ad capsid and scFv with synthetic leucine zipper-like dimerization domains that have been optimized for structural and biological compatibility with the Ad capsid and the secreted scFv. Importantly, we have designed our Zipper domains in pairs, such that only compatible heterodimers can associate, thus eliminating the possibility of aggregate formation. Zipper domains were incorporated into the C-terminus of Ad5 fiber and our knob-deleted chimeric fiber molecule, fiber-fibritin (FF). The ligand is comprised of a scFv fused with the kappa-chain IgG signal peptide and a Zipper peptide. Our results show that Zipper domain-containing fiber or FF molecules trimerize and associate with the virion penton base protein and that these vectors can be amplified. Further, we demonstrate that peptide Zippers can be genetically fused to scFv without decreasing ligand recognition of antigen. Most important, we show that Zipper-tagged virions and scFv can self-associate and form targeting complexes capable of binding to target receptors. This approach to targeting ligand design solves the problem of structural and biosynthetic compatibility with the Ad and thus facilitates targeting of the vector to a variety of cellular receptors. Since this gene transfer is independent of the expression of the native Ad5 receptor by the target cells, this strategy results in the derivation of truly targeted Ad vectors suitable for tissue-specific gene therapy.
ENDOCARDITIS CAUSED BY ORGANISM MORPHOLOGICALLY AND CULTURALLY IDENTIFIED AS C. diphtheriae
Authors: B ZHEUTLIN
Journal: Annals of Internal Medicine (1949)

Case Reports1 August 1949ENDOCARDITIS CAUSED BY ORGANISM MORPHOLOGICALLY AND CULTURALLY IDENTIFIED AS C. diphtheriaeBERTRAM ZHEUTLIN, M.D.BERTRAM ZHEUTLIN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-31-2-339 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptCorynebacterium diphtheriae characteristically affects the heart by producing a toxin which causes a myocarditis. Only in unique cases does the diphtheria organism directly affect the pericardium or endocardium. This report deals with a case in which endocarditis was caused by an organism resembling the Klebs-Loeffler bacillus morphologically and culturally, and which proved to be virulent for guinea pigs.CASE REPORTA 19-year-old white enlisted man was admitted to the hospital May 26, 1946, with the chief complaints of sore throat, chilly sensations, and fever. The family history was non-contributory. The past history revealed that the patient had had good general... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Ann Arbor, Michigan*Received for publication March 5, 1947. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byErkrankungen des EndokardDiphtheriaDie Therapie der Endocarditis lenta und ihre Grundlagen 1 August 1949Volume 31, Issue 2Page: 339-343KeywordsDiphtheriaEndocarditisEndocardiumFeversGuinea pigsHeartMyocarditisPericardiumPharyngitisToxins Issue Published: 1 August 1949 PDF downloadLoading ...
TCT-293 Quantifying Total Atherosclerotic Burden Non-Invasively Through Coronary Computed Tomography Angiography: A Comparison With Multivessel Intravascular Ultrasound Data
Authors: Rafael C. Silva, Breno A. Falcao, Thais P. Lima, Gustavo R. Morais, Carlos E. Rochitte, Andre G. Spadaro, Jose Mariani, Expedito Ribeiro, Roberto Kalil-Filho, Pedro A. Lemos
Journal: Journal of the American College of Cardiology (2014)
Abstract 20517: MicroRNA-155: A New Player in Sepsis-Induced Cardiac Dysfunction
Authors: Francisco Vasques-Nóvoa, Catarina Quina-Rodrigues, Rui Cerqueira, Fabiana Baganha, Mariana I Marques, Adelino F Leite-Moreira, Roberto Roncon-Albuquerque
Journal: Circulation (2014)

Introduction: Cardiac dysfunction is an important outcome predictor in patients with septic shock and lacks effective and targeted therapies. MicroRNA-155 (miR-155) is a multifunctional microRNA with important target genes in inflammation, immunity and cardiovascular system. Hypothesis: The present study assessed the role of miR-155 in experimental and human sepsis-induced cardiac dysfunction. Methods: Experimental sepsis was induced using endotoxin injection (LPS) or cecal ligation and puncture (CLP) models. Genetic loss (miR-155 KO) and pharmacological inhibition (LNA-anti-miR; AM) of miR-155 were evaluated. Cardiac function was assessed through echocardiography; mortality analysis was also performed. Quantification of myocardial miR-155, pro-inflammatory cytokine mRNA profile, miR-155 targets, apoptosis, cellular adhesion proteins and activation of pro-inflammatory intracellular signaling pathways were assessed. In another experiment, myocardial miR-155 expression, cellular localization and associations between its levels and other clinical variables were evaluated using post-mortem samples from septic shock (SS) patients. Results: Myocardial miR-155 levels were increased in experimental and human septic myocardium. This was associated with a decreased ejection fraction (EF) and cardiac output (CO) and increased diastolic LV diameter (LVDd) in septic WT animals. Knockout and anti-miR-155 treated animals and presented with preserved EF, CO and LVDd, compared with WT; this was accompanied by ~50% mortality reduction. Experimental sepsis induced downregulation of SOCS1 and CD47, myocardial cytokine upregulation, increased apoptosis and adhesion protein expression as well as pro-inflammatory kinase and transcription factor activation, all of which were attenuated in KO and AM. In human myocardium, miR-155 expression was positively associated with 24h antemortem period plasma troponin I levels. Conclusions: miR-155 is upregulated in experimental and human septic myocardium. Loss or inhibition of miR-155 attenuated sepsis-induced cardiac dysfunction, blunted proinflammatory activation and reduced mortality. This suggests miR-155 as a potential target in human sepsis-associated cardiac dysfunction.
Abstract 3715: Inflammatory and Thrombotic Changes in Bereavement: A Potential Mechanism of Increased Cardiovascular Risk
Authors: Thomas Buckley, Marie-Christine Morel-Kopp, Roger Bartrop, Sharon McKinley, Christopher Ward, Anastasia S Mihailidou, Kerrie Goldstone, Margaret Bramwell, Belinda Hocking, Dianne Roche, Monica Spinaze, Christopher Tennant, Geoffrey Tofler
Journal: Circulation (2007)

Background: Bereavement is associated with increased risk of cardiovascular disease (CVD) especially in early bereavement. The mechanism of increased risk has not been well studied. This prospective study evaluated inflammatory and thrombotic measures in bereaved spouses and parents, within 2 weeks of bereavement and again at 6 months. Methods: Fifty-one subjects (35F/17M; aged 65.2 ± 13.1 years (mean ± SD) were prospectively studied within 2 weeks of bereavement and at 6 months, and compared to 43 non-bereaved relatives of discharged patients; age 61.1 ± 11.1 years). All participants had haemostatic measures obtained between 8 –11 am and processed within one hour. White cell subpopulations and activation marker levels were obtained using flow cytometry. Group results were analysed using ANOVA controlling for age. Results: Acute bereavement versus controls: Compared to controls, acutely bereaved had a higher white cell count (WBC) 7.1 vs 6.2 10 9 /L (p&lt;0.001), higher neutrophil count 4.4 vs 3.5 10 9 /L (p=0.001) and a trend towards higher monocyte count 468 vs 525/uL (p=0.06). Acutely bereaved subjects also had a reduced T suppressor cell number (CD8 + ) (406 vs 496 MFI, p=0.02), increased activation marker CD26 on CD4 T cells (541 vs 496 MFI, p =0.02) and increased NK cells positive for CD57 (46.5% vs 39.8%, p=0.05). Acutely bereaved subjects had higher levels of vWF-Ag than controls 126% vs 116% (p=0.04), and higher cortisol levels (340 vs 277 nmol/L (p=0.007). Bereavement - acute versus 6 months: Compared to acute assessment results shown above, the bereaved at 6 months showed reduced WBC count (6.2 10 9 /L; p=0.003), neutrophil count (3.7 10 9 /L; p&lt;0.001), monocyte count (486, p=0.009) and CD57 + NK cells (p &lt;0.001). vWF-Ag was also lower (114%; p=0.02) as was factor VIII-ac (1.33 vs 1.17, p = 0.001). Fibrinogen and C-reactive protein did not change significantly from acute to 6 months. Conclusion: Acute bereavement is associated with increased inflammatory and prothrombotic changes. These findings provide insight into potential mechanisms for the increased CVD risk with bereavement and clues to potential preventive measures.