tbuckley/cabot-search huggingface dataset:
Reactive oxygen species in acute lung injury
Authors: R Ruffmann
Journal: European Respiratory Journal (1998)

Neurons are highly polarized cells with functionally distinct axonal and somatodendritic compartments. Voltage-gated sodium channels Na<sub>v</sub>1.2 and Na<sub>v</sub>1.6 are highly enriched at axon initial segments (AISs) and nodes of Ranvier, where they are necessary for generation and propagation of action potentials. Previous studies using reporter proteins in unmyelinated cultured neurons suggest that an ankyrinG-binding motif within intracellular loop 2 (L2) of sodium channels is sufficient for targeting these channels to the AIS, but mechanisms of channel targeting to nodes remain poorly understood. Using a CD4-Na<sub>v</sub>1.2/L2 reporter protein in rat dorsal root ganglion neuron–Schwann cell myelinating cocultures, we show that the ankyrinG-binding motif is sufficient for protein targeting to nodes of Ranvier. However, reporter proteins cannot capture the complexity of full-length channels. To determine how native, full-length sodium channels are clustered in axons, and to show the feasibility of studying these channels <i>in vivo</i>, we constructed fluorescently tagged and functional mouse Na<sub>v</sub>1.6 channels for <i>in vivo</i> analysis using <i>in utero</i> brain electroporation. We show here that wild-type tagged-Na<sub>v</sub>1.6 channels are efficiently clustered at nodes and AISs <i>in vivo</i>. Furthermore, we show that mutation of a single invariant glutamic acid residue (E1100) within the ankyrinG-binding motif blocked Na<sub>v</sub>1.6 targeting in neurons both <i>in vitro</i> and <i>in vivo</i>. Additionally, we show that caseine kinase phosphorylation sites within this motif, while not essential for targeting, can modulate clustering at the AIS. Thus, the ankyrinG-binding motif is both necessary and sufficient for the clustering of sodium channels at nodes of Ranvier and the AIS.
VCAM-1 has a tissue-specific role in mediating interleukin-4–induced eosinophil accumulation in rat models: evidence for a dissociation between endothelial-cell VCAM-1 expression and a functional role in eosinophil migration
Authors: Karen Y. Larbi, Andrew R. Allen, Frederick W. K. Tam, Dorian O. Haskard, Roy R. Lobb, Patricia M. R. Silva, Sussan Nourshargh
Journal: Blood (2000)
Symptomatic gastro-oesophageal reflux in a patient with achlorhydria
Authors: A J Bredenoord
Journal: Gut (2006)

Intraluminal impedance monitoring makes it possible to detect gastro-oesophageal reflux, independent of its pH.1 This is useful because other factors apart from acidity are important in symptom generation.2 Here, we describe a patient with achlorhydria in which impedance monitoring was used to identify gastro-oesophageal reflux as the cause of her symptoms.

A 72 year old female presented at our department. She complained of a retrosternal burning sensation which occurred at least five times a day. Eighteen months previously, her general practitioner prescribed monthly vitamin B12 injections after a routine blood test had revealed a megaloblastic macrocytic anaemia. She had underwent laparoscopic cholecystectomy for symptomatic gall stones four years previously.

Oesophageal manometry and 24 hour pH monitoring were performed. Results of oesophageal manometry were unremarkable. Ambulatory 24 …
Enhancement of Coronary Vasodilator Action of Adenosine Triphosphate by Dipyridamole
Authors: SKODA AFONSO, GEORGE S. O'BRIEN
Journal: Circulation Research (1967)

It has been reported that previously administered dipyridamole intensifies the coronary vasodilator action of adenosine compounds. In the present study, a combination of dipyridamole and ATP at doses that alone are ineffective was examined for its effect on the coronary sinus blood flow. In 10 anesthetized dogs, heart rate, arterial blood pressure, cardiac output, and coronary sinus blood flow were measured before and during a 20-min constant-rate infusion of (a) ATP alone, 1 mg/min; (b) a combination of ATP, 1 mg/min, and dipyridamole, 0.005 mg/kg/min; and (c) dipyridamole alone, 0.005 mg/kg/ min. Coronary sinus flow was measured by a newly developed thermodilution flowmeter. Consistently during the infusion of ATP or dipyridamole alone no changes in the measured parameters occurred, whereas during infusion of the combination a very marked and sustained elevation (+493%) of coronary flow occurred, associated with a moderate increase in cardiac rate (+37%) and output (+42%) and a decrease in arterial blood pressure (-17%). In 7 other dogs, coronary vasodilator responses to ATP were determined before and 1 hour after a single 10-mg dose of dipyridamole. After dipyridamole, the coronary vasodilator action of ATP increased 5- to 100-fold. In a third group of 3 dogs, dipyridamole did not enhance the coronary vasodilator effects of nitroglycerin, bradykinin, or acetylcholine.
New cholesterol drugs are overpriced, independent analysis finds
Authors: Michael McCarthy
Journal: BMJ (2015)

Two new cholesterol lowering drugs in the class known as PCSK9 inhibitors are likely to prove effective in reducing deaths from cardiovascular disease but are hugely overpriced, a new cost effectiveness analysis has concluded.1

The analysis, released on 8 September, was conducted by the Institute for Clinical and Economic Review, a Boston based non-profit organization that performs cost effectiveness reviews of new treatments, tests, and health delivery programs

Currently the wholesale price for treatment with either of the two drugs, alirocumab (marketed as Praluent) and evolocumab (Repatha), is set at more than $14 000 (£9000; €12 500) a year. But the new analysis shows that, on the basis of a cost effectiveness threshold of $100 000 per quality of life year saved, the annual price should be in the range …
Differentiation of Pluripotent Embryonic Stem Cells Into Cardiomyocytes
Authors: Kenneth R. Boheler, Jaroslaw Czyz, David Tweedie, Huang-Tian Yang, Sergey V. Anisimov, Anna M. Wobus
Journal: Circulation Research (2002)

Embryonic stem (ES) cells have been established as permanent lines of undifferentiated pluripotent cells from early mouse embryos. ES cells provide a unique system for the genetic manipulation and the creation of knockout strains of mice through gene targeting. By cultivation in vitro as 3D aggregates called embryoid bodies, ES cells can differentiate into derivatives of all 3 primary germ layers, including cardiomyocytes. Protocols for the in vitro differentiation of ES cells into cardiomyocytes representing all specialized cell types of the heart, such as atrial-like, ventricular-like, sinus nodal-like, and Purkinje-like cells, have been established. During differentiation, cardiac-specific genes as well as proteins, receptors, and ion channels are expressed in a developmental continuum, which closely recapitulates the developmental pattern of early cardiogenesis. Exploitation of ES cell-derived cardiomyocytes has facilitated the analysis of early cardiac development and has permitted in vitro "gain-of-function" or "loss-of-function" genetic studies. Recently, human ES cell lines have been established that can be used to investigate cardiac development and the function of human heart cells and to determine the basic strategies of regenerative cell therapy. This review summarizes the current state of ES cell-derived cardiogenesis and provides an overview of how genomic strategies coupled with this in vitro differentiation system can be applied to cardiac research.
Mouse retrovirus mediates porcine endogenous retrovirus transmission into human cells in long-term human-porcine chimeric mice
Authors: Yong-Guang Yang, James C. Wood, Ping Lan, Robert A. Wilkinson, Megan Sykes, Jay A. Fishman, Clive Patience
Journal: Journal of Clinical Investigation (2004)

Porcine endogenous retrovirus (PERV) is a potential pathogen in clinical xenotransplantation; transmission of PERV in vivo has been suggested in murine xenotransplantation models. We analyzed the transmission of PERV to human cells in vivo using a model in which immunodeficient NOD/SCID transgenic mice were transplanted with porcine and human lymphohematopoietic tissues. Our results demonstrate, we believe for the first time, that human and pig cells can coexist long-term (up to 25 weeks) without direct PERV infection of human cells. Despite the transplantation of porcine cells that did not produce human-tropic PERV, human cells from the chimeric mice were frequently found to contain PERV sequences. However, this transmission was due to the pseudotyping of PERV-C (a virus without human tropism) by xenotropic murine leukemia virus, rather than to de novo generation of human-tropic PERV. Thus, pseudotyping might account for the PERV transmission previously observed in mice. The absence of direct human cell infection following long-term in vivo coexistence with large numbers of porcine cells provides encouragement regarding the potential safety of using pigs that do not produce human-tropic PERV as source animals for transplantation to humans.
Deficiency of ATP-Binding Cassette Transporters A1 and G1 in Macrophages Increases Inflammation and Accelerates Atherosclerosis in Mice
Authors: Marit Westerterp, Andrew J. Murphy, Mi Wang, Tamara A. Pagler, Yuliya Vengrenyuk, Mojdeh S. Kappus, Darren J. Gorman, Prabhakara R. Nagareddy, Xuewei Zhu, Sandra Abramowicz, John S. Parks, Carrie Welch, Edward A. Fisher, Nan Wang, Laurent Yvan-Charvet, Alan R. Tall
Journal: Circulation Research (2013)

Plasma high-density lipoprotein levels are inversely correlated with atherosclerosis. Although it is widely assumed that this is attributable to the ability of high-density lipoprotein to promote cholesterol efflux from macrophage foam cells, direct experimental support for this hypothesis is lacking.To assess the role of macrophage cholesterol efflux pathways in atherogenesis.We developed mice with efficient deletion of the ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) in macrophages (MAC-ABC(DKO) mice) but not in hematopoietic stem or progenitor populations. MAC-ABC(DKO) bone marrow (BM) was transplanted into Ldlr(-/-) recipients. On the chow diet, these mice had similar plasma cholesterol and blood monocyte levels but increased atherosclerosis compared with controls. On the Western-type diet, MAC-ABC(DKO) BM-transplanted Ldlr(-/-) mice had disproportionate atherosclerosis, considering they also had lower very low-density lipoprotein/low-density lipoprotein cholesterol levels than controls. ABCA1/G1-deficient macrophages in lesions showed increased inflammatory gene expression. Unexpectedly, Western-type diet-fed MAC-ABC(DKO) BM-transplanted Ldlr(-/-) mice displayed monocytosis and neutrophilia in the absence of hematopoietic stem and multipotential progenitor cells proliferation. Mechanistic studies revealed increased expressions of machrophage colony stimulating factor and granulocyte colony stimulating factor in splenic macrophage foam cells, driving BM monocyte and neutrophil production.These studies show that macrophage deficiency of ABCA1/G1 is proatherogenic likely by promoting plaque inflammation and uncover a novel positive feedback loop in which cholesterol-laden splenic macrophages signal BM progenitors to produce monocytes, with suppression by macrophage cholesterol efflux pathways.
Asthma programme in Finland: a community problem needs community solutions
Authors: T Haahtela
Journal: Thorax (2001)

Finland, like many other western countries, has experienced profound structural changes during the post-war period: urbanisation, increasing education, smaller family size, improved hygiene for food and household water, and prophylaxis and effective care of many potentially dangerous infectious diseases. Many of these factors have been associated with the increased risk for asthma and allergies1 which has also been found in Finland.2 

In 1993 the Ministry of Social Affairs and Health in Finland recognised asthma as an important public health issue by appointing a working group to design a national programme for the prevention and alleviation of problems caused by asthma and for reduction of the relevant costs. The group decided to create an action programme emphasising guideline implementation and follow up, which are often neglected in consensus reports on asthma treatment. The 10 year programme was launched in 1994.3 The goals of prevention and treatment were stated as follows: (1) recovery of as many patients as possible with early asthma; (2) asthmatic patients should feel well and their ability for work and functional capacity should correspond with their age; (3) decline in the percentage of patients with severe and moderate asthma from the current 40% to 20%; (4) decrease in the number of bed days of asthmatic patients by 50% by the year 2000 (that is, to 50 000 a year); and (5) reduction in the annual treatment costs per patient by 50% as a result of more effective prevention and treatment of symptoms.

The measures towards achieving the goals were as follows: (1) early diagnosis and active treatment; (2) guided self-management as the primary form of treatment; (3) decrease in respiratory irritants such as smoking and tobacco smoke; (4) implementation of rehabilitation on an outpatient basis combined with normal treatment, planned individually and timed appropriately; (5) increase …
Continuing Medical Education and Quality Improvement: A Match Made in Heaven?
Authors: Kaveh G. Shojania, Ivan Silver, Wendy Levinson
Journal: Annals of Internal Medicine (2012)

New models of continuing medical education (CME) seek not only to impart knowledge but to change physicians' behavior and even play a role in facilitating organizational improvement. These CME models thus share some of the same basic goals as the field of quality improvement (QI), namely behavioral change and systems redesign to improve patient outcomes. This article provides some practical ideas about how CME providers and QI experts may beneficially integrate these 2 fields. It outlines several models for harnessing the existing engagement in traditional CME to achieve the goal of equipping practitioners with knowledge and skills related to QI, while also addressing the widely recognized problems with traditional CME. The authors touch on possible incentives to make such integrated models of CME and QI attractive to practitioners.
Loss of Betaglycan Expression in Ovarian Cancer: Role in Motility and Invasion
Authors: Nadine Hempel, Tam How, Mei Dong, Susan K. Murphy, Timothy A. Fields, Gerard C. Blobe
Journal: Cancer Research (2007)

The transforming growth factor-beta (TGF-beta) superfamily members, TGF-beta, activin, and inhibin, all have prominent roles in regulating normal ovarian function. Betaglycan, or the type III TGF-beta receptor, is a coreceptor that regulates TGF-beta, activin, and inhibin signaling. Here, we show that betaglycan expression is frequently decreased or lost in epithelial derived ovarian cancer at both the mRNA and protein level, with the degree of loss correlating with tumor grade. Treatment of ovarian cancer cell lines with the methyltransferase inhibitor 5-aza-2-deoxycytidine and the histone deacetylase inhibitor trichostatin A resulted in significant synergistic induction of betaglycan message levels and increased betaglycan protein expression, indicating that epigenetic silencing may play a role in the loss of betaglycan expression observed in ovarian cancer. Although restoring betaglycan expression in Ovca429 ovarian cancer cells is not sufficient to restore TGF-beta-mediated inhibition of proliferation, betaglycan significantly inhibits ovarian cancer cell motility and invasiveness. Furthermore, betaglycan specifically enhances the antimigratory effects of inhibin and the ability of inhibin to repress matrix metalloproteinase levels in these cells. These results show, for the first time, epigenetic regulation of betaglycan expression in ovarian cancer, and a novel role for betaglycan in regulating ovarian cancer motility and invasiveness.
Macrophages may promote cancer growth via a GM-CSF/HB-EGF paracrine loop that is enhanced by CXCL12
Authors: Antonella Rigo, Michele Gottardi, Alberto Zamò, Pierluigi Mauri, Massimiliano Bonifacio, Mauro Krampera, Ernesto Damiani, Giovanni Pizzolo, Fabrizio Vinante
Journal: Molecular Cancer (2010)

Abstract Background Increased numbers of tumour-associated macrophages correlate with shortened survival in some cancers. The molecular bases of this correlation are not thoroughly understood. Events triggered by CXCL12 may play a part, as CXCL12 drives the migration of both CXCR4-positive cancer cells and macrophages and may promote a molecular crosstalk between them. Results Samples of HER1-positive colon cancer metastases in liver, a tissue with high expression of CXCL12, were analysed by immunohistochemistry. In all of the patient biopsies, CD68-positive tumour-associated macrophages presented a mixed CXCL10 (M1)/CD163 (M2) pattern, expressed CXCR4, GM-CSF and HB-EGF, and some stained positive for CXCL12. Cancer cells stained positive for CXCR4, CXCL12, HER1, HER4 and GM-CSF. Regulatory interactions among these proteins were validated via experiments in vitro involving crosstalk between human mononuclear phagocytes and the cell lines DLD-1 (human colon adenocarcinoma) and HeLa (human cervical carcinoma), which express the above-mentioned ligand/receptor repertoire. CXCL12 induced mononuclear phagocytes to release HB-EGF, which activated HER1 and triggered anti-apoptotic and proliferative signals in cancer cells. The cancer cells then proliferated and released GM-CSF, which in turn activated mononuclear phagocytes and induced them to release more HB-EGF. Blockade of GM-CSF with neutralising antibodies or siRNA suppressed this loop. Conclusions CXCL12-driven stimulation of cancer cells and macrophages may elicit and reinforce a GM-CSF/HB-EGF paracrine loop, whereby macrophages contribute to cancer survival and expansion. The involvement of mixed M1/M2 GM-CSF-stimulated macrophages in a tumour-promoting loop may challenge the paradigm of tumour-favouring macrophages as polarized M2 mononuclear phagocytes.
Markers of Bone Metabolism and Survival in Men with Hormone-Refractory Metastatic Prostate Cancer
Authors: Richard J. Cook, Robert Coleman, Janet Brown, Allan Lipton, Pierre Major, Yong Jiang Hei, Fred Saad, Matthew R. Smith
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To evaluate the relative prognostic value for specific markers of osteoblast and osteoclast activity while controlling for previously reported prognostic variables among men with hormone-refractory metastatic prostate cancer. Experimental Design: The 643 subjects in this report were participants in multicenter randomized controlled trial of zoledronic acid in men with metastatic prostate cancer. All subjects had bone metastases and disease progression despite medical or surgical castration. Relationships between baseline covariates and overall survival were examined by Cox proportional hazard model. Serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide were assessed as representative specific markers of osteoblast and osteoclast activity, respectively. Other covariates in the model were age, log prostate-specific antigen, hemoglobin, lactate dehydrogenase, albumin, analgesic use, and Eastern Cooperative Oncology Group performance status. Results: Serum BAP was significantly correlated with urinary N-telopeptide (correlation coefficient = 0.674; 95% confidence interval, 0.628-0.715; P &amp;lt; 0.0001). In univariate analyses, higher levels of serum BAP and urinary N-telopeptide levels were significantly associated with shorter overall survival. After controlling for the other variables, including N-telopeptide, in multivariate models, higher serum BAP levels were consistently associated with shorter survival. In contrast, urinary N-telopeptide levels were not significantly associated with survival in multivariate analyses. Variables retained in the reduced multivariate model were age, log prostate-specific antigen, hemoglobin, lactate dehydrogenase, analgesic use, and BAP. Conclusions: Serum BAP significantly correlates with urinary N-telopeptide in men with androgen-independent prostate cancer and bone metastases. In multivariate models, higher levels of serum BAP but not urinary N-telopeptide are associated with shorter overall survival.
An Iatrogenic Confounding Variable
Authors: Peter C. Albertsen
Journal: JNCI Journal of the National Cancer Institute (2009)

modest decline in prostate cancer mortality, but the absolute decline in the number of deaths averted is relatively modest when compared with the number of men now diagnosed with this disease. Evidence from a recently published randomized trial ( 7 ) indicates that 9 years after diagnosis of screen-detected prostate cancer, only one prostate cancer death is averted for every 48 men who are diagnosed and treated for this disease. Unfortunately, an unintended consequence of PSA testing is the large number of men diagnosed with incidental disease that now confounds our ability to identify potential causes of clinically signifi cant disease. The study by Stark et al. is a case in point. These researchers chose a classic study design, the case – control study, to assess the potential impact of a specifi c variable, T. vaginalis infection, on an outcome of interest, prostate cancer. They turned to the Physician’s Health Study because of the large sample size and the availability of serum drawn at baseline that allowed researchers to assess exposure to T. vaginalis . PSA testing, however, has altered the population of men diagnosed with prostate cancer during the follow-up period. Before the late 1980s, men with newly diagnosed prostate cancer presented with clinically signifi cant disease often in advanced stages. Now most men are identifi ed with localized disease usually 5 – 10 years earlier in the natural course of the disease ( 8 ).
Bayes Empirical Bayes Inference of Amino Acid Sites Under Positive Selection
Authors: Ziheng Yang, Wendy S W Wong, Rasmus Nielsen
Journal: Molecular Biology and Evolution (2005)

Codon-based substitution models have been widely used to identify amino acid sites under positive selection in comparative analysis of protein-coding DNA sequences. The nonsynonymous-synonymous substitution rate ratio (dN/dS, denoted ω) is used as a measure of selective pressure at the protein level, with ω > 1 indicating positive selection. Statistical distributions are used to model the variation in ω among sites, allowing a subset of sites to have ω > 1 while the rest of the sequence may be under purifying selection with ω < 1. An empirical Bayes (EB) approach is then used to calculate posterior probabilities that a site comes from the site class with ω > 1. Current implementations, however, use the naive EB (NEB) approach and fail to account for sampling errors in maximum likelihood estimates of model parameters, such as the proportions and ω ratios for the site classes. In small data sets lacking information, this approach may lead to unreliable posterior probability calculations. In this paper, we develop a Bayes empirical Bayes (BEB) approach to the problem, which assigns a prior to the model parameters and integrates over their uncertainties. We compare the new and old methods on real and simulated data sets. The results suggest that in small data sets the new BEB method does not generate false positives as did the old NEB approach, while in large data sets it retains the good power of the NEB approach for inferring positively selected sites.