tbuckley/cabot-search huggingface dataset:
Dermal Swellings and Ocular Injury after Exposure to Reindeer
Authors: Boris Kan, Domenico Otranto, Kristian Fossen, Kjetil Åsbakk
Journal: New England Journal of Medicine (2012)

Myiasis associated with migratory dermal swellings and ocular injury due to Hypoderma tarandi is identified in children who had visited reindeer in Norway or Sweden.
6-<i>C</i>-(<i>E</i>-phenylethenyl)-Naringenin Suppresses Colorectal Cancer Growth by Inhibiting Cyclooxygenase-1
Authors: Haitao Li, Feng Zhu, Hanyong Chen, Ka Wing Cheng, Tatyana Zykova, Naomi Oi, Ronald A. Lubet, Ann M. Bode, Mingfu Wang, Zigang Dong
Journal: Cancer Research (2013)

Abstract Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors and cyclooxygenase-1 (COX-1) is now being reconsidered as a target for chemoprevention. Our aims were to determine whether selective COX-1 inhibition could delay or prevent cancer development and also clarify the underlying mechanisms. Data clearly showed that COX-1 was required for maintenance of malignant characteristics of colon cancer cells or tumor promoter-induced transformation of preneoplastic cells. We also successfully applied a ligand-docking computational method to identify a novel selective COX-1 inhibitor, 6-C-(E-phenylethenyl)-naringenin (designated herein as 6CEPN). 6CEPN could bind to COX-1 and specifically inhibited its activity both in vitro and ex vivo. In colorectal cancer cells, it potently suppressed anchorage-independent growth by inhibiting COX-1 activity. 6CEPN also effectively suppressed tumor growth in a 28-day colon cancer xenograft model without any obvious systemic toxicity. Taken together, COX-1 plays a critical role in human colorectal carcinogenesis, and this specific COX-1 inhibitor merits further investigation as a potential preventive agent against colorectal cancer. Cancer Res; 74(1); 243–52. ©2013 AACR.
Horizontal Transfer of a Virulence Operon to the Ancestor of Mycobacterium tuberculosis
Authors: Vania Rosas-Magallanes, Patrick Deschavanne, Lluis Quintana-Murci, Roland Brosch, Brigitte Gicquel, Olivier Neyrolles
Journal: Molecular Biology and Evolution (2006)

The contribution of interspecies horizontal gene transfer (HGT) to the evolution and virulence of Mycobacterium tuberculosis, the agent of tuberculosis in humans, has been barely investigated. Here we have studied the evolutionary history of the M. tuberculosis Rv0986-8 virulence operon recently identified, through functional genomics approaches, as playing an important role in parasitism of host phagocytic cells. We showed that among actinobacteria, this operon is specific to the M. tuberculosis complex and to ancestral Mycobacterium prototuberculosis species. These data, together with phylogenetic reconstruction and other in silico analyses, provided strong evidence that this operon has been aquired horizontally by the ancestor of M. tuberculosis, before the recent evolutionary bottleneck that preceded the clonal-like evolution of the M. tuberculosis complex. Genomic signature profiling further suggested that the transfer was plasmid mediated and that the operon originated from a γ-proteobacterium donor species. Our study points out for the first time the contribution of HGT to the emergence of M. tuberculosis and close relatives as major pathogens. In addition, our data underline the importance of deciphering gene transfer networks in M. tuberculosis in order to better understand the evolutionary mechanisms involved in mycobacterial virulence.
Rotation of the Myocardial Wall of the Outflow Tract Is Implicated in the Normal Positioning of the Great Arteries
Authors: Fanny Bajolle, Stéphane Zaffran, Robert G. Kelly, Juliette Hadchouel, Damien Bonnet, Nigel A. Brown, Margaret E. Buckingham
Journal: Circulation Research (2006)

Congenital heart defects frequently involve a failure of outflow tract (OFT) formation during development. We analyzed the remodeling of the OFT, using the y96-Myf5-nlacZ-16 transgene, which marks a subpopulation of myocardial cells of the pulmonary trunk. Expression analyses of reporter transcript and protein suggest that the myocardial wall of the OFT rotates before and during the formation of the great arteries. Rotational movement was confirmed by Di-I injection experiments with cultured embryos. We subsequently examined the expression of the transgene in mouse models for OFT defects. In hearts with persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), or transposition of the great arteries, rotation of the myocardial wall of the OFT is arrested or fails to initiate. This is observed in Splotch (Pax3) mutants with PTA or DORV and may be a result of defects in neural crest migration, known to affect OFT septation. However, in Pitx2deltac mutant embryos, where cardiac neural crest cells are present in the heart, PTA and DORV are again associated with a rotation defect. This is also seen in Pitx2deltac mutants, which have transposition of the great arteries. Because Pitx2c is involved in left-right signaling, these results suggest that embryonic laterality affects rotation of the myocardial wall during OFT maturation. We propose that failure of normal rotation of OFT myocardium may underlie major forms of congenital heart disease.
A Spontaneous Acinar Cell Carcinoma Model for Monitoring Progression of Pancreatic Lesions and Response to Treatment Through Noninvasive Bioluminescence Imaging
Authors: Ning Zhang, Scott Lyons, Ed Lim, Peter Lassota
Journal: Clinical Cancer Research (2009)

We have generated an EL1-luc/TAg transgenic mouse model that develops spontaneous and bioluminescent acinar cell carcinomas. We applied this model to noninvasively monitor tumor development and drug response.EL1-luc/TAg transgenic mice of 11 weeks of age were treated with rapamycin (5 mg/kg, i.p.) or vehicle for 6 to 12 weeks. Tumor development was monitored through bioluminescence imaging and necropsy at the study end point.EL1-luc/TAg transgenic mice showed pancreas-specific bioluminescence signal before tumor progression and produced increasing light emission from the onset of the pancreatic acinar cell carcinomas. The latency of tumor development ranged from 10 to >20 weeks of age in these mice. Progression of the primary acinar cell carcinoma was accompanied by emergence of metastatic lesions in the abdominal organs, including liver and gastrointestinal fat tissues. Rapamycin treatment suppressed tumor development.The EL1-luc/TAg mouse provides a noninvasive approach for monitoring spontaneous acinar cell carcinoma development and comprises a convenient tool for the evaluation of novel therapeutics against pancreatic cancers. Tumor growth suppression through inhibition of the mammalian target of rapamycin pathway further validates this model as clinically relevant.
A randomised, double-blind, placebo-controlled trial of a recombinant version of human -fetoprotein (MM-093) in patients with active rheumatoid arthritis
Authors: L C Pollard, J Murray, M Moody, E J Stewart, E H S Choy
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background:</b> Rheumatoid arthritis (RA) tends to remit during pregnancy, with more patients achieving remission in the third trimester, coinciding with an increase in levels of α-fetoprotein (AFP). In vitro and animal studies have shown that AFP has immunomodulatory properties. MM-093 is a non-glycosylated, recombinant version of human AFP. <b>Objective:</b> To assess the safety, tolerability and clinical effects of MM-093 during a 12-week, randomised, double-blind, placebo-controlled study. <b>Methods:</b> 12 patients with RA, who had active disease and were on stable doses of methotrexate, received weekly subcutaneous injections of placebo or 21 mg of MM-093. Assessments were carried out at baseline and weekly thereafter. <b>Results:</b> Baseline characteristics were similar in both groups. There was one dropout in the placebo group, due to flare of disease. Treatment with MM-093 was well tolerated. No serious adverse event was observed. By day 85, MM-093 produced a significant mean improvement from baseline in Disease Activity Score 28 (DAS28; 0.913 vs 0.008, p = 0.033) and patient's global assessment (28.9% vs −36.3%, p = 0.02) compared with placebo. <b>Conclusion:</b> This is the first randomised, controlled trial of MM-093, a recombinant version of human AFP, in patients with RA. MM-093 was well tolerated. Evidence of efficacy was observed, suggesting that MM-093 may have therapeutic potential in RA.
Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice
Authors: Emilio Ramos, Léon Kautz, Richard Rodriguez, Michael Hansen, Victoria Gabayan, Yelena Ginzburg, Marie-Paule Roth, Elizabeta Nemeth, Tomas Ganz
Journal: Hepatology (2011)

In response to iron loading, hepcidin synthesis is homeostatically increased to limit further absorption of dietary iron and its release from stores. Mutations in HFE, transferrin receptor 2 (Tfr2), hemojuvelin (HJV), or bone morphogenetic protein 6 (BMP6) prevent appropriate hepcidin response to iron, allowing increased absorption of dietary iron, and eventually iron overload. To understand the role each of these proteins plays in hepcidin regulation by iron, we analyzed hepcidin messenger RNA (mRNA) responsiveness to short and long-term iron challenge in iron-depleted Hfe , Tfr2 , Hjv , and Bmp6 mutant mice. After 1-day (acute) iron challenge, Hfe-/- mice showed a smaller hepcidin increase than their wild-type strain-matched controls, Bmp6-/- mice showed nearly no increase, and Tfr2 and Hjv mutant mice showed no increase in hepcidin expression, indicating that all four proteins participate in hepcidin regulation by acute iron changes. After a 21-day (chronic) iron challenge, Hfe and Tfr2 mutant mice increased hepcidin expression to nearly wild-type levels, but a blunted increase of hepcidin was seen in Bmp6-/- and Hjv-/- mice. BMP6, whose expression is also regulated by iron, may mediate hepcidin regulation by iron stores. None of the mutant strains (except Bmp6-/- mice) had impaired BMP6 mRNA response to chronic iron loading. Conclusion: TfR2, HJV, BMP6, and, to a lesser extent, HFE are required for the hepcidin response to acute iron loading, but are partially redundant for hepcidin regulation during chronic iron loading and are not involved in the regulation of BMP6 expression. Our findings support a model in which acute increases in holotransferrin concentrations transmitted through HFE, TfR2, and HJV augment BMP receptor sensitivity to BMPs. A distinct regulatory mechanism that senses hepatic iron may modulate hepcidin response to chronic iron loading. (HEPATOLOGY 2011;)
Myocardial and non-myocardial release of myoglobin and creatine-kinase MB following cardiac operations with hypothermic potassium cardioplegia
Authors: J C. H SYLVEN, V. BOMFIM, T. IVERT, C. OLIN
Journal: Cardiovascular Research (1982)

Serum time-activity curves for myoglobin, creatine-kinase (CK) and its isoenzyme MB were determined during and after coronary bypass surgery and aortic valve replacement. Hypothermic potassium cardioplegia was the method employed to initiate cardiac arrest. Cardiac myoglobin and CK-MB release rates were maximal 0.5 to 1.0 h post aortic cross-clamp release (PACR) with maximal concentrations at 1 and 4 h PACR respectively. The cardiac release ceased within 5 h PACR but was followed by a noncardiac release with maximal concentrations from 10 to 35 h PACR. The cardiac myoglobin release was significantly lower in the coronary bypass group, whereas no significant intergroup difference was observed for CK-MB. The cumulative CK-MB release corresponded roughly to about 5 g of myocardium.
Chief of Great Ormond Street takes name off medical register
Authors: A. O'Dowd
Journal: BMJ (2010)

Jane Collins, the chief executive of Great Ormond Street Hospital for Children in London, has removed her name from the medical register, it has emerged.

A newspaper article published at the weekend claiming that the decision was taken to avoid the possibility of future investigation by the General Medical Council has been flatly denied by the trust and Dr Collins.

The trust was criticised last year by England’s healthcare watchdog, the Care Quality Commission, for how it handled the case of 17 month old Peter Connelly, known as Baby P, who died in 2007 after suffering numerous injuries inflicted by his stepfather ( BMJ 2009;338:b1967, doi:10.1136/bmj.b1967).

The boy was seen a few days …
Functional P2Y <sub>2</sub> Nucleotide Receptors Mediate Uridine 5′-Triphosphate–Induced Intimal Hyperplasia in Collared Rabbit Carotid Arteries
Authors: Cheikh I. Seye, Qiongman Kong, Laurie Erb, Richard C. Garrad, Brent Krugh, Meifang Wang, John T. Turner, Michael Sturek, Fernando A. González, Gary A. Weisman
Journal: Circulation (2002)

Extracellular uridine 5'-triphosphate (UTP) induces mitogenic activation of smooth muscle cells (SMCs) through binding to P2Y2 nucleotide receptors. P2Y2 receptor mRNA is upregulated in intimal lesions of rat aorta, but it is unclear how this G-protein-coupled receptor contributes to development of intimal hyperplasia.This study used a silicone collar placed around rabbit carotid arteries to induce vascular injury and intimal thickening. Collar placement caused rapid upregulation of P2Y2 receptor mRNA in medial SMCs before appearance of neointima. Fura-2 digital imaging of single SMCs was used to measure changes in myoplasmic calcium concentration (Ca(m)) in response to P2Y receptor agonists. In contrast to UDP, activation by UTP or adenosine 5'-triphosphate (ATP) greatly increased Ca(m), which indicates upregulation of functional P2Y2 receptors at which UTP and ATP are equipotent agonists. The number of responsive cells was significantly greater for freshly dispersed SMCs from collared arteries than for controls. Perivascular infusion of UTP (100 micromol/L) within the collar significantly enhanced neointimal development. Intimas that resulted from UTP exposure were infiltrated by macrophages. Moreover, increased expression of osteopontin occurred in response to in situ application of UTP. ATP or UTP also stimulated osteopontin expression in cultured SMCs in a dose-dependent manner. Furthermore, P2Y2 antisense oligonucleotide inhibited osteopontin expression induced by UTP.These findings indicate for the first time a role for the UTP/ATP receptor, P2Y2, in development of intimal hyperplasia associated with atherosclerosis and restenosis.
Automated mortality monitoring in Scotland from 2009
Authors: A P Wagner, E McKenzie, C Robertson, J McMenamin, A Reynolds, H Murdoch
Journal: Eurosurveillance (2013)

Mortality monitoring systems are important for gauging the effect of influenza and other wide ranging health threats. We present the daily all-cause mortality monitoring system routinely used in Scotland, which differs from others by using two different statistical models for calculating expected mortality. The first model is an extended Serfling model, which captures annual seasonality in mortality using sine and cosine terms, and is frequently seen in other systems. Serfling models fit to summer seasonality well, but not to the winter peak. Thus, during the winter, there are frequent 'excesses', higher than expected mortality, making it harder to directly judge if winter mortality is higher than in previous years. The second model, a Generalised Additive Model, resolves this by allowing a more flexible seasonal pattern that includes the winter peak. Thus, excesses under the second model directly indicate if winter mortality is higher than in previous years, useful, for example, in judging if a new strain of seasonal influenza is more likely to produce death than previous ones. As common in all-cause mortality monitoring systems, the Scottish system uses a reporting delay correction: we discuss the difficulties of interpretation when such a correction is used and possible avenues for future work that may address these difficulties.
HCN3 Contributes to the Ventricular Action Potential Waveform in the Murine Heart
Authors: Stefanie Fenske, Robert Mader, Andreas Scharr, Christos Paparizos, Xiaochun Cao-Ehlker, Stylianos Michalakis, Lior Shaltiel, Martha Weidinger, Juliane Stieber, Susanne Feil, Robert Feil, Franz Hofmann, Christian Wahl-Schott, Martin Biel
Journal: Circulation Research (2011)

The hyperpolarization-activated current I(h) that is generated by hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) plays a key role in the control of pacemaker activity in sinoatrial node cells of the heart. By contrast, it is unclear whether I(h) is also relevant for normal function of cardiac ventricles.To study the role of the HCN3-mediated component of ventricular I(h) in normal ventricular function.To test the hypothesis that HCN3 regulates the ventricular action potential waveform, we have generated and analyzed a HCN3-deficient mouse line. At basal heart rate, mice deficient for HCN3 displayed a profound increase in the T-wave amplitude in telemetric electrocardiographic measurements. Action potential recordings on isolated ventricular myocytes indicate that this effect was caused by an acceleration of the late repolarization phase in epicardial myocytes. Furthermore, the resting membrane potential was shifted to more hyperpolarized potentials in HCN3-deficient mice. Cardiomyocytes of HCN3-deficient mice displayed approximately 30% reduction of total I(h). At physiological ionic conditions, the HCN3-mediated current had a reversal potential of approximately -35 mV and displayed ultraslow deactivation kinetics.We propose that HCN3 together with other members of the HCN channel family confer a depolarizing background current that regulates ventricular resting potential and counteracts the action of hyperpolarizing potassium currents in late repolarization. In conclusion, our data indicate that HCN3 plays an important role in shaping the cardiac action potential waveform.
Contribution of Adventitial Fibroblasts to Neointima Formation and Vascular Remodeling
Authors: Saverio Sartore, Angela Chiavegato, Elisabetta Faggin, Rafaella Franch, Massimo Puato, Simonetta Ausoni, Paolo Pauletto
Journal: Circulation Research (2001)

The adventitial layer surrounding the blood vessels has long been exclusively considered a supporting tissue the main function of which is to provide adequate nourishment to the muscle layers of tunica media. Although functionally interconnected, the adventitial and medial layers are structurally interfaced at the external elastic lamina level, clearly distinguishable at the maturational phase of vascular morphogenesis. Over the last few years the “passive” role that the adventitia seemed to play in experimental and spontaneous vascular pathologies involving proliferation, migration, differentiation, and apoptosis of vascular smooth muscle cells (VSMCs) has been questioned. It has been demonstrated that fibroblasts from the adventitia display an important partnership with the resident medial VSMCs in terms of phenotypic conversion, proliferation, apoptotic, and migratory properties the result of which is neointima formation and vascular remodeling. This article is an attempt at reviewing the major themes and more recent findings dealing with the phenotypic conversion process that leads adventitial “passive” (static) fibroblasts to become “activated” (mobile) myofibroblasts. This event shows some facets in common with vascular morphogenesis, ie, the process of recruitment, incorporation, and phenotypic conversion of cells surrounding the primitive endothelial tube in the definitive vessel wall. We hypothesize that during the response to vascular injuries in the adult, “activation” of adventitial fibroblasts is, at least in part, reminiscent of a developmental program that also invests, although with distinct spatiotemporal features, medial VSMCs.
Sequential assessment of an antidrug antibody response in a patient with a systemic delayed-onset sulphonamide hypersensitivity syndrome reaction
Authors: K. Bedard, S. Smith, A. Cribb
Journal: British Journal of Dermatology (2000)

Journal Article Sequential assessment of an antidrug antibody response in a patient with a systemic delayed‐onset sulphonamide hypersensitivity syndrome reaction Get access K. Bedard, K. Bedard Laboratory of Pharmacogenetics, University of Prince Edward Island, 550 University Avenue, Charlottetown, PE, Canada C1A 4P3 Search for other works by this author on: Oxford Academic Google Scholar S. Smith, S. Smith Dermatology Associates, 477 N. El Camino Real B‐303, Encinitas, CA 92024, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar A. Cribb A. Cribb Laboratory of Pharmacogenetics, University of Prince Edward Island, 550 University Avenue, Charlottetown, PE, Canada C1A 4P3 Dr Alastair Cribb. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 2, 1 February 2000, Pages 253–258, https://doi.org/10.1046/j.1365-2133.2000.03293.x Published: 01 February 2000
Combination therapy in idiopathic pulmonary fibrosis: the way ahead will be hard
Authors: Athol Wells
Journal: European Respiratory Journal (2015)

In retrospect, 2014 will be seen as the year in which idiopathic pulmonary fibrosis (IPF) therapies came of age. Treatment effects reported previously were inconclusive with regard to both pirfenidone (two positive studies [1, 2] and a negative study [2]) and nintedanib (a single phase II study in which trends were marginal due to under-powering [3]). The ASCEND pirfenidone trial [4] and the two INPULSIS nintedanib trials [5] ended uncertainty. The two agents appear remarkably similar in both tolerability and efficacy, with a 50% reduction in forced vital capacity (FVC) decline. Whither now? No biomarker data exist to indicate that either agent might be more efficacious in individual patients. Initially, the routine use of these therapies is likely to be sequential, with one agent replaced by the other when side-effects are problematic or treatment failure is evident, however this is defined. In the longer term, combinations of pirfenidone and nintedanib appear attractive in principle, based both on the possibility of synergy in a disease in which there is a multiplicity of coactivated pathways, and also on precedence in other lung diseases including asthma, chronic obstructive pulmonary disease, lung cancer and pulmonary artery hypertension [6]. However, the road to combination regimens in IPF is likely to have many twists and turns. Two particular problems need to be addressed, even supposing that additive or synergistic benefits exist (something that has yet to be established). Tolerability issues are important, as both agents give rise to significant gastrointestinal side-effects. It should also be understood from the outset that demonstrating efficacy will not be straightforward. Intense multinational activity was needed to show treatment benefits against placebo arms characterised by FVC declines approximating 220 mL·year−1. The treatment advances of 2014 sound the death knell of placebo-controlled evaluation in IPF: it seems inevitable that combination regimens will be compared with monotherapy. The rate of FVC decline of approximately 110 mL·year−1 in patients receiving either pirfenidone or nintedanib will pose major challenges with regard to powering future trials [6]. The current issue of the European Respiratory Journal ( ERJ ) features two studies that are highly relevant to tolerability and study design issues. Combination therapy is the future for IPF treatment but many questions remain regarding tolerability and study design <http://ow.ly/Kuykl>