tbuckley/cabot-search huggingface dataset:
Abstract 248: Integrin-β1 Regulates Cardiac Stem Cell Self-renewal and Differentiation
Authors: Victoria Florea, Christy N Taylor, Paola A Martinez, Courtney Lamondin, Joshua M Hare, Claudia O Rodrigues
Journal: Circulation Research (2013)

Background: Adult cardiac stem cells (CSCs) capable of self-renewal and differentiation into cardiac, smooth muscle and endothelial lineages have been shown to promote tissue repair after ischemic injury and improve heart function. Despite their potential role in cardiac regeneration, evidence suggests that resident CSCs are impaired in conditions such as myocardial infarction, limiting their regenerative capacity. Methods and Results: The growth rate of CSCs is significantly reduced by 40% (p&lt;0.05) under hypoxic stress (0.5% O 2 ). Using an extracellular-matrix (ECM) and adhesion-focused PCR array, we found that incubation of CSCs for 18 hours under hypoxia leads to down-regulation of several genes, including osteopontin, thrombospondin-1 and integrins. Due to their critical role in communicating extracellular signals regulating stem cell mobilization, proliferation, survival, migration and differentiation we decided to investigate the role of integrins in CSCs self-renewal and differentiation. Our gene expression studies showed that integrin-β1 (Itgb1) is the most abundant integrin expressed in CSCs. Therefore, we knocked down (KD) Itgb1 in CSCs and evaluated these cells regarding adhesion, growth and differentiation properties. Our results showed that reduction in Itgb1 levels in CSCs significantly decreased their interaction with extracellular matrix components fibronectin, laminin and vitronectin by 32%, 20% and 24% (p&lt;0.05), respectively. KD of Itgb1 in CSCs reduced growth by 40% (p&lt;0.05), similar to what we observed by with wild-type cells in hypoxia. Assessment of endothelial differentiation showed that KD cells have a higher angiogenic potential vs. NS-control, as demonstrated by upregulation of vWF (3-fold), VEGF (2.5-fold), Pecam1 (2.3-fold) and Nos3 (1.9-fold) (p&lt;0.05). Interestingly, Itgb1 KD per se induced upregulation of these vascular markers in CSCs. Conclusions: Our results suggest that Itgb1 plays an important role in CSCs self-renewal, differentiation and cell adhesion. It is possible that loss of self-renewal is a consequence of changes in CSCs fate as knockdown of Itgb1 leads to upregulation of endothelial lineage markers in these cells. This would limit the expansion of CSCs and their regenerative capacity.
Acute exacerbations in the INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis
Authors: Harold R. Collard, Luca Richeldi, Dong Soon Kim, Hiroyuki Taniguchi, Inga Tschoepe, Maurizio Luisetti, Jesse Roman, Gregory Tino, Rozsa Schlenker-Herceg, Christoph Hallmann, Roland M. du Bois
Journal: European Respiratory Journal (2017)

Time to first investigator-reported acute exacerbation was a key secondary end-point in the INPULSIS trials of nintedanib in patients with idiopathic pulmonary fibrosis (IPF). We used the INPULSIS trial data to investigate risk factors for acute exacerbation of IPF and to explore the impact of nintedanib on risk and outcome of investigator-reported and adjudicated confirmed/suspected acute exacerbations. Mortality following these events and events adjudicated as not acute exacerbations was analysed using the log rank test. Risk of acute exacerbations was most strongly associated with the following variables: baseline forced vital capacity (higher risk with lower value), baseline supplemental oxygen (higher risk with use), baseline antacid medication (higher risk with use), treatment (higher risk with placebo), and for confirmed/suspected acute exacerbations, cigarette smoking. Mortality was similar following investigator-reported and adjudicated confirmed/suspected acute exacerbations. Nintedanib had no significant effect on risk of mortality post-exacerbation. Investigator-reported acute exacerbations of IPF are associated with similar risk factors and outcomes as adjudicated confirmed/suspected acute exacerbations.
Hypokalemia from Beta<sub>2</sub>-Receptor Stimulation by Circulating Epinephrine
Authors: M. J. Brown, D. C. Brown, M. B. Murphy
Journal: New England Journal of Medicine (1983)

To determine whether epinephrine-induced hypokalemia is due to beta2-adrenoceptor stimulation, and whether hypokalemia can occur at physiologic concentrations of the agonist, epinephrine was infused into six normal volunteers at a rate of 0.1 microgram per kilogram of body weight per minute. The circulating epinephrine concentration was increased to 1.74 +/- 0.65 ng per milliliter, plasma potassium was reduced by 0.82 +/- 0.19 meq per liter, plasma insulin fell by 12 +/- 4 mU per liter, plasma renin activity was elevated, and tachycardia occurred. Isoproterenol infused at 0.02 micrograms per kilogram per minute caused similar tachycardia (25 beats per minute) and elevation in plasma renin activity (6.0 to 6.5 ng per milliliter per hour), but no hypokalemia. The difference in responses to the two catecholamines was ascribed to the relative beta2-selectivity of epinephrine. This hypothesis was tested in six subjects given infusions of epinephrine (0.05 micrograms per kilogram per minute) after administration of either 2.5 or 5 mg of ICI 118551--a selective beta2-receptor antagonist--or placebo. After placebo, epinephrine infusion elevated the circulating epinephrine concentration and reduced plasma potassium; hypokalemia was prevented by the beta2-antagonist. This drug only partially inhibited the rises in plasma renin and glucose and the shortening of systolic time intervals; there was no tachycardia. Fifteen-fold to 30-fold increases in circulating epinephrine concentration appear to cause hypokalemia by a specific beta2-receptor effect distinct from other actions of epinephrine. This phenomenon may be of physiologic importance after severe myocardial infarction, when similar increases in plasma epinephrine have occurred.
Indian government agrees radical plan for universal healthcare
Journal: BMJ (2017)

The Indian government has agreed a new health policy programme that will introduce free drugs and diagnostic services into public hospitals across the country.

The National Health Policy 2017 will also lead to a phased increase in healthcare spending from the current 1.15% to 2.5% of India’s gross domestic product.

The plan, designed to help the country achieve “universal access to good quality healthcare services,” will expand existing primary healthcare packages to cover cardiovascular diseases, cancer, diabetes, mental health, rehabilitation, and palliative care.

The policy emphasises the need for a “stronger partnership” between the public and private healthcare sectors, and says that the government …
Online health searching can help doctor-patient relationship, study finds
Authors: Jacqui Wise
Journal: BMJ (2017)

Most people would still usually make an appointment with their GP after searching online health information and their confidence in their family doctor is rarely affected, research published in BJGP Open has found.1

The Belgian study also found that over 80% of respondents experienced no difference in the severity of their symptoms after searching online, and most said that the search did not make them more worried.

The researchers surveyed 718 …
Drugging the Cancers Addicted to DNA Repair
Authors: Jac A. Nickoloff, Dennie Jones, Suk-Hee Lee, Elizabeth A. Williamson, Robert Hromas
Journal: JNCI Journal of the National Cancer Institute (2017)

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.
Effect of low versus high frequency stimulation on freezing of gait and other axial symptoms in Parkinson patients with bilateral STN DBS: a mini-review
Authors: Tao Xie, Mahesh Padmanaban, Lisa Bloom, Ellen MacCracken, Breanna Bertacchi, Abraham Dachman, Peter Warnke
Journal: Translational Neurodegeneration (2017)

Some studies have shown that low frequency stimulation (LFS, most commonly 60 Hz), compared to high frequency stimulation (HFS, most commonly 130 Hz), has beneficial effects, short-term or even long-term, on improving freezing of gait (FOG) and other axial symptoms, including speech and swallowing function, in Parkinson disease (PD) patients with bilateral subthalamic nucleus deep brain stimulation (STN DBS). However, other studies failed to confirm this. It seems not clear what determines the difference in response to LFS. Differences in study design, such as presence or absence of FOG, exact LFS used (60 Hz versus 80 Hz), study size, open label versus randomized double blind assessment, retrospective versus prospective evaluation, medication On or Off state, total electric energy delivered maintained or not with the change in frequency, and the location of active contacts could all potentially affect the results. This mini-review goes over the literature with the aforementioned factors in mind, focusing on the effect of LFS versus HFS on FOG and other axial symptoms in PD with bilateral STN DBS, in an effort to extract the essential data to guide our clinical management of axial symptoms and explore the potential underlying mechanisms as well. Overall, LFS of 60 Hz seems to be consistently effective in patients with FOG at the usual HFS in regards to improving FOG, speech, swallowing function and other axial symptoms, though LFS could reduce tremor control in some patients. Whether LFS simply addresses the axial symptoms in the context of HFS or has other beneficial effects requires further studies, along with the mechanism.
Abstract P146: Fas-ligand Induces Cardiomyopathy via the Activation of the Erk1/2 Pathway
Authors: Anne-Cecile Huby, Enkhsaikhan Purevjav, Jeffrey A Towbin
Journal: Circulation Research (2011)

Fas receptor and its ligand, Fas-L, are the most well characterized co-stimulatory molecules playing an essential role in the induction of programmed cell death or apoptosis. Increase of circulating Fas-L in serum and in cardiomyocytes are described in different models of cardiac diseases such as myocarditis, pressure overload, AND myocardial infarction/ischemia. In addition, associated activation of inflammatory pathwayshas been observed. However, no studies have yet revealed mechanisms underlying the pathogenecity of FasL in the heart. Transgenic mice (C57/Bl6) with cardiac-specific over-expression of Fas-L were investigated. We characterized cardiac function by echocardiography. Cellular and molecular studies were performed on heart tissue using genomic, histologic, immunological, and protein analysis techniques. Fas-L transgenic mice had a significant rate of mortality (p&lt;0.0001) compared to WT due to heart failure. Histological studies of Fas-L hearts revealed predominant perivascular fibrosis associated with inflammation. Expression studies of secondary messengers of the activated Fas/FasL system demonstrated up-regulation of an active CASP-3 confirming induction of apoptosis in myocardium. Down-regulation of FLIP, NIK and NF-κB was evident. Interestingly, RIP was up-regulated leading to the activation of ERK1/2 (4.27±0.158 vs 10.086±1.591 in WT and FasL mice hearts, respectively, p=0.022). Analysis of inflammatory mediators revealed increase in secretion of interleukines (IL-17, IL-6, IL-1β and TNF-α) and diffuse infiltration of CD3 positive cells. Studies of fibrotic pathways showed an increased expression of periostin and osteopontin, but not activation of TGFβ1, showing that periostin and osteopontin can be activated independently of TGFβ1 via the ERK1/2 pathway, Our findings suggest that Fas-L induces cardiac failure, via an activation of the ERK1/2 pathway, which is an important player involved in the hypertrophic response in the heart. Targeting the ERK1/2 pathway in cardiac diseases associated with Fas-L expression may therefore be able to prevent progression to cardiomyopathy.
Adaptive principles of weight regulation: Insufficient, but perhaps necessary, for understanding obesity
Authors: Daniel Nettle, Clare Andrews, Melissa Bateson
Journal: Behavioral and Brain Sciences (2017)

We reflect on the major issues raised by a thoughtful and diverse set of commentaries on our target article. We draw attention to the need to differentiate between ultimate and proximate explanation; the insurance hypothesis (IH) needs to be understood as an ultimate-level argument, although we welcome the various suggestions made about proximate mechanisms. Much of this response is concerned with clarifying the interrelationships between adaptationist explanations like the IH, constraint explanations, and dysfunction explanations, in understanding obesity. We also re-examine the empirical evidence base, concurring that it is equivocal and only partially supportive. Several commentators offer additional supporting evidence, whereas others propose alternative explanations for the evidence we reviewed and suggest ways that our current knowledge could be strengthened. Finally, we take the opportunity to clarify some of the assumptions and predictions of our formal model.
Flexural erythematous eruption following autologous peripheral blood stem cell transplantation: a study of four cases
Authors: V. Brazzelli, M. Ardigò, M.G. Chiesa, C. Vassallo, M. Varettoni, R.G. Borroni, E.P. Alessandrino, G. Borroni
Journal: British Journal of Dermatology (2008)

Autologous bone marrow transplantation and autologous peripheral blood stem cell transplantation (APBSCT) are alternative therapeutic options in the treatment of various malignancies. We describe four patients undergoing APBSCT for malignancies; they developed a cutaneous eruption characterized by confluent erythematous and hyperpigmented patches within the flexural areas during the first month after transplantation. The lesions were poorly circumscribed without epidermal changes such as scaling, xerosis, erosions or atrophy. The skin patches were treated with topical corticosteroids and resolved within a few days with discoloration. Histopathological findings were characterized by focal vacuolar degeneration of the basal layer with epidermal dysmaturation. We believe that these cutaneous eruptions are consistent with an interplay of high‐dose chemotherapy and local factors such as friction, local skin temperature and eccrine gland distribution, which could explain the constant location of this eruption in the axillae and genital area.
New EMA policy on access to documents still falls short, say campaigners
Authors: Jacqui Wise
Journal: BMJ (2017)

Proposed changes to the way the European Medicines Agency allows access to documents it holds are still too restrictive, warn campaigners.

The EMA launched a public consultation on the revision to its policy on access to documents, which invited stakeholders to comment by 18 May 2017.1

A coalition of organisations—Health Action International, the International Society of Drug Bulletins, NoGracias, the Nordic Cochrane Centre, and the journal Prescrire —said that the revised policy falls short on proactive disclosure.2

In a joint response they raised the concern that …
Effects of Epinephrine on Glucose Metabolism in Patients With Alcoholic Cirrhosis
Authors: T Schricker, G Albuszies, H Weidenbach, K Beckh, H Ensinger, T Anhäupl, P Radermacher, J Vogt, G Adler, M Georgieff
Journal: Hepatology (1996)

The cirrhotic liver has been shown to be resistant to the actions of various glucoregulatory hormones. The objective of this study was to investigate the effects of epinephrine on hepatic glucose metabolism in cirrhotic patients. Thirteen cirrhotic and eight healthy subjects were studied. Hepatic glucose production and turnover of alanine and glycerol were measured using stable isotope technique before and during 70 and 150 minutes of epinephrine infusion (0.1 microgram/kg/min). β–Adrenoreceptor binding sites and affinity in mononuclear leukocyte membranes also were determined. Hepatic glucose production and alanine turnover in normals significantly increased during epinephrine infusion, but did not change in cirrhotics. Glycerol turnover increased after 70 minutes of epinephrine infusion in both groups. Epinephrine induced a significant rise of high–affinity β–adrenoreceptor binding sites in normals, yielding a significant correlation between hepatic glucose production and receptor density (r = .94, P &lt; .0001). In cirrhotic patients, similar changes in the number of high–affinity β– adrenoreceptors were observed, but no correlation with hepatic glucose production was detected. The cirrhotic liver did not respond normally to the stimulatory effect of epinephrine on hepatic glucose production. Because this blunted response was not related to changes of β– adrenoreceptors, our findings suggest that epinephrine resistance in cirrhosis was caused by a postreceptor defect.
Chemotherapy-Based Stem Cell Mobilization Does Not Result in Significant Paraprotein Reduction in Myeloma Patients in the Era of Novel Induction Regimens
Authors: Anthony Oyekunle, Evgenii Shumilov, Philippe Kostrewa, Andreas Burchert, Patrick Wuchter, Ulrike Bacher, Gerald Wulf, Nicolaus Kroeger
Journal: Blood (2016)
Clinical Characteristics, Biological Markers and Comorbidity Indexes As Predictors of Transplant-Related Mortality after Allogeneic Hematopoietic Stem Cell Transplantation: Which One Should We Choose?
Authors: Alienor Xhaard, Renato Cunha, Marc Busson, Marie Robin, Nathalie Dhedin, Tereza Coman, Aurelie Cabannes-Hamy, Flore Sicre de Fontbrune, David Michonneau, Gerard Socie, Rodrigo T. Calado, Regis Peffault De Latour
Journal: Blood (2016)
PTU-178 Measurement of esophago-gastric junction cross-sectional area and distensibility by EndoFLIP® (endolumenal functional lumen imaging probe) for the diagnosis of patients with gastro-esophageal reflux disease (GERD): Abstract PTU-178 Figure 1
Authors: E Tucker, R Sweis, A Anggiansah, E Telakis, J Wright, K Knowles, T Wong, M Fox
Journal: Gut (2012)

<h3>Objective</h3> To assess current management practice of heart failure with reduced ejection fraction (HFrEF) in multinational primary care (PC) and determine whether N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP)-guided referral of HFrEF patients from PC to a cardiologist could improve care, defined as adherence to European Society of Cardiology (ESC) guideline-recommended pharmacotherapy. <h3>Methods</h3> PRospective Evaluation of natriuretic peptide-based reFERral of patients with chronic HF in PC (PREFER) study enrolled HFrEF patients from PC considered clinically stable and those with NT-pro-BNP ≥600 pg/mL were referred to a cardiologist for optimisation of HF treatment. The primary outcome of adherence to ESC HF guidelines after referral to specialist was assessed at the second visit within 4 weeks of cardiologist’s referral and no later than 6 months after the baseline visit. Based on futility interim analysis, the study was terminated early. <h3>Results</h3> In total, 1415 HFrEF patients from 223 PCs from 18 countries in Europe were enrolled. Of these, 1324 (96.9%) were considered clinically stable and 920 (65.0%) had NT-pro-BNP ≥600 pg/mL (mean: 2631 pg/mL). In total, 861 (60.8%) patients fulfilled both criteria and were referred to a cardiologist. Before cardiologist consultation, 10.1% of patients were on ESC guideline-recommended HFrEF medications and 2.7% were on recommended dosages of HFrEF medication (defined as ≥50% of ESC guideline-recommended dose). Postreferral, prescribed HFrEF drugs remained largely unchanged except for an increase in diuretics (+4.6%) and mineralocorticoid receptor antagonists (+7.9%). No significant increase in patients’ adherence to guideline-defined drug combinations (11.2% post-referral vs 10.1% baseline) or drug combinations and dosages (3.3% postreferral vs 2.7% baseline) was observed after cardiologist consultation. <h3>Conclusions</h3> PREFER demonstrates substantial suboptimal treatment of HFrEF patients in the real world. Referral of patients with elevated NT-pro-BNP levels from PC to cardiologist did not result in meaningful treatment optimisation for treatments with known mortality and morbidity benefit.
Systemic Therapy for Metastatic Renal-Cell Carcinoma
Authors: Toni K. Choueiri, Robert J. Motzer
Journal: New England Journal of Medicine (2017)

Kidney cancers have been extensively studied, and insights from an increased understanding of tumor biology have led to increases in survival rates. Therapies aimed at tumor signaling pathways and immunotherapies have improved the outlook for patients with renal cancer.
STUDIES ON AN UNCOMPLICATED CORYZA OF THE DOMESTIC FOWL
Authors: John B. Nelson
Journal: The Journal of Experimental Medicine (1936)

Minute coccobacilliform bodies have regularly been found in the nasal exudate of fowl infected both by injection and by contact with the coryza of slow onset. These bodies are commonly less than 0.5micro in diameter and are predominantly extracellular. They have consistently failed to grow in artificial media. They are held back by Berkefeld V filters which are impermeable to Hemophilus gallinarum but may pass through filters which are permeable to the test organism. The coccoid bodies are morphologically similar to a cultivable non-infective bacterium which may occasionally be isolated from exudate of the infected fowls.