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Krzysztof Narkiewicz, Laura E K Ratcliffe, Emma C Hart, Linford J B Briant, Marzena Chrostowska, Jacek Wolf, Anna Szyndler, Dagmara Hering, Ana P Abdala, Nathan Manghat, Amy E Burchell, Claire Durant, Melvin D Lobo, Paul A Sobotka, Nikunj K Patel, James C Leiter, Zoar J Engelman, Angus K Nightingale, Julian F R Paton
Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity...
August 2016: JACC. Basic to Translational Science
Caroline Wilson
The spread of breast cancer cells to bone and survival in this new metastatic environment is influenced not only by the genetic signature of the cells, but also multiple host cells and soluble factors produced locally (paracrine) or from distant sites (endocrine). Disrupting this metastatic process has been evaluated in clinical trials of the bone targeted agents bisphosphonates and denosumab and have shown that these agents reduce the recurrence of breast cancer in postmenopausal women only, suggesting the efficacy of the drugs are influenced by levels of reproductive endocrine hormones...
September 2016: Journal of Bone Oncology
V R Knight-Schrijver, V Chelliah, L Cucurull-Sanchez, N Le Novère
Recent growth in annual new therapeutic entity (NTE) approvals by the U.S. Food and Drug Administration (FDA) suggests a positive trend in current research and development (R&D) output. Prior to this, the cost of each NTE was considered to be rising exponentially, with compound failure occurring mainly in clinical phases. Quantitative systems pharmacology (QSP) modelling, as an additional tool in the drug discovery arsenal, aims to further reduce NTE costs and improve drug development success. Through in silico mathematical modelling, QSP can simulate drug activity as perturbations in biological systems and thus understand the fundamental interactions which drive disease pathology, compound pharmacology and patient response...
2016: Computational and Structural Biotechnology Journal
C Grassberger, H Paganetti
The variety of treatment options for cancer patients has increased significantly in recent years. Not only do we combine radiation with surgery and chemotherapy, new therapeutic approaches such as immunotherapy and targeted therapies are starting to play a bigger role. Physics has made significant contributions to radiation therapy treatment planning and delivery. In particular, treatment plan optimization using inverse planning techniques has improved dose conformity considerably. Furthermore, medical physics is often the driving force behind tumor control and normal tissue complication modeling...
October 19, 2016: Physics in Medicine and Biology
Peter L Stern, Richard Harrop
The natural history of a patient's cancer is often characterised by genetic diversity and sequential sweeps of clonal dominance. It is therefore not surprising that identifying the most appropriate tumour-associated antigen for targeted intervention is challenging. The 5T4 oncofoetal antigen was identified by searching for surface molecules shared between human trophoblast and cancer cells with the rationale that they may function to allow survival of the foetus as a semi-allograft in the mother or a tumour in its host...
October 18, 2016: Cancer Immunology, Immunotherapy: CII
Daniel Todt, Stephanie Walter, Richard J P Brown, Eike Steinmann
Hepatitis E virus (HEV), an important agent of viral hepatitis worldwide, can cause severe courses of infection in pregnant women and immunosuppressed patients. To date, HEV infections can only be treated with ribavirin (RBV). Major drawbacks of this therapy are that RBV is not approved for administration to pregnant women and that the virus can acquire mutations, which render the intra-host population less sensitive or even resistant to RBV. One of the proposed modes of action of RBV is a direct mutagenic effect on viral genomes, inducing mismatches and subsequent nucleotide substitutions...
October 13, 2016: Viruses
Ana Vrdoljak, Vanja Ivković, Sandra Karanović, Živka Dika, Ivana Vuković, Jelena Kos, Mario Laganović, Tajana Željković Vrkić, Margareta Fištrek Prlić, Ivan Pećin, Bojan Jelaković
OBJECTIVE: It was observed that glomerular hyperfiltration (GHF) is associated with progression of kidney disease in diabetics, patients in stage 1 hypertension (HT), and we found previously that eGFR decreased faster also in prehypertensives (PHT) with GHF. Here we analyzed whether GHF in PHT is associated with other biomarkers of early renal impairment. DESIGN AND METHOD: From 954 subjects enrolled in ENAH follow-up study, 371(137 m;mean age = 46years) were eligible for further analysis:100 with optimal,72 with normal BP,70 with PHT(high normal BP),and 129 with newly diagnosed untreated HT...
September 2016: Journal of Hypertension
Anna Dominiczak
Human primary or essential hypertension is a complex, polygenic trait with some 50% contribution from genes and environment. Richard Lifton and colleagues provided elegant dissection of several rare Mendelian forms of hypertension, exemplified by the glucocorticoid remediable aldosteronism and Liddle's syndrome. These discoveries illustrate that a single gene mutation can explain the entire pathogenesis of severe, early onset hypertension as well as dictating the best treatment.The dissection of the much more common polygenic hypertension has proven much more difficult...
September 2016: Journal of Hypertension
Christian Brinch Mollerup, Petur Weihe Dalsgaard, Marie Mardal, Kristian Linnet
High-resolution mass spectrometry (HRMS) is widely used for the drug screening of biological samples in clinical and forensic laboratories. With the continuous addition of new psychoactive substances (NPS), keeping such methods updated is challenging. HRMS allows for combined targeted and non-targeted screening; first, peaks are identified by software algorithms, and identifications are based on reference standard data. Remaining unknown peaks are attempted identified with in silico and literature data. However, several thousand peaks remain where most are unidentifiable or uninteresting in drug screening...
October 17, 2016: Drug Testing and Analysis
Jeremy W Luk, Matthew J Worley, Evan Winiger, Ryan S Trim, Christian J Hopfer, John K Hewitt, Sandra A Brown, Tamara L Wall
PURPOSE: To examine the associations between substance use and antisocial behavior trajectories and seven risky behaviors over time. METHOD: Data were collected from a high-risk sample of adolescents followed into young adulthood. Five trajectory classes, identified based on dual development of substance use and antisocial behavior symptoms, were used to predict three risky driving and four risky sexual behaviors. RESULTS: In this high-risk sample (n=530), participants reported notably high overall rates of reckless driving (55...
October 11, 2016: Drug and Alcohol Dependence
Martina Hahn, Sibylle C Roll
A 50-year-old male patient with comorbid human immunodeficiency virus developed a relapse of bipolar disorder after a switch from oral aripiprazole 10 mg/day to intramuscular aripiprazole depot 200 mg every 28 days plus oral aripiprazole 5 mg/day. The patient was concomitantly taking lopinavir, saquinavir, ritonavir, silybum marianum extract, and omeprazole. Only 1 week after the switch, the patient developed mood swings, irritability, depressive mood, and lack of drive. The oral aripiprazole was increased again to stabilize the patient...
December 2016: Drug Saf Case Rep
Chang Liu, Yanlan Huang, Joyce C Pressley
BACKGROUND: While driving impaired is a well-recognized risk factor for motor vehicle (MV) crash, recent trends in recreational drug use and abuse may pose increased threats to occupant safety. This study examines mechanisms through which drug and/or alcohol combinations contribute to fatal MV crash. METHODS: The Fatality Analysis Reporting System (FARS) for 2008-2013 was used to examine drugs, alcohol, driver restraint use, driver violations/errors and other behaviors of drivers of passenger vehicles who were tested for both alcohol and drugs (n = 79,932)...
December 2016: Injury Epidemiology
Zhentong Wei, Yan Liu, Yishu Wang, Yandong Zhang, Qinghua Luo, Xiaxia Man, Feng Wei, Xiaowei Yu
Ovarian cancer (OVCa) stem cells are associated with tumor growth, metastasis, and recurrence, which are driving forces behind a majority of the OVCa-related mortality. This subpopulation of cancer cells are characterized by uncontrolled proliferation, high invasiveness, and resistance against the current platinum-based therapy. Thus, targeting OVCa cancer stem cells has been focused in recent therapeutic development. Isolation and purification of cancer stem cells are, however, challenging for the lack of sensitive and specific markers...
November 2016: Medical Oncology
Natalie Weber, Kristin Schwanke, Stephan Greten, Meike Wendland, Bogdan Iorga, Martin Fischer, Cornelia Geers-Knörr, Jan Hegermann, Christoph Wrede, Jan Fiedler, Henning Kempf, Annika Franke, Birgit Piep, Angelika Pfanne, Thomas Thum, Ulrich Martin, Bernhard Brenner, Robert Zweigerdt, Theresia Kraft
Human pluripotent stem cell (hPSC)-derived cardiomyocytes hold great potential for in vitro modeling of diseases like cardiomyopathies. Yet, knowledge about expression and functional impact of sarcomeric protein isoforms like the myosin heavy chain (MyHC) in hPSC-cardiomyocytes is scarce. We hypothesized that ventricular β-MyHC expression alters contraction and calcium kinetics and drives morphological and electrophysiological differentiation towards ventricular-like cardiomyocytes. To address this, we (1) generated human embryonic stem cell-derived cardiomyocytes (hESC-CMs) that switched towards exclusive β-MyHC, and (2) functionally and morphologically characterized these hESC-CMs at the single-cell level...
November 2016: Basic Research in Cardiology
G André Ng
Antiarrhythmic drug therapy has seen significant challenges over the past 3 decades with unexpected results from clinical trials such as CAST, SWORD and more recently PALLAS showing harm in patients whom antiarrhythmic drugs were given based on their intended antiarrhythmic actions and previously demonstrated efficacy. These results question whether the precise mechanism of action of the drugs was understood and highlight the complexity of the situation where there is the combination of multiple actions of the antiarrhythmic drugs on various molecular systems, some of which may be unknown with associated adverse outcome, and their interaction with pre-existing abnormality in disease states in patients treated...
October 12, 2016: Pharmacology & Therapeutics
Gudrun Høiseth, Linn Engeset Austdal, Elisabeth Wiik, Stig Tore Bogstrand, Jørg Mørland
Objective Elderly drivers are somewhat more likely to be involved in car crashes than middle aged drivers, but less likely to be involved than the younger drivers. This study aimed to assess the extent of drug use in elderly suspected drunk and drugged drivers, with respect to which drugs were detected and at which concentrations. Methods Blood samples from elderly suspected drunk and drugged drivers from February 1(st) 2012 to May 22(th) 2013 were identified from the database at the Norwegian Institute of Public Health and were retrospectively analyzed for a broad repertoire of drugs relevant for impairment...
October 14, 2016: Traffic Injury Prevention
Panagiotis Angelikopoulos, Lev Sarkisov, Zoe Cournia, Paraskevi Gkeka
Ligand-functionalized nanoparticles (NPs) are a promising platform for imaging and drug delivery applications. A number of recent molecular simulation and theoretical studies explored how these NPs interact with model lipid membranes. However, interactions between ligand-coated NPs leading to possible cooperative effects and association have not been investigated. In this coarse-grained molecular dynamics study, we focus on a specific case of several anionic, ligand-coated NPs embedded in a lipid membrane. Several new effects are observed...
October 14, 2016: Nanoscale
C W Cheung, T Cw Chan, P P Chen, M C Chu, W Cm Chui, P T Ho, F Lam, S W Law, J Ly Lee, S Hs Wong, V Kc Wong
Opioids are increasingly used to control chronic non-cancer pain globally. International opioid guidelines have been issued in many different countries but a similar document is not generally available in Hong Kong. Chronic opioid therapy has a role in multidisciplinary management of chronic non-cancer pain despite insufficient evidence for its effectiveness and safety for long-term use. This document reviews the current literature to inform Hong Kong practitioners about the rational use of chronic opioid therapy in chronic non-cancer pain...
October 2016: Hong Kong Medical Journal, Xianggang Yi Xue za Zhi
Juliana Nichterwitz Scherer, Roberta Silvestrin, Felipe Ornell, Vinícius Roglio, Tanara Rosangela Vieira Sousa
BACKGROUND: Substance use disorders are associated with the increased risk of driving under the influence (DUI), but little is known about crack-cocaine and its relationship with road traffic crashes (RTC). METHOD: A multicenter sample of 765 crack-cocaine users was recruited in six Brazilian capitals in order to estimate the prevalence of DUI and RTC involvement. Legal, psychiatric, and drug-use aspects related with traffic safety were evaluated using the Addiction Severity Index - 6th version (ASI-6) and the Mini International Neuropsychiatric Interview...
October 1, 2016: Drug and Alcohol Dependence
Oliver Rawashdeh, Shannon J Clough, Randall L Hudson, Margarita L Dubocovich
The suprachiasmatic nucleus (SCN)-often referred to as the master circadian clock-is essential in generating physiologic rhythms and orchestrating synchrony among circadian clocks. This study tested the hypothesis that periodic motivation induced by rhythmically pairing 2 reinforcing stimuli [methamphetamine (METH) and running wheel (RW)] restores autonomous circadian activity in arrhythmic SCN-lesioned (SCNX) C3H/HeN mice. Sham-operated and SCNX mice were treated with either METH (1.2 mg/kg, i.p.) or vehicle in association, dissociation, or absence of an RW...
October 12, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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