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Francisco J Martín-Sánchez, Michael Christ, Òscar Miró, W Frank Peacock, John J McMurray, Héctor Bueno, Alan S Maisel, Louise Cullen, Martin R Cowie, Salvatore Di Somma, Elke Platz, Josep Masip, Uwe Zeymer, Christiaan Vrints, Susanna Price, Christian Mueller
Acute heart failure (AHF) is a multi-organ dysfunction syndrome. In addition to known cardiac dysfunction, non-cardiac comorbidity, frailty and disability are independent risk factors of mortality, morbidity, cognitive and functional decline, and risk of institutionalization. Frailty, a treatable and potential reversible syndrome very common in older patients with AHF, increases the risk of disability and other adverse health outcomes. This position paper highlights the need to identify frailty in order to improve prognosis, the risk-benefits of invasive diagnostic and therapeutic procedures, and the definition of older-person-centered and integrated care plans...
November 1, 2016: International Journal of Cardiology
L R Amodeo, M S McMurray, J D Roitman
In a continuously changing environment, in which behavioral outcomes are rarely certain, animals must be able to learn to integrate feedback from their choices over time and adapt to changing reward contingencies to maintain flexible behavior. The orbitofrontal region of prefrontal cortex (OFC) has been widely implicated as playing a role in the ability to flexibly control behavior. We used a probabilistic reversal learning task to measure rats' behavioral flexibility and its neural basis in the activity of single neurons in OFC...
March 17, 2016: Neuroscience
Aris Polyzos, Amy Holt, Christopher Brown, Celica Cosme, Peter Wipf, Alex Gomez-Marin, Maríadel R Castro, Sylvette Ayala-Peña, Cynthia T McMurray
Oxidative damage to mitochondria (MT) is a major mechanism for aging and neurodegeneration. We have developed a novel synthetic antioxidant, XJB-5-131, which directly targets MT, the primary site and primary target of oxidative damage. XJB-5-131 prevents the onset of motor decline in an HdhQ(150/150) mouse model for Huntington's disease (HD) if treatment starts early. Here, we report that XJB-5-131 attenuates or reverses disease progression if treatment occurs after disease onset. In animals with well-developed pathology, XJB-5-131 promotes weight gain, prevents neuronal death, reduces oxidative damage in neurons, suppresses the decline of motor performance or improves it, and reduces a graying phenotype in treated HdhQ(150/150) animals relative to matched littermate controls...
May 1, 2016: Human Molecular Genetics
Aloke Sarkar, Kumudha Balakrishnan, Jefferson Chen, Viralkumar Patel, Sattva S Neelapu, John S McMurray, Varsha Gandhi
The resistance of apoptosis in cancer cells is pivotal for their survival and is typically ruled by mutations or dysregulation of core apoptotic cascade. Mantle cell lymphoma (MCL) is a non-Hodgkin's B-cell malignancy expressing higher anti-apoptotic proteins providing survival advantage. B-PAC-1, a procaspase activating compound, induces apoptosis by sequestering Zn bound to procaspase-3, but the amino acids holding Zn in Caspase-3 is not known. Here we show that reintroduction of WT caspase-3 or 7 in Caspase3-7 double knock-out (DKO) mouse embryonic fibroblasts (MEF) promoted B-PAC-1 to induce apoptosis (27-43%), but not in DKO MEFs or MEFs expressing respective Casp3-7 catalytic mutants (12-13%)...
January 19, 2016: Oncotarget
John M Knight, Garbo Mak, Joanne Shaw, Paul Porter, Catherine McDermott, Luz Roberts, Ran You, Xiaoyi Yuan, Valentine O Millien, Yuping Qian, Li-Zhen Song, Vincent Frazier, Choel Kim, Jeong Joo Kim, Richard A Bond, Joshua D Milner, Yuan Zhang, Pijus K Mandal, Amber Luong, Farrah Kheradmand, John S McMurray, David B Corry
Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice...
2015: PloS One
Tim Y Hou, Rola Barhoumi, Yang-Yi Fan, Gonzalo M Rivera, Rami N Hannoush, David N McMurray, Robert S Chapkin
The mechanisms by which n-3 polyunsaturated fatty acids (n-3 PUFA), abundant in fish oil, exert their anti-inflammatory effects have not been rigorously defined. We have previously demonstrated that n-3 PUFA decrease the amount of phosphatidylinositol-(4,5)-bisphosphate, [PI(4,5)P2], in CD4(+) T cells, leading to suppressed actin remodeling upon activation. Since discrete pools of PI(4,5)P2 exist in the plasma membrane, we determined whether n-3 PUFA modulate spatial organization of PI(4,5)P2 relative to raft and non-raft domains...
January 2016: Biochimica et Biophysica Acta
Cynthia T McMurray, Jan Vijg
This issue of Current Opinions focuses on the dual role of DNA in life and death. In ancient Roman religion and myth, Janus is the god who looks both to the past and to the future. He guides the beginnings of life, its progression from one condition to another, and he foresees distant events. The analogy to DNA could not be stronger. Closely interacting with the environment, our basic genetics provides the origin of life, guides the quality of health with age, predicts disease, and ultimately foresees our end...
June 2014: Current Opinion in Genetics & Development
Jennifer C Gardiner, Anthony J Kirkup, John Curry, Sian Humphreys, Paul O'Regan, Michael Postlethwaite, Kimberley C Young, Linda Kitching, Brian T Ethell, David Winpenny, Gordon McMurray
Patients with overactive bladder often exhibit abnormal bladder contractions in response to intravesical cold saline (positive ice-water test). The molecular entity involved in cold sensation within the urinary bladder is unknown, but a potential candidate is the ion channel, transient receptor potential (melastatin)-8 (TRPM8). The objective of the present study was to investigate the role of TRPM8 in a bladder-cooling reflex evoked in anaesthetised guinea-pigs that is comparable to the positive ice-water test seen in patients...
October 5, 2014: European Journal of Pharmacology
Michael McMurray
Multisubunit protein complexes are essential for cellular function. Genetic analysis of essential processes requires special tools, among which temperature-sensitive (Ts) mutants have historically been crucial. Many researchers assume that the effect of temperature on such mutants is to drive their proteolytic destruction. In fact, degradation-mediated elimination of mutant proteins likely explains only a fraction of the phenotypes associated with Ts mutants. Here I discuss insights gained from analysis of Ts mutants in oligomeric proteins, with particular focus on the study of septins, GTP-binding subunits of cytoskeletal filaments whose structures and functions are the subject of current investigation in my and many other labs...
September 2014: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
Matthew S McMurray, Leslie R Amodeo, Jamie D Roitman
Alcohol use is common in adolescence, with a large portion of intake occurring during episodes of binging. This pattern of alcohol consumption coincides with a critical period for neurocognitive development and may impact decision-making and reward processing. Prior studies have demonstrated alterations in adult decision-making following adolescent usage, but it remains to be seen if these alterations exist in adolescence, or are latent until adulthood. Here, using a translational model of voluntary binge alcohol consumption in adolescents, we assess the impact of alcohol intake on risk preference and behavioral flexibility during adolescence...
2014: PloS One
William B Hood, Antonio L Dans, Gordon H Guyatt, Roman Jaeschke, John J V McMurray
BACKGROUND: Digitalis glycosides have been in clinical use for the treatment of heart failure (HF) for longer than 200 years. In recent years, several trials have been conducted to address concerns about their efficacy and toxicity. OBJECTIVES: To examine the effectiveness of digitalis glycosides in treating HF in patients with normal sinus rhythm. To examine the effects of digitalis in patients taking diuretics and angiotensin-converting enzyme inhibitors; in patients with varying severity and duration of disease; in patients with prior exposure to digitalis versus no prior exposure; and in patients with "HF due to systolic dysfunction" versus "HF with preserved ejection fraction...
April 28, 2014: Cochrane Database of Systematic Reviews
Sarah A Nickolls, Sian Humphreys, Mellissa Clark, Gordon McMurray
Agonists at the µ-opioid receptor are known to produce potent analgesic responses in the clinical setting, therefore, an increased understanding of the molecular interactions of ligands at this receptor could lead to improved analgesics. As historically morphine has been shown to be a poor recruiter of β-arrestin in recombinant cell systems and this can be overcome by the co-expression of GRK2, we investigated the effects of GRK2 co-expression, in a recombinant µ-opioid receptor cell line, on ligand affinity and intrinsic activity in both β-arrestin recruitment and [(35)S]GTPγS binding assays...
2013: PloS One
R J McMurray, A K T Wann, C L Thompson, J T Connelly, M M Knight
The primary cilium regulates cellular signalling including influencing wnt sensitivity by sequestering β-catenin within the ciliary compartment. Topographic regulation of intracellular actin-myosin tension can control stem cell fate of which wnt is an important mediator. We hypothesized that topography influences mesenchymal stem cell (MSC) wnt signaling through the regulation of primary cilia structure and function. MSCs cultured on grooves expressed elongated primary cilia, through reduced actin organization...
2013: Scientific Reports
Faiez Zannad, Wendy Gattis Stough, Patrick Rossignol, Johann Bauersachs, John J V McMurray, Karl Swedberg, Allan D Struthers, Adriaan A Voors, Luis M Ruilope, George L Bakris, Christopher M O'Connor, Mihai Gheorghiade, Robert J Mentz, Alain Cohen-Solal, Aldo P Maggioni, Farzin Beygui, Gerasimos S Filippatos, Ziad A Massy, Atul Pathak, Ileana L Piña, Hani N Sabbah, Domenic A Sica, Luigi Tavazzi, Bertram Pitt
Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HF-REF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These clinical benefits are observed in addition to those of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. The morbidity and mortality benefits of MRAs may be mediated by several proposed actions, including antifibrotic mechanisms that slow heart failure progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis...
November 2012: European Heart Journal
Lindsay McMurray, Elizabeth M Beck, Matthew J Gaunt
No abstract text is available yet for this article.
September 10, 2012: Angewandte Chemie
Yvonne Mbaki, Jennifer Gardiner, Gordon McMurray, Andrew G Ramage
Central and peripheral 5-hydroxytryptamine (5-HT) receptors play a critical role in the regulation of micturition. Bolus doses of 5-HT(2A/2C) receptor agonists have been shown to activate the external urethral sphincter (EUS) and to inhibit micturition. This study was designed to determine the contribution of these two 5-HT receptor subtypes to activation of the EUS and inhibition of micturition utilising pharmacokinetic knowledge to better control drug exposure. Recordings of urethral and bladder pressure, EUS-Electromyogram (EMG), the micturition reflex induced by bladder filling, blood pressure and heart rate were made in anaesthetized female rats...
May 5, 2012: European Journal of Pharmacology
Tim Y Hou, Jennifer M Monk, Yang-Yi Fan, Rola Barhoumi, Yong Q Chen, Gonzalo M Rivera, David N McMurray, Robert S Chapkin
n-3 PUFA (polyunsaturated fatty acids), i.e. DHA (docosahexaenoic acid), found in fish oil, exhibit anti-inflammatory properties; however, the molecular mechanisms remain unclear. Since PtdIns(4,5)P2 resides in raft domains and DHA can alter the size of rafts, we hypothesized that PtdIns(4,5)P2 and downstream actin remodelling are perturbed by the incorporation of n-3 PUFA into membranes, resulting in suppressed T-cell activation. CD4+ T-cells isolated from Fat-1 transgenic mice (membranes enriched in n-3 PUFA) exhibited a 50% decrease in PtdIns(4,5)P2...
April 1, 2012: Biochemical Journal
Kelly Conlon, Wes Miner, Scott McCleary, Gordon McMurray
UNLABELLED: Preclinically, studies investigating urethral function have shown that the clinical benefit of agents such as duloxetine may partly reflect increases in urethral striated muscle activity via a central mode of action. Duloxetine has been shown to inhibit the presynaptic reuptake of 5-HT and norepinephrine in Onuf's nucleus, leading to an increased activity of pudendal motor neurones and a subsequent increase in the strength of urethral sphincter contractions. Preclinical studies have postulated a role for both 5-HT(2C) receptors and 5-HT(2A) receptors in external urethral sphincter (EUS) function, with differences between species that may reflect the differing physiological roles of the EUS in different preclinical species...
July 2012: BJU International
Ashwin S Dharmadhikari, Randall J Basaraba, Martie L Van Der Walt, Karin Weyer, Matsie Mphahlele, Kobus Venter, Paul A Jensen, Melvin W First, Sydney Parsons, David N McMurray, Ian M Orme, Edward A Nardell
A natural TB infection model using guinea pigs may provide useful information for investigating differences in transmission efficiency and establishment of active disease by clinical TB strains in a highly susceptible host under controlled environmental conditions. We sought to examine the capacity of naturally transmitted multidrug-resistant Mycobacterium tuberculosis to establish infection and produce active disease in guinea pigs. Guinea pigs were continuously exposed for 4 months to the exhaust air of a 6-bed multidrug-resistant tuberculosis inpatient hospital ward in South Africa...
July 2011: Tuberculosis
Amminikutty Jeevan, Teizo Yoshimura, Lan H Ly, Vijaya R Dirisala, David N McMurray
Interleukin-4 (IL-4), a pleiotropic cytokine produced by T-helper type 2 (Th2) cells, is involved in promoting humoral immune responses, allergic reactions and asthma. Previous studies suggested an important role for IL-4 in susceptibility to pulmonary tuberculosis; however, the role of IL-4 has not been studied in the guinea pig, a highly relevant model for this disease. In the present study, we cloned a cDNA for guinea pig IL-4 and examined, for the first time, mRNA expression by real-time RT-PCR in cultured guinea pig cells...
January 2011: Tuberculosis
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