L-NAME treatment in pigs

Abstract only availableNω-nitro-L-arginine-methyl-ester (L-NAME) inhibits the enzyme nitric oxide synthase (NOS) which generates the physiologic messenger gas, nitric oxide (NO). In addition to its role as a vasodilator NO inhibits inflammation and vascular smooth muscle cell proliferation. It was shown recently that rats fed L-NAME contain evidence of inflammation and increased collagen in their coronary vasculature when compared with control rats. We hypothesized that L-NAME treatment will cause inflammation and an increase in collagen in the coronary vasculature of pigs compared with control pigs. To test this hypothesis we have four pigs, two received L-NAME in their drinking water and two did not. We have samples of the left ventricle (LV), right ventricle (RV), and left anterior descending (LAD), left circumflex (LCX), and right (RCA) coronary arteries of the heart. Similar to studies in the rat, we will stain these samples for monocyte chemoattractant protein-1 (MCP-1), a marker of inflammation; alpha smooth muscle actin (αSMA), a marker of vascular smooth muscle, and picrosirius red (PSR) a marker of collagen. We will photograph sections of the coronary vasculature stained with these markers and use a computer image analysis system to count the amount of MCP-1, vascular smooth muscle, and collagen. Preliminary results suggest that we have insufficient statistical power to show differences in the parameters measured and need to examined greater numbers of animals.Louis Stokes Missouri Alliance for Minority Participatio

The Necessary Evil: Balancing the risks and benefits of fluvoxamine in a patient with treatment refractory depression on warfarin:A Case Report

Warfarin, a commonly prescribed anticoagulant, has a narrow therapeutic index; and is metabolised by a number of cytochrome P-450 isoenzymes. Fluvoxamine is an effective antidepressant. It is a potent SSRI, with proven efficacy on obsessive-compulsive symptoms, anxiety, and psychotic depression. It is also a potent inhibitor of a number of cytochrome P-450 isoenzymes and has the potential to cause pharmacokinetic interactions with warfarin, resulting in elevated International Normalised Ratio (INR). We report a case of an elderly man, who was on warfarin for atrial fibrillation. He also suffered from severe and complex depressive episodes, with marked anxiety, and obsessive-compulsive symptoms which at times were impervious to reassurance and rational explanations. The depression responded inadequately to a number of trial of antidepressants, including a combination of antidepressants. Hence a decision was taken to commence Fluvoxamine. Co-administration resulted in the marked and rapid elevation of INR, necessitating adjustment in the dose of Warfarin. Although Fluvoxamine, by dint of its pharmacokinetic profile as a Selective Serotonin Reuptake Inhibitor (SSRI) has a high likelihood of interaction with Warfarin, there are very clinical few case-reports of such an interaction. Over the years, the use of Fluvoxamine in clinical practice has declined following the availability of other SSRIs that have less effect on the cytochrome enzyme system. However, in certain clinical situations where the use of Fluvoxamine is warranted, careful consideration of the drug interactions is highly recommended The case demonstrates the necessity of close monitoring when Fluvoxamine is co-administered with Warfarin, as the INR is elevated and the risk of haemorrhage increases even at small doses of Fluvoxamine. This close monitoring becomes even more relevant in the elderly because of prolonged half-life of Fluvoxamine in this population

Using mentoring to improve the foundation placement in psychiatry: review of literature and a practical example

In the past few years, mentoring in clinical settings has attracted the attention of medical educators, clinicians, managers, and policy makers. Most of the Royal Colleges of medical and surgical specialities have some form of mentoring schemes and various regional divisions of Health Education England support mentoring and coaching in the workplace. Despite the importance of this topic and the great need to provide more support to doctors in recent times, there is a paucity of literature on examples of mentoring schemes in clinical settings and practicalities of setting up such schemes in hospitals. This paper describes the implementation of a mentoring scheme in a large mental health trust in the UK to support junior doctors and the issues involved in creating such scheme. We hope that this article will be useful to clinicians who would like to start similar schemes in their workplace

Inactivation of anandamide signaling : A continuing Debate

Copyright 2011 Elsevier B.V., All rights reserved.Peer reviewedPublisher PD

Cellular Basis for Response Diversity in the Olfactory Periphery

An emerging idea in olfaction is that temporal coding of odor specificity can be intrinsic to the primary olfactory receptor neurons (ORNs). As a first step towards understanding whether lobster ORNs are capable of generating odor-specific temporal activity and what mechanisms underlie any such heterogeneity in discharge pattern, we characterized different patterns of activity in lobster ORNs individually and ensemble using patch-clamp recording and calcium imaging. We demonstrate that lobster ORNs show tonic excitation, tonic inhibition, phaso-tonic excitation, and bursting, and that these patterns are faithfully reflected in the calcium signal. We then demonstrate that the various dynamic patterns of response are inherent in the cells, and that this inherent heterogeneity is largely determined by heterogeneity in the underlying intrinsic conductances

Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties

From computational simulations of a serotonin 2A receptor (5-HT2AR) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT2AR, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization

The effects of Δ9-tetrahydrocannabinol on the dopamine system

Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, is a pressing concern to global mental health. Patterns of use are changing drastically due to legalisation, availability of synthetic analogues (‘spice’), cannavaping and aggrandizements in the purported therapeutic effects of cannabis. Many of THC’s reinforcing effects are mediated by the dopamine system. Due to complex cannabinoid-dopamine interactions there is conflicting evidence from human and animal research fields. Acute THC causes increased dopamine release and neuron activity, whilst long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of the drug

CNS targets of adipokines

This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this record.Our understanding of adipose tissue as an endocrine organ has been transformed over the last twenty years. During this time a number of adipocyte-derived factors or adipokines have been identified. This paper will review evidence for how adipokines acting via the central nervous system (CNS) regulate normal physiology and disease pathology. The reported CNS-mediated effects of adipokines are varied and include the regulation of energy homeostasis, autonomic nervous system activity, the reproductive axis, neurodevelopment, cardiovascular function, and cognition. Due to the wealth of information available and the diversity of their known functions, the archetypal adipokines leptin and adiponectin will be the focused on extensively. Other adipokines with established CNS actions will also be discussed. Due to the difficulties associated with studying CNS function on a molecular level in humans, the majority of our knowledge, and as such the studies described in this paper, comes from work in experimental animal models; however, where possible the relevant data from human studies are also highlighted

Deconvolution of complex G protein–coupled receptor signaling in live cells using dynamic mass redistribution measurements

Label-free biosensor technology based on dynamic mass redistribution (DMR) of cellular constituents promises to translate GPCR signaling into complex optical 'fingerprints' in real time in living cells. Here we present a strategy to map cellular mechanisms that define label-free responses, and we compare DMR technology with traditional second-messenger assays that are currently the state of the art in GPCR drug discovery. The holistic nature of DMR measurements enabled us to (i) probe GPCR functionality along all four G-protein signaling pathways, something presently beyond reach of most other assay platforms; (ii) dissect complex GPCR signaling patterns even in primary human cells with unprecedented accuracy; (iii) define heterotrimeric G proteins as triggers for the complex optical fingerprints; and (iv) disclose previously undetected features of GPCR behavior. Our results suggest that DMR technology will have a substantial impact on systems biology and systems pharmacology as well as for the discovery of drugs with novel mechanisms