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https://www.readbyqxmd.com/read/28530802/discovery-of-n-5-fluoropyridin-2-yl-6-methyl-4-pyrimidin-5-yloxy-picolinamide-vu0424238-a-novel-negative-allosteric-modulator-of-metabotropic-glutamate-receptor-subtype-5-selected-for-clinical-evaluation
#1
Andrew S Felts, Alice L Rodriguez, Anna L Blobaum, Ryan D Morrison, Brittney S Bates, Analisa Thompson Gray, Jerri M Rook, Mohammed N Tantawy, Frank W Byers, Sichen Chang, Daryl F Venable, Vincent B Luscombe, Gilles D Tamagnan, Colleen M Niswender, J Scott Daniels, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley, Kyle A Emmitte
Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28528268/optimistic-honesty-understanding-surgeon-and-patient-perspectives-on-hopeful-communication-in-pancreatic-cancer-care
#2
Kim Blakely, Paul J Karanicolas, Frances C Wright, Lesley Gotlib Conn
BACKGROUND: Prognosis conversations between surgical oncologists and patients with pancreatic cancer are critically important and challenging. Surgeons and their patients often have discrepant understandings of prognosis despite extensive conversations. Little is known about how surgeons approach prognosis conversations with these patients; patients' experiences with these conversations are also not well understood. This qualitative study sought to better understand surgeon and patient perspectives on communication in pancreatic cancer care with a view toward improvement...
May 17, 2017: HPB: the Official Journal of the International Hepato Pancreato Biliary Association
https://www.readbyqxmd.com/read/28525727/some-of-the-canmat-recommendations-for-the-pharmacological-treatment-of-late-life-depression-are-not-congruent-with-available-evidence-or-expert-opinion
#3
Daniel Blumberger, David Conn, John S Kennedy, Benoit H Mulsant, Bruce G Pollock, Kiran Rabheru, Mark J Rapoport, Dallas Seitz
No abstract text is available yet for this article.
May 2017: Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie
https://www.readbyqxmd.com/read/28522971/altered-functional-connectivity-of-the-basal-nucleus-of-meynert-in-mild-cognitive-impairment-a-resting-state-fmri-study
#4
Hui Li, Xiuqin Jia, Zhigang Qi, Xiang Fan, Tian Ma, Hong Ni, Chiang-Shan R Li, Kuncheng Li
Background: Cholinergic dysfunction plays an important role in mild cognitive impairment (MCI). The basal nucleus of Meynert (BNM) provides the main source of cortical cholinergic innervation. Previous studies have characterized structural changes of the cholinergic basal forebrain in individuals at risk of developing Alzheimer's disease (AD). However, whether and how functional connectivity of the BNM (BNM-FC) is altered in MCI remains unknown. Objective: The aim of this study was to identify alterations in BNM-FC in individuals with MCI as compared to healthy controls (HCs), and to examine the relationship between these alterations with neuropsychological measures in individuals with MCI...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28522253/challenges-in-the-development-of-an-m4-pam-preclinical-candidate-the-discovery-sar-and-in-vivo-characterization-of-a-series-of-3-aminoazetidine-derived-amides
#5
James C Tarr, Michael R Wood, Meredith J Noetzel, Jeanette L Bertron, Rebecca L Weiner, Alice L Rodriguez, Atin Lamsal, Frank W Byers, Sichen Chang, Hyekyung P Cho, Carrie K Jones, Colleen M Niswender, Michael W Wood, Nicholas J Brandon, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, Craig W Lindsley
This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0...
May 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28498785/laparoscopic-adrenalectomy-for-conn-s-syndrome-is-beneficial-to-patients-and-is-cost-effective-in-england
#6
Ioannis Christakis, John A Livesey, Gregory P Sadler, Radu Mihai
PURPOSE: Adrenalectomy has the potential to cure or improve the control of hypertension in patients with primary hyperaldosteronism due to unilateral adrenal adenoma (Conn's syndrome). This study assesses the patients' perception of, and costs associated with, laparoscopic adrenalectomy for Conn's syndrome. MATERIALS AND METHODS: Clinical, radiological, operative, and pathological data were collected on patients undergoing adrenalectomy for Conn's syndrome over 8-years period in a UK tertiary referral center...
May 12, 2017: Journal of Investigative Surgery: the Official Journal of the Academy of Surgical Research
https://www.readbyqxmd.com/read/28489923/differences-of-microparticle-patterns-between-sickle-cell-anemia-and-hemoglobin-sc-patients
#7
Yohann Garnier, Séverine Ferdinand, Maryse Etienne-Julan, Gisèle Elana, Marie Petras, Lydia Doumdo, Benoit Tressières, Marie-Laure Lalanne-Mistrih, Marie-Dominique Hardy-Dessources, Philippe Connes, Marc Romana
Sickle cell anemia (SCA) and hemoglobin SC (HbSC) disease are the two most common forms of sickle cell disease (SCD), a frequent hemoglobinopathy which exhibits a highly variable clinical course. Although high levels of microparticles (MPs) have been consistently reported in SCA and evidence of their harmful impact on the SCA complication occurrences have been provided, no data on MP pattern in HbSC patients has been reported so far. In this study, we determined and compared the MP patterns of 84 HbSC and 96 SCA children, all at steady-state, using flow cytometry...
2017: PloS One
https://www.readbyqxmd.com/read/28472649/allosteric-modulation-of-gpcrs-new-insights-and-potential-utility-for-treatment-of-schizophrenia-and-other-cns-disorders
#8
REVIEW
Daniel J Foster, P Jeffrey Conn
G-protein-coupled receptors (GPCRs) play critical roles in regulating brain function. Recent advances have greatly expanded our understanding of these receptors as complex signaling machines that can adopt numerous conformations and modulate multiple downstream signaling pathways. While agonists and antagonists have traditionally been pursued to target GPCRs, allosteric modulators provide several mechanistic advantages, including the ability to distinguish between closely related receptor subtypes. Recently, the discovery of allosteric ligands that confer bias and modulate some, but not all, of a given receptor's downstream signaling pathways can provide pharmacological modulation of brain circuitry with remarkable precision...
May 3, 2017: Neuron
https://www.readbyqxmd.com/read/28466542/association-between-oxidative-stress-and-vascular-reactivity-in-children-with-sickle-cell-anaemia-and-sickle-haemoglobin-c-disease
#9
Berenike Möckesch, Philippe Connes, Keyne Charlot, Sarah Skinner, Marie-Dominique Hardy-Dessources, Marc Romana, Stéphane Jumet, Marie Petras, Lydia Divialle-Doumdo, Cyril Martin, Benoît Tressières, Vanessa Tarer, Olivier Hue, Maryse Etienne-Julan, Sophie Antoine, Vincent Pialoux
Oxidative stress and haemolysis-associated nitric oxide (NO) depletion plays a crucial role in the development of vasculopathy in sickle cell anaemia (SS). However it remains unknown whether oxidative stress and haemolysis levels influence vascular function in patients with sickle haemoglobin C disease (SC). Microvascular response to heat (using Laser Doppler flowmetry on finger), oxidative stress biomarkers, NO metabolites, endothelin-1 and haematological parameters were compared between patients with SS and SC...
May 3, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28462687/don-t-rock-the-analytical-boat-correlation-is-not-causation
#10
Vicki S Conn
No abstract text is available yet for this article.
June 2017: Western Journal of Nursing Research
https://www.readbyqxmd.com/read/28448715/acyl-carrier-protein-cyanylation-delivers-a-ketoacyl-synthase-carrier-protein-cross-link
#11
Grace A R Thiele, Connie P Friedman, Kathleen J S Tsai, Joris Beld, Casey H Londergan, Louise K Charkoudian
Acyl carrier proteins (ACPs) are central hubs in polyketide and fatty acid biosynthetic pathways, but the fast motions of the ACP's phosphopantetheine (Ppant) arm make its conformational dynamics difficult to capture using traditional spectroscopic approaches. Here we report that converting the terminal thiol of Escherichia coli ACP's Ppant arm into a thiocyanate activates this site to form a selective cross-link with the active site cysteine of its partner ketoacyl synthase (FabF). The reaction releases a cyanide anion, which can be detected by infrared spectroscopy...
May 8, 2017: Biochemistry
https://www.readbyqxmd.com/read/28446243/targeting-metabotropic-glutamate-receptors-for-novel-treatments-of-schizophrenia
#12
REVIEW
James Maksymetz, Sean P Moran, P Jeffrey Conn
Support for the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has led to increasing focus on restoring proper glutamatergic signaling as an approach for treatment of this devastating disease. The ability of metabotropic glutamate (mGlu) receptors to modulate glutamatergic neurotransmission has thus attracted considerable attention for the development of novel antipsychotics. Consisting of eight subtypes classified into three groups based on sequence homology, signal transduction, and pharmacology, the mGlu receptors provide a wide range of targets to modulate NMDAR function as well as glutamate release...
April 26, 2017: Molecular Brain
https://www.readbyqxmd.com/read/28442253/optimization-of-m4-positive-allosteric-modulators-pams-the-discovery-of-vu0476406-a-non-human-primate-in-vivo-tool-compound-for-translational-pharmacology
#13
Bruce J Melancon, Michael R Wood, Meredith J Noetzel, Kellie D Nance, Eileen M Engelberg, Changho Han, Atin Lamsal, Sichen Chang, Hyekyung P Cho, Frank W Byers, Michael Bubser, Carrie K Jones, Colleen M Niswender, Michael W Wood, Darren W Engers, Dedong Wu, Nicholas J Brandon, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, Craig W Lindsley
This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties...
April 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28433046/-the-risks-of-retroperitoneoscopic-adrenalectomy
#14
P Zonča, M Peteja, P Vávra, V Richter, P Ostruszka
INTRODUCTION: Minimally invasive adrenalectomy has become the gold standard for surgery of the suprarenal gland. Retroperitoneoscopic adrenalectomy with dorsal approach is preferred. The aim of our case report is to discuss potential complications that may arise from retroperitoneoscopic adrenalectomy, specifically an intra-operative injury of the inferior vena cava. CASE REPORT: A 47-year-old male patient was admitted to undergo elective adrenalectomy on the right side...
2017: Rozhledy V Chirurgii: Měsíčník Československé Chirurgické Společnosti
https://www.readbyqxmd.com/read/28427812/synthesis-and-evaluation-of-4-6-disubstituted-pyrimidines-as-cns-penetrant-pan-muscarinic-antagonists-with-a-novel-chemotype
#15
Aaron M Bender, Rebecca L Weiner, Vincent B Luscombe, Hyekyung P Cho, Colleen M Niswender, Darren W Engers, Thomas M Bridges, P Jeffrey Conn, Craig W Lindsley
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M4 (IC50s<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma Kp,uu=0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CLp=5...
April 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28418376/a-circrna-from-sepallata3-regulates-splicing-of-its-cognate-mrna-through-r-loop-formation
#16
Vanessa M Conn, Véronique Hugouvieux, Aditya Nayak, Stephanie A Conos, Giovanna Capovilla, Gökhan Cildir, Agnès Jourdain, Vinay Tergaonkar, Markus Schmid, Chloe Zubieta, Simon J Conn
Circular RNAs (circRNAs) are a diverse and abundant class of hyper-stable, non-canonical RNAs that arise through a form of alternative splicing (AS) called back-splicing. These single-stranded, covalently-closed circRNA molecules have been identified in all eukaryotic kingdoms of life(1), yet their functions have remained elusive. Here, we report that circRNAs can be used as bona fide biomarkers of functional, exon-skipped AS variants in Arabidopsis, including in the homeotic MADS-box transcription factor family...
April 18, 2017: Nature Plants
https://www.readbyqxmd.com/read/28411485/cerebral-and-muscle-microvascular-oxygenation-in-children-with-sickle-cell-disease-influence-of-hematology-hemorheology-and-vasomotion
#17
Keyne Charlot, Sophie Antoine-Jonville, Berenike Moeckesch, Stéphane Jumet, Marc Romana, Xavier Waltz, Lydia Divialle-Doumdo, Marie-Dominique Hardy-Dessources, Marie Petras, Benoît Tressières, Vanessa Tarer, Olivier Hue, Maryse Etienne-Julan, Philippe Connes
The present study investigated cerebral and muscle hemoglobin oxygen saturation (tissue oxygen index, TOI) in children with sickle cell anemia (SS), sickle cell hemoglobin C disease (SC) and healthy children (AA). TOI was measured by near-infrared spectroscopy (NIRS) and spectral analysis of the TOI variability was used to assess flowmotion and vasomotion. Arterial oxyhemoglobin saturation (SpO2), hemorheological and hematological parameters were also measured in SS and SC children. Both TOI were lower in SS compared to both AA and SC children, with SC exhibiting lower values than AA children...
April 4, 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28405951/posterior-retroperitonoscopic-adrenalectomy-a-back-door-access-with-an-unusually-rapid-learning-curve
#18
Sohail Bakkar, Gabriele Materazzi, Lorenzo Fregoli, Piermarco Papini, Paolo Miccoli
Posterior retroperitonoscopic adrenalectomy (PRA) has become a standard approach to the adrenal gland. The aim of this study was to report an initial experience with the procedure following a proper preparatory phase highlighting the rapidity, safety and effectiveness by which it could be introduced into a surgeon's practice. Between May 2015 and July 2016, 14 PRAs were performed in 14 patients (9 females and 5 males). The average age was 46 years, BMI: 25.5 kg/m(2), and ASA score: 2. Indications included: incidenatloma (n = 5), Conn's adenoma (n = 5), and Cushing's adenoma (n = 4)...
April 12, 2017: Updates in Surgery
https://www.readbyqxmd.com/read/28377093/decompression-of-keratocystic-odontogenic-tumors-leading-to-increased-fibrosis-but-without-any-change-in-epithelial-proliferation
#19
Sarah Awni, Brendan Conn
OBJECTIVE: The aim of this study was to investigate whether decompression treatment induces changes in the histology or biologic behavior of keratocystic odontogenic tumor (KCOT). STUDY DESIGN: Seventeen patients with KCOT underwent decompression treatment with or without enucleation. Histologic evaluation and immunohistochemical expression of p53, Ki-67, and Bcl-2 were analyzed by using conventional microscopy. RESULTS: KCOT showed significantly increased fibrosis (P = ...
December 30, 2016: Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
https://www.readbyqxmd.com/read/28376441/peer-support-interventions-for-adults-with-diabetes-a-meta-analysis-of-hemoglobin-a1c-outcomes
#20
REVIEW
Sonal J Patil, Todd Ruppar, Richelle J Koopman, Erik J Lindbloom, Susan G Elliott, David R Mehr, Vicki S Conn
PURPOSE: Peer support intervention trials have shown varying effects on glycemic control. We aimed to estimate the effect of peer support interventions delivered by people affected by diabetes (those with the disease or a caregiver) on hemoglobin A1c (HbA1c) levels in adults. METHODS: We searched multiple databases from 1960 to November 2015, including Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, CINAHL, and Scopus. We included randomized controlled trials (RCTs) of adults with diabetes receiving peer support interventions compared with otherwise similar care...
November 2016: Annals of Family Medicine
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