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https://www.readbyqxmd.com/read/28427812/synthesis-and-evaluation-of-4-6-disubstituted-pyrimidines-as-cns-penetrant-pan-muscarinic-antagonists-with-a-novel-chemotype
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
https://www.readbyqxmd.com/read/28373229/the-intentional-brain-motion-emotion-and-the-development-of-modern-neuropsychiatry
#7
Rory Conn
No abstract text is available yet for this article.
April 2017: British Journal of Psychiatry: the Journal of Mental Science
https://www.readbyqxmd.com/read/28367732/how-to-craft-a-strong-discussion-section
#8
Vicki S Conn
No abstract text is available yet for this article.
May 2017: Western Journal of Nursing Research
https://www.readbyqxmd.com/read/28359434/anxiety-management-in-primary-care-implementing-the-national-institute-of-clinical-excellence-guidelines
#9
Monica K Conn, Sheree Shafer, Thomas Cline
More than 40 million Americans suffer from anxiety disorders, ranking them as one of the most common mental health disorders in America. The purpose of this pilot study was to educate providers on the National Institute Clinical Excellence (NICE) anxiety guidelines and monitor providers' perceived competence in managing anxiety. Results showed perceived competence increased significantly pre-intervention to immediately post-intervention (p=0.001), and data revealed the scores did not change significantly immediately post-to six-weeks post (p=0...
April 2017: Archives of Psychiatric Nursing
https://www.readbyqxmd.com/read/28347668/corrigendum-to-novel-glyt1-inhibitor-chemotypes-by-scaffold-hopping-part-2-development-of-a-3-3-0-based-series-and-other-piperidine-bioisosteres-bioorg-med-chem-lett-24-2014-1062-1066
#10
Douglas J Sheffler, Michael T Nedelcovych, Richard Williams, Stephen C Turner, Brittany B Duerk, Megan R Robbins, Sataya B Jadhav, Colleen M Niswender, Carrie K Jones, P Jeffrey Conn, R Nathan Daniels, Craig W Lindsley
No abstract text is available yet for this article.
May 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28346715/cabergoline-related-impulse-control-disorder-in-an-adolescent-with-a-giant-prolactinoma
#11
C Bulwer, R Conn, A Shankar, F Ferrau, S Kapur, A Ederies, M Korbonits, H A Spoudeas
Giant prolactinomas, rare in children, can have devastating endocrine, neurological and visual sequelae. Dopamine agonists (DA) are effective first-line therapy with few side-effects at doses usually used for prolactinoma treatment(1) , but higher-dose therapy for Parkinson's disease has well-recognized associations with impulse control disorders (ICD) including pathological gambling, impulsive eating, compulsive shopping and hypersexuality. Such associations are not well recognized with prolactinomas; to our knowledge this is the first reported case of hypersexuality in an adolescent receiving cabergoline for a giant prolactinoma...
March 27, 2017: Clinical Endocrinology
https://www.readbyqxmd.com/read/28346094/drug-library-screening-for-the-identification-of-ionophores-that-correct-the-mistrafficking-disorder-associated-with-oxalosis-kidney-disease
#12
Shurong Hou, Franck Madoux, Louis Scampavia, Jo Ann Janovick, P Michael Conn, Timothy P Spicer
Primary hyperoxaluria is the underlying cause of oxalosis and is a life-threatening autosomal recessive disease, for which treatment may require dialysis or dual liver-kidney transplantation. The most common primary hyperoxaluria type 1 (PH1) is caused by genetic mutations of a liver-specific enzyme alanine:glyoxylate aminotransferase (AGT), which results in the misrouting of AGT from the peroxisomes to the mitochondria. Pharmacoperones are small molecules with the ability to modify misfolded proteins and route them correctly within the cells, which may present an effective strategy to treat AGT misrouting in PH1 disorders...
January 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28340403/micro-and-macrovascular-function-in-children-with-sickle-cell-anaemia-and-sickle-cell-haemoglobin-c-disease
#13
Berenike Möckesch, Keyne Charlot, Stéphane Jumet, Marc Romana, Lydia Divialle-Doumdo, Marie-Dominique Hardy-Dessources, Marie Petras, Benoît Tressieres, Vanessa Tarer, Olivier Hue, Maryse Etienne-Julan, Philippe Connes, Sophie Antoine-Jonville
It is unclear whether vascular function is affected similarly in children with sickle cell anaemia (SS) and children with sickle haemoglobin C (SC) disease. Therefore, we compared micro and macrovascular functions in healthy (AA) children, children with SS and SC disease, and assessed their association with physical activity. Participants (24 SS, 22 SC and 16 AA), were compared in terms of 1) thermal hyperaemic response (finger pad warming to 42°C) measured by Laser Doppler techniques, 2) arterial stiffness determined by pulse wave velocity, 3) daily energy expenditure related to moderate and intense physical activities estimated by questionnaire and 4) fitness level, evaluated by the six-minute walk test...
February 4, 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28336323/m1-muscarinic-activation-induces-long-lasting-increase-in-intrinsic-excitability-of-striatal-projection-neurons
#14
Xiaohui Lv, Jonathan W Dickerson, Jerri M Rook, Craig W Lindsley, P Jeffrey Conn, Zixiu Xiang
The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M1) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability...
March 20, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28332881/an-individualized-approach-to-the-evaluation-and-management-of-primary-aldosteronism
#15
Anand Vaidya, Carl D Malchoff, Richard J Auchus
OBJECTIVE: With the increased emphasis on personalized and individualized medicine, the American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on personalized medicine as it applies to adrenal diseases. METHODS: Synthesis of literature review, guidelines from professional societies, and personal experience. RESULTS: Since Conn described primary aldosteronism (PA) over 60 years ago, debate has raged about the prevalence of PA in the hypertensive population, the wisdom of broadly screening for PA, and prudent approach to the evaluation and management of these patients...
March 23, 2017: Endocrine Practice
https://www.readbyqxmd.com/read/28315760/medication-adherence-outcomes-of-771-intervention-trials-systematic-review-and-meta-analysis
#16
REVIEW
Vicki S Conn, Todd M Ruppar
Excellent medication adherence contributes to decreases in morbidity, mortality, and health care costs. Although researchers have tested many interventions to increase adherence, results are sometimes conflicting and often unclear. This systematic review applied meta-analytic procedures to integrate primary research that tested medication adherence interventions. Comprehensive searching completed in 2015 located 771 published and unpublished intervention studies with adherence behavior outcomes. Random-effects model analysis calculated standardized mean difference effect sizes...
March 16, 2017: Preventive Medicine
https://www.readbyqxmd.com/read/28289026/substrate-recognition-and-modification-by-a-pathogen-associated-aminoglycoside-resistance-16s-rrna-methyltransferase
#17
Kellie Vinal, Graeme L Conn
The pathogen-associated 16S rRNA methyltransferase NpmA catalyzes m(1)A1408 modification to block the action of structurally diverse aminoglycoside antibiotics. Here we describe the development of a fluorescence polarization binding assay and its use, together with complementary functional assays, to dissect the mechanism of NpmA substrate recognition. These studies reveal that electrostatic interactions made by the NpmA β2/3 linker are collectively critical for docking of NpmA on a conserved 16S rRNA tertiary surface...
March 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28280815/lyotropic-liquid-crystal-engineering-moving-beyond-binary-compositional-space-ordered-nanostructured-amphiphile-self-assembly-materials-by-design
#18
REVIEW
Leonie van 't Hag, Sally L Gras, Charlotte E Conn, Calum J Drummond
Ordered amphiphile self-assembly materials with a tunable three-dimensional (3D) nanostructure are of fundamental interest, and crucial for progressing several biological and biomedical applications, including in meso membrane protein crystallization, as drug and medical contrast agent delivery vehicles, and as biosensors and biofuel cells. In binary systems consisting of an amphiphile and a solvent, the ability to tune the 3D cubic phase nanostructure, lipid bilayer properties and the lipid mesophase is limited...
March 10, 2017: Chemical Society Reviews
https://www.readbyqxmd.com/read/28276092/bone-microarchitecture-assessed-by-hr-pqct-as-predictor-of-fracture-risk-in-postmenopausal-women-the-ofely-study
#19
Elisabeth Sornay-Rendu, Stephanie Boutroy, François Duboeuf, Roland D Chapurlat
Several cross-sectional studies have shown that impairment of bone microarchitecture contributes to skeletal fragility. The aim of this study was to prospectively investigate the prediction of fracture (Fx) by bone microarchitecture assessed by high-resolution peripheral computed tomography (HR- pQCT) in postmenopausal women. We measured microarchitecture at the distal radius and tibia with HR-pQCT in the OFELY study, in addition to areal BMD with dual-energy X-ray absorptiometry (DXA) in 589 women, mean ± SD age 68 ± 9 years...
March 9, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28237763/continued-optimization-of-the-m5-nam-ml375-discovery-of-vu6008667-an-m5-nam-with-high-cns-penetration-and-a-desired-short-half-life-in-rat-for-addiction-studies
#20
Kevin M McGowan, Kellie D Nance, Hykeyung P Cho, Thomas M Bridges, P Jeffrey Conn, Carrie K Jones, Craig W Lindsley
This letter describes the continued optimization of M5 NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375has an excessively long elimination half-life in rat (t1/2=80h), which can be problematic in certain rodent addiction paradigms (e.g., reinstatement). Thus, we required an M5 NAM of comparable potency to ML375, but with a rat t1/2 of less than 4h. Steep SAR plagued this chemotype, and here we detail aniline replacements that offered some improvements over ML375, but failed to advance. Ultimately, incorporation of a single methyl group to the 9b-phenyl ring acted as a metabolic shunt, providing (S)-11 (VU6008667), an equipotent M5 NAM, with high CNS penetration, excellent selectivity versus M1-4 and the desired short half-life (t1/2=2...
March 15, 2017: Bioorganic & Medicinal Chemistry Letters
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