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https://www.readbyqxmd.com/read/29346838/first-in-human-study-to-assess-safety-pharmacokinetics-and-pharmacodynamics-of-bms-962212-a-direct-reversible-small-molecule-factor-xia-inhibitor-in-non-japanese-and-japanese-healthy-subjects
#1
Vidya Perera, Joseph M Luettgen, Zhaoqing Wang, Charles E Frost, Cynthia Yones, Cesare Russo, John Lee, Yue Zhao, Frank P LaCreta, Xuewen Ma, Robert M Knabb, Dietmar Seiffert, Mary DeSouza, Pierre Mugnier, Brenda Cirincione, Takayo Ueno, Robert J A Frost
AIMS: To assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class Factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. METHODS: This was a randomized, placebo-controlled, double-blind, sequential, ascending dose study of 2 hour (Part A) and 5 day (Part B) intravenous (IV) infusions of BMS-962212. Part A used 4 doses (1.5, 4, 10, and 25 mg h-1 ) assigned to BMS-962212 or placebo in a 3:1 ratio per dose. Part B used 4 doses (1, 3, 9, and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese subjects (n = 4 active, n = 1 placebo) per dose...
January 18, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29346828/dynamic-posterior-stabilization-versus-posterior-lumbar-intervertebral-fusion-a-matched-cohort-study-based-on-the-spine-tango-registry
#2
Kathrin S Bieri, Kelly Goodwin, Emin Aghayev, Hans-Joachim Riesner, Ralph Greiner-Perth
PURPOSE:  The primary aim of dynamic stabilization is to stabilize the spine and preserve function without overstressing adjacent segments, which is a potential risk of fusion surgery. However, direct comparative analyses of the two approaches are still limited, and little is known about the association of patient-reported outcomes with these treatment options. OBJECTIVE:  To compare the clinical outcomes of dynamic posterior stabilization using the DSS Stabilization System (Paradigm Spine, LLC, New York, New York, United States) versus posterior lumbar intervertebral fusion (PLIF) based on data from a spine registry...
January 18, 2018: Journal of Neurological Surgery. Part A, Central European Neurosurgery
https://www.readbyqxmd.com/read/29346785/impulsivity-and-saliva-cortisol-in-patients-with-suicide-attempt-and-controls
#3
Ute Lewitzka, Michael Bauer, Bettina Ripke, Thomas Bronisch, Lydia Günther
OBJECTIVES: The objective of this study was to prove concepts in the characterization of suicidal patients and the possible usefulness of those markers to potentially identify patients with a higher risk for suicidality. METHODS: Patients with a recent suicide attempt were compared with patients suffering from depression, adjustment disorder, anxiety, or eating disorders without suicidality, healthy controls and remitted patients with a history of at least 1 suicide attempt (≥1 year)...
January 18, 2018: Neuropsychobiology
https://www.readbyqxmd.com/read/29346778/diverse-brain-myeloid-expression-profiles-reveal-distinct-microglial-activation-states-and-aspects-of-alzheimer-s-disease-not-evident-in-mouse-models
#4
Brad A Friedman, Karpagam Srinivasan, Gai Ayalon, William J Meilandt, Han Lin, Melanie A Huntley, Yi Cao, Seung-Hye Lee, Patrick C G Haddick, Hai Ngu, Zora Modrusan, Jessica L Larson, Joshua S Kaminker, Marcel P van der Brug, David V Hansen
Microglia, the CNS-resident immune cells, play important roles in disease, but the spectrum of their possible activation states is not well understood. We derived co-regulated gene modules from transcriptional profiles of CNS myeloid cells of diverse mouse models, including new tauopathy model datasets. Using these modules to interpret single-cell data from an Alzheimer's disease (AD) model, we identified microglial subsets-distinct from previously reported "disease-associated microglia"-expressing interferon-related or proliferation modules...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29346769/switching-on-depression-and-potentiation-in-the-cerebellum
#5
Andrew R Gallimore, Taegon Kim, Keiko Tanaka-Yamamoto, Erik De Schutter
Long-term depression (LTD) and long-term potentiation (LTP) in the cerebellum are important for motor learning. However, the signaling mechanisms controlling whether LTD or LTP is induced in response to synaptic stimulation remain obscure. Using a unified model of LTD and LTP at the cerebellar parallel fiber-Purkinje cell (PF-PC) synapse, we delineate the coordinated pre- and postsynaptic signaling that determines the direction of plasticity. We show that LTP is the default response to PF stimulation above a well-defined frequency threshold...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29346768/activation-of-ampk-regulated-crh-neurons-in-the-pvh-is-sufficient-and-necessary-to-induce-dietary-preference-for-carbohydrate-over-fat
#6
Shiki Okamoto, Tatsuya Sato, Michihiro Tateyama, Haruaki Kageyama, Yuko Maejima, Masanori Nakata, Satoshi Hirako, Takashi Matsuo, Sanda Kyaw, Tetsuya Shiuchi, Chitoku Toda, Udval Sedbazar, Kumiko Saito, Nur Farehan Asgar, Boyang Zhang, Shigefumi Yokota, Kenta Kobayashi, Fabienne Foufelle, Pascal Ferré, Masamitsu Nakazato, Hiroaki Masuzaki, Seiji Shioda, Toshihiko Yada, Barbara B Kahn, Yasuhiko Minokoshi
Food selection is essential for metabolic homeostasis and is influenced by nutritional state, food palatability, and social factors such as stress. However, the mechanism responsible for selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) remains unknown. Here, we show that activation of a subset of corticotropin-releasing hormone (CRH)-positive neurons in the rostral region of the paraventricular hypothalamus (PVH) induces selection of an HCD over an HFD in mice during refeeding after fasting, resulting in a rapid recovery from the change in ketone metabolism...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29346767/functional-principles-of-posterior-septal-inputs-to-the-medial-habenula
#7
Yo Otsu, Salvatore Lecca, Katarzyna Pietrajtis, Charly Vincent Rousseau, Païkan Marcaggi, Guillaume Pierre Dugué, Caroline Mailhes-Hamon, Manuel Mameli, Marco Alberto Diana
The medial habenula (MHb) is an epithalamic hub contributing to expression and extinction of aversive states by bridging forebrain areas and midbrain monoaminergic centers. Although contradictory information exists regarding their synaptic properties, the physiology of the excitatory inputs to the MHb from the posterior septum remains elusive. Here, combining optogenetics-based mapping with ex vivo and in vivo physiology, we examine the synaptic properties of posterior septal afferents to the MHb and how they influence behavior...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29346761/ino80-chromatin-remodeling-coordinates-metabolic-homeostasis-with-cell-division
#8
Graeme J Gowans, Alicia N Schep, Ka Man Wong, Devin A King, William J Greenleaf, Ashby J Morrison
Adaptive survival requires the coordination of nutrient availability with expenditure of cellular resources. For example, in nutrient-limited environments, 50% of all S. cerevisiae genes synchronize and exhibit periodic bursts of expression in coordination with respiration and cell division in the yeast metabolic cycle (YMC). Despite the importance of metabolic and proliferative synchrony, the majority of YMC regulators are currently unknown. Here, we demonstrate that the INO80 chromatin-remodeling complex is required to coordinate respiration and cell division with periodic gene expression...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29346759/nf-%C3%AE%C2%BAb-chromatin-interactions-drive-diverse-phenotypes-by-modulating-transcriptional-noise
#9
Victor C Wong, Victor L Bass, M Elise Bullock, Arvind K Chavali, Robin E C Lee, Walther Mothes, Suzanne Gaudet, Kathryn Miller-Jensen
Noisy gene expression generates diverse phenotypes, but little is known about mechanisms that modulate noise. Combining experiments and modeling, we studied how tumor necrosis factor (TNF) initiates noisy expression of latent HIV via the transcription factor nuclear factor κB (NF-κB) and how the HIV genomic integration site modulates noise to generate divergent (low-versus-high) phenotypes of viral activation. We show that TNF-induced transcriptional noise varies more than mean transcript number and that amplification of this noise explains low-versus-high viral activation...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29346735/mechanisms-of-modulation-of-calcium-phosphate-pathological-mineralization-by-mobile-and-immobile-small-molecule-inhibitors
#10
Meng Li, Jing Zhang, Lijun Wang, Baoshan Wang, Christine V Putnis
Potential pathways for inhibiting crystal growth are either via disrupting local microenvironments surrounding crystal-solution interfaces or physically blocking solute molecule attachment. However, the actual mode of inhibition may be more complicated due to the characteristic time scale for the inhibitor adsorption and relaxation to a well-bound state at crystal surfaces. Here we demonstrate the role of citrate (CA) and hydroxycitrate (HCA) in brushite (DCPD, CaHPO4·2H2O) crystallization over a broad range of both inhibitor concentrations and supersaturations by in situ atomic force microscopy (AFM)...
January 18, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29346722/layer-by-layer-epitaxial-growth-of-defect-engineered-strontium-cobaltites
#11
Tassie Andersen, Seyoung Cook, Gang Wan, Hawoong Hong, Laurence D Marks, Dillon D Fong
Control over structure and composition of (ABO3) perovskite oxides offers exciting opportunities since these materials possess unique, tunable properties. Perovskite oxides with cobalt B-site cations are particularly promising, as the range of the cation's stable oxidation states leads to many possible structural frameworks. Here, we report growth of strontium cobalt oxide thin films by molecular beam epitaxy, and conditions necessary to stabilize different defect concentration phases. In situ X-ray scattering is used to monitor structural evolution during growth, while in situ X-ray absorption near-edge spectroscopy is used to probe oxidation state and measure changes to oxygen vacancy concentration as a function of film thickness...
January 18, 2018: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29346699/teaching-chronic-pain-in-the-family-medicine-residency
#12
Kimberly Zoberi, Kelly M Everard
BACKGROUND AND OBJECTIVES: Chronic pain is a significant condition affecting many Americans. Primary care physicians play an important role in chronic pain management, but many residents and physicians feel poorly prepared to manage it. METHODS: Data were collected as part of the 2016 Council of Academic Family Medicine Educational Research Alliance (CERA) Program Director Survey, which was sent electronically to 484 program directors in the United States. The authors sought to determine whether residency directors' attitudes about treating chronic pain were associated with the amount of time devoted to teaching family medicine residents about chronic pain assessment, therapy (use of opioids, use adjuvant pain medications, use of other nonopioids, use of nonpharmacological treatments), and risk management (risk assessment, use of pain management contracts, informed consent when prescribing opioids, and urine drug monitoring)...
January 2018: Family Medicine
https://www.readbyqxmd.com/read/29346630/vitamin-d-toxicity-a-16-year-retrospective-study-at-an-academic-medical-center
#13
John P Lee, Michael Tansey, Jennifer G Jetton, Matthew D Krasowski
Background: Interest in vitamin D has increased during the past 2 decades, with a corresponding increase in laboratory testing of 25-hydroxyvitamin D [25(OH)D]. The vast majority of specimens tested display normal or deficient levels of 25(OH)D; concentrations rarely fall in the potentially toxic range. Methods: We performed a retrospective investigation of elevated 25(OH)D levels during a 16-year period at the University of Iowa Hospitals and Clinics (UIHC), a 734-bed tertiary-/quaternary-care academic medical center in the midwestern United States...
January 13, 2018: Laboratory Medicine
https://www.readbyqxmd.com/read/29346611/combined-roles-of-atp-and-small-hairpin-rna-in-the-activation-of-rig-i-revealed-by-solution-based-analysis
#14
Neelam Shah, Simone A Beckham, Jacqueline A Wilce, Matthew C J Wilce
RIG-I (retinoic acid inducible gene-I) is a cytosolic innate immune protein that senses viral dsRNA with a 5'-triphosphate overhang. Upon interaction with dsRNA a de-repression of the RIG-I CARD domains takes place that ultimately leads to the production of type I interferons and pro-inflammatory cytokines. Here we investigate the RIG-I conformational rearrangement upon interaction with an activating 5'-triphosphate-10-base pair dsRNA hairpin loop (10bp) compared with a less active 5'-triphosphate-8-base pair dsRNA hairpin loop (8bp)...
January 13, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29346606/characteristics-of-cases-with-repeated-sexually-transmitted-infections-massachusetts-2014-2016
#15
Katherine K Hsu, Lauren E Molotnikov, Kathleen A Roosevelt, Heather R Elder, R Monina Klevens, Alfred DeMaria, Sevgi O Aral
Background: Persons with prior sexually transmitted infections (STIs) are at high risk for re-infection. No recent studies have examined the frequency with which persons within a geographic area are diagnosed and reported with multiple bacterial STIs over time. Methods: We conducted a retrospective, population-based study of confirmed syphilis, gonorrhea, and chlamydial infections reported to the Massachusetts state surveillance system within a two-year period, July 28, 2014 - July 27, 2016...
January 13, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29346580/smoking-sex-and-non-small-cell-lung-cancer-steroid-hormone-receptors-in-tumor-tissue-s0424
#16
Ting-Yuan David Cheng, Amy K Darke, Mary W Redman, Gary R Zirpoli, Warren Davis, Rochelle Payne Ondracek, Wiam Bshara, Angela R Omilian, Robert Kratzke, Mary E Reid, Julian R Molina, Jill M Kolesar, Yuhchyau Chen, Robert M MacRae, James Moon, Philip Mack, David R Gandara, Karen Kelly, Regina M Santella, Kathy S Albain, Christine B Ambrosone
Background: To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking. Methods: Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-α, ER-β, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)...
January 13, 2018: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29346561/floricolin-c-elicits-intracellular-ros-accumulation-and-disrupts-mitochondria-to-exert-fungicidal-action
#17
Ming Zhang, Wenqiang Chang, Hongzhuo Shi, Ying Li, Sha Zheng, Wei Li, Hongxiang Lou
Candida albicans, one most prevalent fungal pathogen, causes severe mucosal and invasive infections in predisposed individuals. The rise of fungal infection and drug-resistance demands the development of novel antifungal agents. In this study, we observed that floricolin C (FC), a p-terphenyl pigment from an endolichenic fungus, killed C. albicans cells at planktonic state or within biofilms through reactive oxygen species (ROS) accumulation. Further test revealed that FC could directly damage the mitochondria to cause ROS accumulation...
January 15, 2018: FEMS Yeast Research
https://www.readbyqxmd.com/read/29346551/brazil-s-family-health-strategy-factors-associated-with-programme-uptake-and-coverage-expansion-over-15-years-1998-2012
#18
Monica Viegas Andrade, Augusto Quaresma Coelho, Mauro Xavier Neto, Lucas Resende de Carvalho, Rifat Atun, Marcia C Castro
Universal Health Coverage (UHC) is one of the United Nations Sustainable Development Goals (SDGs). Achieving UHC will require strong health systems to promote and deliver equitable and integrated healthcare services through primary healthcare (PHC). In Brazil, the Family Health Strategy (FHS) delivers PHC through the public health system. Created in 1994, the FHS covered almost 123 million individuals (63% of the Brazilian population) by 2015. The FHS has been associated with many health improvements, but gaps in coverage still remain...
January 15, 2018: Health Policy and Planning
https://www.readbyqxmd.com/read/29346533/density-of-emerald-ash-borer-coleoptera-buprestidae-adults-and-larvae-at-three-stages-of-the-invasion-wave
#19
Stephen J Burr, Deborah G McCullough, Therese M Poland
Emerald ash borer (EAB) (Agrilus planipennis Fairmaire) (Coleoptera: Buprestidae), an invasive phloem-feeding buprestid, has killed hundreds of millions of ash (Fraxinus spp.) trees in the United States and two Canadian provinces. We evaluated EAB persistence in post-invasion sites and compared EAB adult captures and larval densities in 24 forested sites across an east-west gradient in southern Michigan representing the Core (post-invasion), Crest (high EAB populations), and Cusp (recently infested areas) of the EAB invasion wave...
January 16, 2018: Environmental Entomology
https://www.readbyqxmd.com/read/29346515/a-brain-based-pain-facilitation-mechanism-contributes-to-painful-diabetic-polyneuropathy
#20
Andrew R Segerdahl, Andreas C Themistocleous, Dean Fido, David L Bennett, Irene Tracey
The descending pain modulatory system represents one of the oldest and most fundamentally important neurophysiological mechanisms relevant to pain. Extensive work in animals and humans has shown how a functional imbalance between the facilitatory and inhibitory components is linked to exacerbation and maintenance of persistent pain states. Forward translation of these findings into clinical populations is needed to verify the relevance of this imbalance. Diabetic polyneuropathy is one of the most common causes of chronic neuropathic pain; however, the reason why ∼25-30% of patients with diabetes develop pain is not known...
January 15, 2018: Brain: a Journal of Neurology
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