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Jamie W Sleigh, Susana Vacas, Alana M Flexman, Pekka O Talke
BACKGROUND: The depth of dexmedetomidine-induced sedation is difficult to assess without arousing the patient. We evaluated frontal electroencephalogram (EEG) as an objective measure of dexmedetomidine-induced sedation. Our aims were to characterize the response patterns of EEG during a wide range of dexmedetomidine-induced sedation and to determine which spectral power best correlated with assessed levels of dexmedetomidine-induced sedation. METHODS: Sedline EEG sensor was positioned on the forehead of 16 volunteers...
June 20, 2018: Anesthesia and Analgesia
Michael A van der Kooij, Ioannis Zalachoras, Carmen Sandi
Social dominance can be attained through social competitions. Recent work in both humans and rodents has identified trait anxiety as a crucial predictor of social competitiveness. In addition, the anxiolytic GABAA positive modulator, diazepam, injected either systemically or into the ventral tegmental area (VTA) was shown to increase social dominance. Here, we investigated the impact of pharmacologically targeting GABAA receptors in the VTA for the outcome of a social competition between two unfamiliar male rats, one of them infused with vehicle and the other one with the drug under study...
June 19, 2018: Neuropharmacology
Michael Ohene-Nyako, Amanda L Persons, T Celeste Napier
Methamphetamine abuse co-occurring with HIV infection presents neuropathology in brain regions that mediate reward and motivation. A neuronal signaling cascade altered acutely by meth and some HIV-1 proteins is the mitogen-activated protein kinase (MAPK) pathway. It remains unknown if chronic co-exposure to meth and HIV-1 proteins converge on MAPK in vivo. To make this determination, we studied young adult Fischer 344 HIV-1 transgenic (Tg) and non-Tg rats that self-administered meth (0.02-0.04 mg/kg/0.05 ml iv infusion, 2 h/day for 21 days) and their saline-yoked controls...
June 21, 2018: Brain Structure & Function
Jennifer L Knopp Nee Dickson, Adrienne M Lynn, Geoffrey M Shaw, J Geoffrey Chase
OBJECTIVE: Previous studies examine clinical outcomes of insulin therapy in neonatal intensive care units (NICUs), without first developing safe and effective control protocols. This research quantifies the safety and performance of a computerised model-based control algorithmSTAR-GRYPHON (Stochastic TARgeted Glucose Regulation sYstem to Prevent Hyper- and hypO-glycaemia in Neonates). DESIGN: Retrospective observational study of glycaemic control in very/extremely low birthweight infants treated with insulin from Christchurch Women's Hospital NICU between January 2013 and June 2017...
June 21, 2018: Archives of Disease in Childhood. Fetal and Neonatal Edition
Emanuela Ricciotti, Cecilia Castro, Soon Yew Tang, William T E Briggs, James A West, Dania Malik, Seth D Rhoades, Hu Meng, Xuanwen Li, Nicholas F Lahens, Jeffrey A Sparks, Elizabeth W Karlson, Aalim M Weljie, Julian L Griffin, Garret A FitzGerald
Background -Large scale, placebo controlled trials established that nonsteroidal anti-inflammatory drugs (NSAIDs) confer a cardiovascular hazard: this has been attributed to depression of cardioprotective products of cyclooxygenase (COX)-2, especially prostacyclin (PGI2 ). An alternative mechanism by which NSAIDs might constrain cardioprotection is by enhancing the formation of methylarginines in the kidney that would limit the action of nitric oxide (NO) throughout the vasculature. Methods -Targeted and untargeted metabolomics were employed to investigate the effect of COX-2 deletion or inhibition in mice and in osteoarthritis (OA) patients exposed to NSAIDs on the L-arginine/NO pathway...
June 21, 2018: Circulation
Sumathi Sivapalasingam, Mohamed Kamal, Rabih Slim, Romana Hosain, Weiping Shao, Randall Stoltz, Joseph Yen, Laura G Pologe, Yuan Cao, Michael Partridge, Giane Sumner, Leah Lipsich
BACKGROUND: REGN3470-3471-3479 is a co-formulated cocktail of three human monoclonal antibodies targeting three non-overlapping epitopes on Ebola virus. We investigated safety, tolerability, pharmacokinetics, and anti-drug antibodies in healthy adults. METHODS: This randomised, double-blind, placebo-controlled, dose-escalation study was done at a phase 1 unit in the USA. Healthy adults, aged 18-60 years, with a body-mass index of 18·0-30·0 kg/m2 were randomly assigned (3:1) to receive a single intravenous dose of REGN3470-3471-3479 or placebo on day 1 (baseline) in one of the four sequential ascending intravenous dose cohorts (3 mg/kg, 15 mg/kg, 60 mg/kg, and 150 mg/kg)...
June 18, 2018: Lancet Infectious Diseases
Soichi Hirashima, Akihiko Miyawaki, Kotaro Oho, Yawaka Shitozawa, Motohiro Arai, Norihiko Furuta, Ryoichi Oya
Peritoneal dialysis can be performed at home, and the transfer of solutes in the blood and other body fluids is slow compared to hemodialysis, reducing the load on the circulatory organs and lessening the frequency of hospital visits. We encountered a male patient in his 70s on peritoneal dialysis for end-stage renal failure who developed obsolete mandibular fracture-associated pseudarthrosis accompanied by osteomyelitis, which was treated with noninvasive reduction and fixation using circumferential wiring after the resolution of inflammation...
2018: Journal of UOEH
Masamichi Nogi, Kimio Satoh, Shinichiro Sunamura, Nobuhiro Kikuchi, Taijyu Satoh, Ryo Kurosawa, Junichi Omura, Md Elias Al-Mamun, Mohammad Abdul Hai Siddique, Kazuhiko Numano, Shun Kudo, Satoshi Miyata, Masatoshi Akiyama, Kiichiro Kumagai, Shunsuke Kawamoto, Yoshikatsu Saiki, Hiroaki Shimokawa
Background -Thoracic aortic aneurysm (TAA) and dissection (TAD) are fatal diseases, which cause aortic rupture and sudden death. The small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Previous studies revealed that reduced force generation in AoSMCs causes TAA and TAD. Methods -To examine the role of SmgGDS in TAA formation, we employed an angiotensin II (AngII, 1,000 ng/min/kg, 4 weeks)-induced TAA model. Results -33% Apoe-/- SmgGDS+/- mice died suddenly due to TAA rupture, whereas there was no TAA rupture in Apoe-/- control mice...
June 19, 2018: Circulation
Joseph Jankovic, Ira Goodman, Beth Safirstein, Tonya K Marmon, Dale B Schenk, Martin Koller, Wagner Zago, Daniel K Ness, Sue G Griffith, Michael Grundman, Jay Soto, Susanne Ostrowitzki, Frank G Boess, Meret Martin-Facklam, Joseph F Quinn, Stuart H Isaacson, Omid Omidvar, Aaron Ellenbogen, Gene G Kinney
Importance: Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression. Objective: To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD...
June 18, 2018: JAMA Neurology
Gemma D Banham, Shaun M Flint, Nicholas Torpey, Paul A Lyons, Don N Shanahan, Adele Gibson, Christopher J E Watson, Ann-Marie O'Sullivan, Joseph A Chadwick, Katie E Foster, Rachel B Jones, Luke R Devey, Anna Richards, Lars-Peter Erwig, Caroline O Savage, Kenneth G C Smith, Robert B Henderson, Menna R Clatworthy
BACKGROUND: B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients...
June 14, 2018: Lancet
Matthew Cardinal, Constantino Kantaridis, Tong Zhu, Pengling Sun, Debra D Pittman, John E Murphy, Steven Arkin
BACKGROUND: Tissue factor pathway inhibitor (TFPI) is a protease inhibitor of tissue factor-activated coagulation factor VII (TF-FVIIa) complex and activated factor X (FXa). PF-06741086 is a monoclonal antibody that targets TFPI to increase clotting activity. OBJECTIVES: This study was a randomized, double-blind, sponsor-open, placebo-controlled, single intravenous (IV) or subcutaneous (SC) dose escalation study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06741086...
June 16, 2018: Journal of Thrombosis and Haemostasis: JTH
Matthew A Weber, Eric T Graack, Jamie L Scholl, Kenneth J Renner, Gina L Forster, Michael J Watt
Adult psychiatric disorders characterized by cognitive deficits reliant on prefrontal cortex (PFC) dopamine are promoted by teenage bullying. Similarly, male Sprague-Dawley rats exposed to social defeat in mid-adolescence (P35-39) show impaired working memory in adulthood (P56-70), along with decreased medial PFC (mPFC) dopamine activity that results in part from increased dopamine transporter-mediated clearance. Here, we determined if dopamine synthesis and D2 autoreceptor-mediated inhibition of dopamine release in the adult mPFC are also enhanced by adolescent defeat to contribute to later dopamine hypofunction...
June 14, 2018: European Journal of Neuroscience
Yao Wang, Meixia Chen, Zhiqiang Wu, Chuan Tong, Hanren Dai, Yelei Guo, Yang Liu, Jianhua Huang, Haiyan Lv, Can Luo, Kai-Chao Feng, Qing-Ming Yang, Xiao-Lei Li, Weidong Han
Expressed by cancer stem cells of various epithelial cell origins, CD133 is an attractive therapeutic target for cancers. Autologous chimeric antigen receptor-modified T-cell directed CD133 (CART-133) was first tested in this trial. The anti-tumor specificity and the postulated toxicities of CART-133 were first assessed. Then, we conducted a phase I clinical study in which patients with advanced and CD133-positive tumors received CART-133 cell-infusion. We enrolled 23 patients (14 with hepatocellular carcinoma [HCC], 7 with pancreatic carcinomas, and 2 with colorectal carcinomas)...
2018: Oncoimmunology
Daniel H Moreno, Daniel G Cacione, Jose Cc Baptista-Silva
BACKGROUND: An abdominal aortic aneurysm (AAA) is the pathological enlargement of the aorta and can develop in both men and women. Progressive aneurysm enlargement can lead to rupture. The rupture of an AAA is frequently fatal and accounts for the death from haemorrhagic shock of at least 45 people per 100,000 population. The outcome of people with ruptured AAA varies among countries and healthcare systems, with mortality ranging from 53% to 90%. Definitive treatment for ruptured AAA includes open surgery or endovascular repair...
June 13, 2018: Cochrane Database of Systematic Reviews
Lee Tran, Katon A Kras, Nyssa Hoffman, Jayachandran Ravichandran, Jared M Dickinson, Andrew D'Lugos, Chad C Carroll, Shivam H Patel, Lawrence J Mandarino, Lori Roust, Christos S Katsanos
OBJECTIVE: Obesity alters protein metabolism in skeletal muscle, but consistent evidence is lacking. This study compared muscle protein synthesis in adults with obesity and in lean controls in the fasted state and during an amino acid infusion. METHODS: Ten subjects with obesity (age: 36 ± 3 years; BMI: 34 ± 1 kg/m2 ) and ten controls (age: 35 ± 3 years; BMI: 23 ± 1 kg/m2 ) received an infusion of L-[2,3,3,4,5,5,5,6,6,6-2 H10 ]leucine (0.15 μmol/kg fat-free mass/min) to measure muscle protein synthesis after an overnight fast and during amino acid infusion...
June 12, 2018: Obesity
Ryan M Jones, Lulu Deng, Kogee Leung, Dallan McMahon, Meaghan A O'Reilly, Kullervo Hynynen
Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening recently entered clinical testing for targeted drug delivery to the brain. Sources of variability exist in the current procedures, motivating the development of real-time monitoring and control techniques to improve treatment safety and efficacy. Here we used three-dimensional (3D) transcranial microbubble imaging to calibrate FUS exposure levels for volumetric BBB opening. Methods: Using a sparse hemispherical transmit/receive ultrasound phased array, pulsed ultrasound was focused transcranially into the thalamus of rabbits during microbubble infusion and multi-channel 3D beamforming was performed online with receiver signals captured at the subharmonic frequency...
2018: Theranostics
Christine J Kowalczewski, Justin M Saul
Bone fracture followed by delayed or non-union typically requires bone graft intervention. Autologous bone grafts remain the clinical "gold standard". Recently, synthetic bone grafts such as Medtronic's Infuse Bone Graft have opened the possibility to pharmacological and tissue engineering strategies to bone repair following fracture. This clinically-available strategy uses an absorbable collagen sponge as a carrier material for recombinant human bone morphogenetic protein 2 (rhBMP-2) and a similar strategy has been employed by Stryker with BMP-7, also known as osteogenic protein-1 (OP-1)...
2018: Frontiers in Pharmacology
Stefan Korsatko, Lene Jensen, Martina Brunner, Stefanie Sach-Friedl, Maja D Tarp, Anders G Holst, Simon R Heller, Thomas R Pieber
AIMS: To investigate effects of semaglutide versus placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes. METHODS: This double-blind, placebo-controlled, single-centre trial randomised 38 men and women (treated only with metformin) 1:1 to two 12-week crossover periods of once-weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose level 5...
June 12, 2018: Diabetes, Obesity & Metabolism
E J Powell, T A Reinhardt, E Casas, J D Lippolis
Neutrophils are the first-acting and most prominent cellular defense against mastitis-causing pathogens. This makes neutrophil activation and expansion obvious candidates for targeted therapeutics. The granulocyte colony-stimulating factor (G-CSF) cytokine stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream, which results in neutrophilia as well as increasing the presence of other progenitor cells in the bloodstream. A pegylated form of G-CSF (PEG-gCSF) has been shown to significantly decrease naturally occurring mastitis rates in cows postpartum...
June 6, 2018: Journal of Dairy Science
V Cuvier, U Lorch, S Witte, A Olivier, S Gibot, I Delor, J J Garaud, M Derive, M Magguilli-Salcedo
BACKGROUND: The peptide nangibotide is the first clinical-stage agent targeting the immunoreceptor TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) and is being investigated as a novel therapy for acute inflammatory disorders such as septic shock. AIMS: This first-in-man, randomised, double-blind, ascending dose, placebo-controlled Phase I study evaluated the safety, tolerability, and pharmacokinetics of nangibotide. METHODS: 27 healthy subjects (aged 18-45 years) were randomised into eight groups...
June 8, 2018: British Journal of Clinical Pharmacology
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