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  • 1
    Language: English
    In: British journal of clinical pharmacology, 2020-02, Vol.86 (2), p.338-351
    Description: Aims The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of secukinumab with different devices for subcutaneous (s.c.) administration of 2 mL. Methods A phase 1 study in healthy subjects with 6 devices to administer 2 mL injection volumes was conducted to evaluate the serum PK, safety and tolerability of secukinumab following single s.c. injection of 300 mg in the abdomen (either side) or in the thigh (either leg). Primary PK endpoints were maximum observed serum concentration and area under the serum concentration–time curve. The impact of device, site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 × 1‐mL prefilled syringe or 1 × 2‐mL prefilled syringe. Results Mean serum concentration–time profiles for administration as 2 × 1 mL injections or as 1 × 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 × 1 mL injections. A nonclinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a 1‐year phase 3 study in patients confirmed PK results observed in the phase 1 study. Conclusion Collective evidence from both studies demonstrated that 2‐mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characteristics and were all well tolerated without noticeable local reactions.
    Subject(s): injection device ; Original ; prefilled syringe ; psoriasis ; secukinumab ; subcutaneous administration ; therapeutic monoclonal antibody
    ISSN: 0306-5251
    E-ISSN: 1365-2125
    Source: Hellenic Academic Libraries Link
    Source: PubMed Central
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  • 2
    Language: English
    In: Nature materials, 2013-10, Vol.12 (10), p.919-924
    Description: The diminished surface-area-normalized catalytic activity of highly dispersed Pt nanoparticles compared with bulk Pt is particularly intricate, and not yet understood. Here we report on the oxygen reduction reaction (ORR) activity of well-defined, size-selected Pt nanoclusters; a unique approach that allows precise control of both the cluster size and coverage, independently. Our investigations reveal that size-selected Pt nanoclusters can reach extraordinarily high ORR activities, especially in terms of mass-normalized activity, if deposited at high coverage on a glassy carbon substrate. It is observed that the Pt cluster coverage, and hence the interparticle distance, decisively influence the observed catalytic activity and that closely packed assemblies of Pt clusters approach the surface activity of bulk Pt. Our results open up new strategies for the design of catalyst materials that circumvent the detrimental dispersion effect, and may eventually allow the full electrocatalytic potential of Pt nanoclusters to be realized.
    Subject(s): Catalytic activity ; Chemical engineering ; Clusters ; Deposition ; Dispersions ; Materials science ; Nanoparticles ; Nanostructure ; Oxygen ; Platinum ; Reduction ; Strategy
    ISSN: 1476-1122
    E-ISSN: 1476-4660
    Source: Academic Search Ultimate
    Source: Get It Now
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  • 3
    Language: English
    In: Science translational medicine, 2018-07-11, Vol.10 (449)
    Description: Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant ( = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.
    Subject(s): Aging ; Allosteric properties ; Antiviral agents ; Gene expression ; Geriatrics ; Immune response ; Immunosuppressive agents ; Influenza ; Life span ; Protein kinase ; Rapamycin ; TOR protein ; Vaccination
    ISSN: 1946-6234
    E-ISSN: 1946-6242
    Source: Science Magazine
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  • 4
    Language: English
    In: Journal of the American College of Cardiology, 2012, Vol.60 (18), p.1764-1775
    Description: This study sought to develop a novel approach to optimizing continuous-flow left ventricular assist device (CF-LVAD) function and diagnosing device malfunctions. In CF-LVAD patients, the dynamic interaction of device speed, left and right ventricular decompression, and valve function can be assessed during an echocardiography-monitored speed ramp test. We devised a unique ramp test protocol to be routinely used at the time of discharge for speed optimization and/or if device malfunction was suspected. The patient's left ventricular end-diastolic dimension, frequency of aortic valve opening, valvular insufficiency, blood pressure, and CF-LVAD parameters were recorded in increments of 400 rpm from 8,000 rpm to 12,000 rpm. The results of the speed designations were plotted, and linear function slopes for left ventricular end-diastolic dimension, pulsatility index, and power were calculated. Fifty-two ramp tests for 39 patients were prospectively collected and analyzed. Twenty-eight ramp tests were performed for speed optimization, and speed was changed in 17 (61%) with a mean absolute value adjustment of 424 ± 211 rpm. Seventeen patients had ramp tests performed for suspected device thrombosis, and 10 tests were suspicious for device thrombosis; these patients were then treated with intensified anticoagulation and/or device exchange/emergent transplantation. Device thrombosis was confirmed in 8 of 10 cases at the time of emergent device exchange or transplantation. All patients with device thrombosis, but none of the remaining patients had a left ventricular end-diastolic dimension slope 〉-0.16. Ramp tests facilitate optimal speed changes and device malfunction detection and may be used to monitor the effects of therapeutic interventions and need for surgical intervention in CF-LVAD patients.
    Subject(s): Abridged Index Medicus ; Aged ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Arterial Pressure ; Biological and medical sciences ; Blood Pressure ; Blood Pressure Determination ; Cardiology - methods ; Cardiology. Vascular system ; Cardiovascular system ; Cohort Studies ; Device thrombosis ; Echocardiography - methods ; Emergency and intensive cardiocirculatory care. Cardiogenic shock. Coronary intensive care ; Female ; Heart-Assist Devices - adverse effects ; Humans ; Intensive care medicine ; Investigative techniques, diagnostic techniques (general aspects) ; LVAD ; LVEDD ; Male ; Medical sciences ; Middle Aged ; Models, Statistical ; Prospective Studies ; Prosthesis Failure ; Ramp test ; Thrombosis - diagnosis ; Thrombosis - therapy ; Ultrasonic investigative techniques ; Ventricular Function, Left - physiology
    ISSN: 0735-1097
    E-ISSN: 1558-3597
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Sensors (Basel, Switzerland), 2020-11-19, Vol.20 (22), p.6614
    Description: Current personalized treatment of neurological diseases is limited by availability of appropriate manufacturing methods suitable for long term sensors for neural electrical activities in the brain. An additive manufacturing process for polymer-based biocompatible neural sensors for chronic application towards individualized implants is here presented. To process thermal crosslinking polymers, the developed extrusion process enables, in combination with an infrared (IR)-Laser, accelerated curing directly after passing the outlet of the nozzle. As a result, no additional curing steps are necessary during the build-up. Furthermore, the minimal structure size can be achieved using the laser and, in combination with the extrusion parameters, provide structural resolutions desired. Active implant components fabricated using biocompatible materials for both conductive pathways and insulating cladding keep their biocompatible properties even after the additive manufacturing process. In addition, first characterization of the electric properties in terms of impedance towards application in neural tissues are shown. The printing toolkit developed enables processing of low-viscous, flexible polymeric thermal curing materials for fabrication of individualized neural implants.
    Subject(s): Additive manufacturing ; Biocompatibility ; Biocompatible Materials ; Biomedical materials ; Carbon ; Crosslinking ; Curing ; ECoG ; Electrodes ; electrophysiology ; Extrusion ; Gold ; Graphene ; Humidity ; impedance ; Infrared lasers ; IR curing ; Laser sintering ; Lasers ; Mechanical properties ; Medical equipment ; medical grade silicone rubber ; medical rapid prototyping ; neural implant ; Neural prostheses ; Neurological diseases ; Nozzles ; Patients ; Polymers ; Printing, Three-Dimensional ; Production methods ; Prostheses and Implants ; Rapid prototyping ; Rubber ; Sensors ; Silicones ; Tensile strength ; Toolkits ; Viscosity
    E-ISSN: 1424-8220
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: Physical chemistry chemical physics : PCCP, 2017-01-04, Vol.19 (2), p.1466-1486
    Description: A comprehensive search for stable structures in the low coverage regime (0-1 ML) and at 2 ML and 3 ML using DFT revealed several new aggregation states of water on the non-polar ZnO(101[combining macron]0) surface. Ladder-like structures consisting of half-dissociated dimers, arranged side-by-side along the polar axis, constitute the most stable aggregate at low coverages (≤1 ML) with a binding energy exceeding that of the monolayer. At coverages beyond the monolayer - a regime that has hardly been studied previously - a novel type of structure with a continuous honeycomb-like 2D network of hydrogen bonds was discovered, where each surface oxygen atom is coordinated by additional H-bonding water molecules. This flat double-monolayer has a relatively high adsorption energy, every zinc and oxygen atom is 4-fold coordinated and every hydrogen atom is engaged in a hydrogen bond. Hence this honeycomb double monolayer offers no H-bond donor or acceptor sites for further growth of the water film. At 3 ML coverage, the interface restructures forming a contact layer of half-dissociated water dimers and a liquid-like overlayer of water attached by hydrogen bonds. The structures and their adsorption energies are analysed to understand the driving forces for aggregation and dissociation of water on the surface. We apply a decomposition scheme based on a Born-Haber cycle, discussing difficulties that may occur in applying such an analysis to the adsorption of dissociated molecules and point out alternatives to circumvent the bias against severely stretched bonds. Water aggregation on the ZnO surface is favoured by direct water-water interactions including H-bonds and dipole-dipole interactions and surface- or adsorption-mediated interactions including enhanced water-surface interactions and reduced relaxations of the water molecules and surface. While dissociation of isolated adsorbed molecules is unfavourable, partial or even full dissociation is preferred for aggregates. Nevertheless, direct water-water interactions change very little in the dissociation reaction. Dissociation is governed by a subtle balance between strongly enhanced water-surface interactions and the large energies required for the geometric changes of the water molecule(s) and the surface. Our conclusions are discussed on the background of the current knowledge on water adsorption at metals and non-metallic surfaces.
    Subject(s): Adsorption ; Agglomeration ; Energy of dissociation ; Hydrogen bonds ; Molecular structure ; Monolayers ; Surface chemistry ; Water chemistry
    ISSN: 1463-9076
    E-ISSN: 1463-9084
    Source: Get It Now
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  • 7
    Language: English
    In: Journal of neural engineering, 2018-10, Vol.15 (5), p.056006-056006
    Description: Objective. Optogenetic modulation of neural activity is a ubiquitous tool for basic investigation of brain circuits. While the majority of optogenetic paradigms rely on short light pulses to evoke synchronized activity of optically sensitized cells, many neurobiological processes are associated with slow local field potential (LFP) oscillations. Therefore, we developed a hybrid fiber probe capable of simultaneous electrophysiological recording and optical stimulation and used it to investigate the utility of sinusoidal light stimulation for evoking oscillatory neural activity in vivo across a broad frequency range. Approach. We fabricated hybrid fiber probes comprising a hollow cylindrical array of 9 electrodes and a flexible optical waveguide integrated within the core. We implanted these probes in the hippocampus of transgenic Thy1-ChR2-YFP mice that broadly express the blue-light sensitive cation channel channelrhodopsin 2 (ChR2) in excitatory neurons across the brain. The effects of the sinusoidal light stimulation were characterized and contrasted with those corresponding to pulsed stimulation in the frequency range of physiological LFP rhythms (3-128 Hz). Main results. Within hybrid probes, metal electrode surfaces were vertically aligned with the waveguide tip, which minimized optical stimulation artifacts in neurophysiological recordings. Sinusoidal stimulation resulted in reliable and coherent entrainment of LFP oscillations up to 70 Hz, the cutoff frequency of ChR2, with response amplitudes inversely scaling with the stimulation frequencies. Effectiveness of the stimulation was maintained for two months following implantation. Significance. Alternative stimulation patterns complementing existing pulsed protocols, in particular sinusoidal light stimulation, are a prerequisite for investigating the physiological mechanisms underlying brain rhythms. So far, studies applying sinusoidal stimulation in vivo were limited to single stimulation frequencies. We show the feasibility of sinusoidal stimulation in vivo to induce coherent LFP oscillations across the entire frequency spectrum supported by the gating dynamics of ChR2 and introduce a hybrid fiber probe tailored to continuous light stimulation.
    Subject(s): analog ; channelrhodopsin 2 ; hippocampus ; hybrid probe ; local field potential ; network ; network rhythms ; optical stimulation ; sinusoidal ; stimulation
    ISSN: 1741-2560
    E-ISSN: 1741-2552
    Source: IOPscience extra
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  • 8
    Language: English
    In: Scientific reports, 2015-05-18, Vol.5 (1), p.9669-9669
    Description: Due to the limited regenerative ability of neural tissue, a diverse set of biochemical and biophysical cues for increasing nerve growth has been investigated, including neurotrophic factors, topography, and electrical stimulation. In this report, we explore optogenetic control of neurite growth as a cell-specific alternative to electrical stimulation. By investigating a broad range of optical stimulation parameters on dorsal root ganglia (DRGs) expressing channelrhodopsin 2 (ChR2), we identified conditions that enhance neurite outgrowth by three-fold as compared to unstimulated or wild-type (WT) controls. Furthermore, optogenetic stimulation of ChR2 expressing DRGs induces directional outgrowth in WT DRGs co-cultured within a 10 mm vicinity of the optically sensitive ganglia. This observed enhancement and polarization of neurite growth was accompanied by an increased expression of neural growth and brain derived neurotrophic factors (NGF, BDNF). This work highlights the potential for implementing optogenetics to drive nerve growth in specific cell populations.
    Subject(s): Animals ; Axonogenesis ; Brain-derived neurotrophic factor ; Cell Culture Techniques ; Channelrhodopsins ; Coculture Techniques ; Dorsal root ganglia ; Electrical stimuli ; Ganglia ; Ganglia, Spinal - physiology ; Ganglia, Spinal - radiation effects ; Gene Expression ; Genes, Reporter ; Genetics ; Information processing ; Laboratories ; Light ; Mice ; Nerve growth factor ; Nerve Growth Factors - genetics ; Nerve Growth Factors - metabolism ; Nerve Regeneration ; Nervous system ; Neurites - physiology ; Neurogenesis ; Neurotrophic factors ; Optics ; Physical Stimulation ; Polarization ; Schwann Cells - physiology ; Schwann Cells - radiation effects ; Topography
    ISSN: 2045-2322
    E-ISSN: 2045-2322
    Source: Nature Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
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  • 9
    Language: English
    In: Journal of the American College of Cardiology, 2010, Vol.56 (15), p.1207-1213
    Description: Objectives The objective of the study was to determine the prevalence of bleeding during continuous-flow left ventricular assist device support and to identify potential mechanisms for those bleeding events. Background Bleeding is frequently reported with continuous-flow left ventricular assist devices and may result from anticoagulation coupled with bleeding diathesis such as acquired von Willebrand syndrome. Accordingly, the prevalence of coagulation abnormalities including laboratory assessment for von Willebrand syndrome, bleeding events during device support, and at heart transplantation were evaluated. Methods A retrospective study in all HeartMate II (HM II) (Thoratec Corp., Pleasanton, California) patients who underwent implantation between April 1, 2004, and August 1, 2009, was performed. Bleeding was defined as the need for transfusion 〉7 days after device insertion of 1 U of packed red blood cells. Transfusion at heart transplantation was compared with that in HeartMate XVE patients. Results Seventy-nine HM II devices were implanted. Anticoagulation included warfarin in 68.3%, aspirin in 55.7%, and dipyridamole in 58.2% of the patients. Of the patients, 44.3% had bleeding episodes at 112 ± 183 days after left ventricular assist device implantation, with 50% experiencing an event within 2 months. Gastrointestinal bleeding was the most frequent event. At the index event, the international normalized ratio averaged 1.67 ± 0.53, and the platelet count was 237 ± 119 × 109 /l. Comparison of the transfusion requirements at heart transplantation of 35 HM II patients with 62 HeartMate XVE patients demonstrated twice the transfusion requirements in HM II patients (packed red blood cells, 6.3 ± 0.8 U vs. 3.8 ± 0.5 U; platelets, 12.5 ± 5.4 U vs. 8.6 ± 6.4 U; fresh frozen plasma, 9.6 ± 4.9 U vs. 4.9 ± 3.6 U; and cryoprecipitate, 4.3 ± 3.6 U vs. 2.2 ± 3.5 U; p 〈 0.05 for all). High molecular weight von Willebrand factor multimers were measured in 31 HM II patients and were reduced in all patients; 18 of these 31 (58%) patients had bleeding. Conclusions Patients with the HM II had a high incidence of bleeding events during device support and at heart transplantation. All HM II patients had reduced high molecular weight von Willebrand factor multimers. The role of these abnormalities in the high incidence of bleeding deserves further investigation. Furthermore, alterations in anticoagulation should be considered during device support and before surgery in patients supported with the HM II.
    Subject(s): Abridged Index Medicus ; Adolescent ; Adult ; Age ; Aged ; Anticoagulants ; Biological and medical sciences ; bleeding ; Blood ; Blood platelets ; Blood transfusions ; Bridges ; Cardiology. Vascular system ; Cardiomyopathy ; Cardiovascular ; Chronic obstructive pulmonary disease ; Diabetes ; Drug therapy ; Female ; Follow-Up Studies ; Heart failure ; heart transplant ; Heart Transplantation - adverse effects ; Heart-Assist Devices - adverse effects ; Hemorrhage - epidemiology ; Hemorrhage - etiology ; Humans ; Hypertension ; Internal Medicine ; Intraoperative Complications - blood ; Intraoperative Complications - epidemiology ; Intraoperative Complications - etiology ; left ventricular assist devices ; Male ; Medical sciences ; Middle Aged ; Molecular weight ; Prevalence ; Prevalence studies (Epidemiology) ; Retrospective Studies ; Thoracic surgery ; Thrombosis ; Time Factors ; Treatment Outcome ; von Willebrand Diseases - epidemiology ; von Willebrand Diseases - etiology ; Von Willebrand factor ; von Willebrand syndrome ; Young Adult
    ISSN: 0735-1097
    E-ISSN: 1558-3597
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: ASAIO journal (1992), 2019-02, Vol.65 (2), p.101-103
    Subject(s): Blood Pressure ; Blood Pressure Monitors ; Engineering ; Engineering, Biomedical ; Heart Failure ; Heart-Assist Devices ; Humans ; Life Sciences & Biomedicine ; Science & Technology ; Technology ; Transplantation ; Ventricular Function, Left
    ISSN: 1058-2916
    E-ISSN: 1538-943X
    Source: Hellenic Academic Libraries Link
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
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