Controlled release ibuprofen-poloxamer gel for epidural use - A pharmacokinetic study using microdialysis in pigs

In order to avoid the risks of sideeffects of epidural local anesthetics and opioids, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) epidurally would be an interesting option of analgesic therapy. The fairly short duration of action of spinally administered NSAIDs, e.g., ibuprofen, may be prolonged by using controlled release poloxamer gel formulation. Using a microdialysis technique we studied the epidural and intrathecal pharmacokinetics of ibuprofen after its epidural administration as a poloxamer 407 formulation or a solution formulation. In addition, plasma ibuprofen concentrations were analyzed from central venous blood samples. Ibuprofen concentrations in the epidural space were significantly higher and longer lasting after the epidural gel injection compared with the epidural solution injection. The epidural AUC of ibuprofen was over threefold greater after epidural ibuprofen gel injection compared with the ibuprofen solution injection (p <0.001). The systemic absorption of ibuprofen from 25% poloxamer 407 gel was very low. The in situ forming poloxamer gel acted as a reservoir allowing targeted ibuprofen release at the epidural injection site and restricted ibuprofen molecules to a smaller spinal area. Ibuprofen diffusion from the epidural space to the intrathecal space was steady and prolonged. These results demonstrate that the use of epidurally injectable poloxamer gel can increase and prolong ibuprofen delivery from epidural space to the CSF enhancing thus ibuprofen entry into the central neuroaxis for spinal analgesia. Further toxicological and dose-finding studies are justified. (C) 2016 Elsevier B.V. All rights reserved.Peer reviewe

Biological Functions of the Genes in the Mammaprint Breast Cancer Profile Reflect the Hallmarks of Cancer

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Характеристика экономических отношений на финансовом рынке Украины

Розглянуто проблеми, особливості функціонування та взаємодії учасників фінансового ринку України. Обґрунтовано наявність внутрішніх фінансових джерел формування ресурсного потенціалу вітчизняних банків, доведено їх пріоритетність для країни порівняно із зовнішніми джерелами. Окреслено причини, що зумовлюють дефіцит ресурсного потенціалу в банківській системі України. Ключові слова: заощадження, нагромадження, банки, економічне зростання, посередники, фінансовий ринок, ресурси, трансформація, інвестиційний потенціал.Рассмотрены проблемы, особенности функционирования и взаимодействия участников финансового рынка Украины. Обосновано наличие внутренних финансовых источников формирования ресурсного потенциала отечественных банков, доказана их приоритетность для страны по сравнению с внешними источниками. Очерчены причины, которые предопределяют дефицит ресурсного потенциала в банковской системе Украины. Ключевые слова: сбережения, накопления, банки, экономический рост, посредники, финансовый рынок, ресурсы, трансформация, инвестиционный потенциал.The present paper examines topical problems related to the specific aspects of economic relations in the financial market of Ukraine. The relevance and selection of the theme stem from the fact that financial market as a specific organization form of cash flows takes a leading place in the economic mechanism of market economy. Agents of this market are engaged in a whole range of complex economic relations which in their turn play a key role in securing a dynamic and sustainable economic growth of a country. Development of the financial market and creation of adequate flexible and adaptive economic relations between its players are critical for Ukraine. This is explained by specific aspects of the economic system formation and reforming, which are related to undergoing an intersystem transformation stage. The indicated circumstances predetermined the goal and objectives of the study pursued, which come to examination of economic relations in the financial market of Ukraine, identification of the interaction specificity of various financial intermediaries in the accumulation process of idle cash and its transformation into the investment capital of national economy. Based on the results of the analysis conducted, it is established that unlike countries with developed financial systems, where the majority of institutional participants of the capital market are proportionally developed, it is the banking sector that dominates in Ukraine and has a determinant role in financing the economic development of the state. The availability of domestic financial resources for forming the resource potential of banks is substantiated, and their priority versus external resources for Ukraine is proved. The comparison of gross savings and gross capital formation allowed identifying certain problems as to transformation of the former into investment resources in Ukraine. The paper outlines some causes of a poor resource potential of national banking institutions. Keywords: savings, accumulation, banks, economic growth, intermediaries, financial market, resources, transformation, investment potential

Identification of F-box only protein 7 as a negative regulator of NF-kappaB signalling.

The nuclear factor κB (NF-κB) signalling pathway controls important cellular events such as cell proliferation, differentiation, apoptosis and immune responses. Pathway activation occurs rapidly upon TNFα stimulation and is highly dependent on ubiquitination events. Using cytoplasmic to nuclear translocation of the NF-κB transcription factor family member p65 as a read-out, we screened a synthetic siRNA library targeting enzymes involved in ubiquitin conjugation and de-conjugation for modifiers of regulatory ubiquitination events in NF-κB signalling. We identified F-box protein only 7 (FBXO7), a component of Skp, Cullin, F-box (SCF)-ubiquitin ligase complexes, as a negative regulator of NF-κB signalling. F-box protein only 7 binds to, and mediates ubiquitin conjugation to cIAP1 and TRAF2, resulting in decreased RIP1 ubiquitination and lowered NF-κB signalling activity

Organic electrochemical transistor incorporating an ionogel as solid state electolyte for lactate sensing

The bulk of currently available biosensing techniques often require complex liquid handling, and thus suffer from problems associated with leaking and contamination. We demonstrate the use 10 of an Organic Electrochemical Transistor (OECT) for detection of lactate (an essential analyte in physiological measurements of athlete performance) by integration of a RTIL in a gel-format, as a solid-state electrolyte

Effect of epinephrine on lidocaine clearance in vivo: a microdialysis study in humans.

Background: Local anesthetic nerve block prolonged by epinephrine is thought to result from local vasoconstriction and consequent decreased local anesthetic clearance from the injection site. However, no study has yet confirmed this directly in humans by measuring tissue concentrations of local anesthetic over time. In addition, recent studies have shown that the ␣ 2 -adrenergic receptor agonist, clonidine, also prolongs nerve block without altering local anesthetic clearance. Because epinephrine is also an ␣ 2 -adrenergic receptor agonist, it is possible that epinephrine prolongs local anesthetic block by a pharmacodynamic mechanism and not a pharmacokinetic one. This study was designed to address this issue. Methods: Microdialysis probes were placed adjacent to the superficial peroneal nerve in both feet of eight volunteers. Plain lidocaine (1%) was injected along one peroneal nerve and lidocaine with epinephrine (2.5 g/ml) was injected along the other nerve in a double-blinded, randomized manner. The concentration of lidocaine in tissue was measured at 5-min intervals, and sensory block and cutaneous blood flow were assessed by laser Doppler at 10-min intervals for 5 h. The resulting data for lidocaine concentration versus time were fit to a two-compartment model using modeling software. Results: Epinephrine prolonged sensory block by decreasing local blood flow and slowing clearance. There was no evidence of a pharmacodynamic effect of epinephrine. Conclusion: Although epinephrine activates ␣ 2 -adrenergic receptors, its mechanism for prolonging the duration of local anesthetic block rests on its ability to decrease local anes

Direct detection of extended-spectrum beta-lactamases (CTX-M) from blood cultures by LC-MS/MS bottom-up proteomics

Rapid bacterial species identification and antibiotic susceptibility testing in positive blood cultures have an important impact on the antibiotic treatment for patients. To identify extended-spectrum beta-lactamases (ESBL) directly in positive blood culture bottles, we developed a workflow of saponin extraction followed by a bottom-up proteomics approach using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The workflow was applied to positive blood cultures with Escherichia coli and Klebsiella pneumoniae collected prospectively in two academic hospitals over a 4-month period. Of 170 positive blood cultures, 22 (12.9%) contained ESBL-positive isolates based on standard susceptibility testing. Proteomic analysis identified CTX-M ESBLs in 95% of these isolates directly in positive blood cultures, whereas no false positives were found in the non-ESBL producing positive blood cultures. The results were confirmed by molecular characterisation of beta-lactamase genes. Based on this proof-of-concept study, we conclude that LC-MS/MS-based protein analysis can directly identify extended-spectrum beta lactamases in E. coli and K. pneumoniae positive blood cultures, and could be further developed for application in routine diagnostics

Zelfevaluatie:Programma Thematische wetsevaluatie: opbrengsten en gebruik

Thematisch evalueren van wetten heeft duidelijk meerwaarde maar kent ook valkuilen. Dat blijkt uit het rapport ‘Zelfevaluatie programma Thematische Wetsevaluatie: opbrengsten en gebruik’. In 2015 ontvingen Pro Facto en het WODC van ZonMw de opdracht om het programma Thematische Wetsevaluaties te evalueren. Inmiddels zijn er in het programma 4 thematische wetsevaluaties uitgevoerd: Wilsonbekwaamheid en vertegenwoordiging, Zelfbeschikking, Toezicht en Gedwongen zorg. Systeem van wettelijke regelingen centraal In dit type evaluatie staat niet één wet maar het systeem van wettelijke regelingen rond een zorgthema centraal. Deze overstijgende juridisch-empirische benadering is binnen Nederland maar ook internationaal vernieuwend te noemen. Uitkomsten Uiteraard zijn er onderlinge verschillen tussen de 4 Thematische Wetsevaluaties. Gemeenschappelijke kenmerken zijn: In alle 4 gevallen was sprake van een robuust totstandkomingsproces, mede toe te schrijven aan de vaste selectie- en begeleidingsprocedures van ZonMw. Het ging om 4 adequate evaluaties in termen van aanpak en rapportage; stroomlijning van de (vele) aanbevelingen is echter een aandachtspunt. De bruikbaarheid van de Thematische Wetsevaluaties is bevorderd door valorisatie en verspreiding via secundaire publicaties en presentaties – relevant voor wetenschap en praktijk en ook zeker voor beleidsmakers. Een stimulerende factor in het gebruik van Thematische Wetsevaluaties is de betrokkenheid van en interactie met de potentiële gebruikers, direct vanaf het begin. Voorwaarde voor het opnemen van thematische inzichten in wetgeving en beleid is wel, dat politiek en ambtelijke organisaties daar welwillend tegenover staan. ZonMw kan de bruikbaarheid van de thematische wetsevaluaties (verder) bevorderen, door: Het evaluatieonderzoek een goed afgebakende focus mee te geven. De trajecten goed te timen in relatie tot de (door)ontwikkeling van beleid en wetgeving. Conclusie De eindconclusie is dat het thematisch evalueren van wetgeving duidelijk meerwaarde heeft, maar ook valkuilen kent. Door wetgeving met elkaar in verband te brengen komen lacunes en tegenstrijdigheden eerder aan het licht. Bovendien kan dan de weg naar wetsystematische verbetering worden ingeslagen. Voor de ‘ontvangende’ departementen is daarvoor wel een voorwaarde dat ook daar meer thematisch en minder verkaveld wordt gedacht

All-plastic electrochemical transistor for glucose sensing using a ferrocene mediator.

We demonstrate a glucose sensor based on an organic electrochemical transistor (OECT) in which the channel, source, drain, and gate electrodes are made from the conducting polymer poly(3,4-ethylenedioxythiophene) doped with poly(styrene sulfonate) (PEDOT:PSS). The OECT employs a ferrocene mediator to shuttle electrons between the enzyme glucose oxidase and a PEDOT:PSS gate electrode. The device can be fabricated using a one-layer patterning process and offers glucose detection down to the micromolar range, consistent with levels present in human saliva

Skeletal Muscle Fiber Adaptations Following Resistance Training Using Repetition Maximums or Relative Intensity

The purpose of the study was to compare the physiological responses of skeletal muscle to a resistance training (RT) program using repetition maximum (RM) or relative intensity (RISR). Fifteen well-trained males underwent RT 3 d·wk−1 for 10 weeks in either an RM group (n = 8) or RISR group (n = 7). The RM group achieved a relative maximum each day, while the RISR group trained based on percentages. The RM group exercised until muscular failure on each exercise, while the RISR group did not reach muscular failure throughout the intervention. Percutaneous needle biopsies of the vastus lateralis were obtained pre-post the training intervention, along with ultrasonography measures. Dependent variables were: Fiber type-specific cross-sectional area (CSA); anatomical CSA (ACSA); muscle thickness (MT); mammalian target of rapamycin (mTOR); adenosine monophosphate protein kinase (AMPK); and myosin heavy chains (MHC) specific for type I (MHC1), type IIA (MHC2A), and type IIX (MHC2X). Mixed-design analysis of variance and effect size using Hedge’s g were used to assess within- and between-group alterations. RISR statistically increased type I CSA (p = 0.018, g = 0.56), type II CSA (p = 0.012, g = 0.81), ACSA (p = 0.002, g = 0.53), and MT (p \u3c 0.001, g = 1.47). RISR also yielded a significant mTOR reduction (p = 0.031, g = −1.40). Conversely, RM statistically increased only MT (p = 0.003, g = 0.80). Between-group effect sizes supported RISR for type I CSA (g = 0.48), type II CSA (g = 0.50), ACSA (g = 1.03), MT (g = 0.72), MHC2X (g = 0.31), MHC2A (g = 0.87), and MHC1 (g = 0.59); with all other effects being of trivial magnitude (g \u3c 0.20). Our results demonstrated greater adaptations in fiber size, whole-muscle size, and several key contractile proteins when using RISR compared to RM loading paradigm