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Τρίτη 17 Οκτωβρίου 2017
Scholar : These new articles for Eating Disorders are available online
Differential physiological responses to central leptin overexpression in male and female rats
Abstract
Brains of females are more sensitive to the acute catabolic actions of leptin. However, sex differences in the long-term physiological responses to central leptin receptor modulation are unknown. To this end, we centrally delivered a viral vector to overexpress leptin (Leptin), a neutral leptin receptor antagonist (Leptin-Antagonist), or a green fluorescence protein (Control). We examined chronic changes in body weight and composition in male and female rats. Females displayed greater and sustained responses to Leptin whereas males rapidly lost physiological effects and developed leptin resistance confirmed by lower acute leptin-mediated phosphorylation of STAT3 (P-STAT3). Surprisingly, despite persistent physiological responses, Leptin-females also exhibited reduced acute leptin-mediated P-STAT3, suggesting an onset of leptin resistance near time of death. In line with this interpretation, Leptin-females and Control-females consumed the same amount of food on the last day of the experiment. Both Leptin-Antagonist groups gained similar percentages of their initial body weight and fat mass, whereas only Leptin-Antagonist-females gained lean body mass. Consequently, lean/fat mass ratio with Leptin-Antagonist was preserved in females and decreased in males, suggesting a deterioration of body composition in males. In summary, this study establishes that females are more responsive to long-term central leptin overexpression than males and that leptin antagonism has a greater physiological impact in males. The hormone environment may have played a role in these processes; however, future studies are needed to establish whether physiological responses are mediated by female or male sex hormones.
This article is protected by copyright. All rights reserved.
http://ift.tt/2kVr2fJ
Building primary care in a changing Europe [Internet].
For many citizens primary care is the first point of contact with their health care system, where most of their health needs are satisfied but also acting as the gate to the rest of the system. In that respect primary care plays a crucial role in how patients value health systems as responsive to their needs and expectations.
http://ift.tt/2iiajSI
Microbiomes of the Built Environment: A Research Agenda for Indoor Microbiology, Human Health, and Buildings.
People's desire to understand the environments in which they live is a natural one. People spend most of their time in spaces and structures designed, built, and managed by humans, and it is estimated that people in developed countries now spend 90 percent of their lives indoors. As people move from homes to workplaces, traveling in cars and on transit systems, microorganisms are continually with and around them. The human-associated microbes that are shed, along with the human behaviors that affect their transport and removal, make significant contributions to the diversity of the indoor microbiome.
http://ift.tt/2gMe1kf
Assessing Chronic Disease Management in European Health Systems: Country reports [Internet].
Many countries are exploring innovative approaches to redesign delivery systems to provide appropriate support to people with long-standing health problems. Central to these efforts to enhance chronic care are approaches that seek to better bridge the boundaries between professions, providers and institutions, but, as this study clearly demonstrates, countries have adopted differing strategies to design and implement such approaches.
http://ift.tt/2ii9xoM
Global Health Research in an Unequal World: Ethics Case Studies from Africa.
This book is a collection of fictionalised case studies of everyday ethical dilemmas and challenges, encountered in the process of conducting global health research in places where the effects of global, political and economic inequality are particularly evident. It is a training tool to fill the gap between research ethics guidelines, and their implementation 'on the ground'. The case studies, therefore, focus on 'relational' ethics: ethical actions and ideas that emerge through relations with others, rather than in regulations.
http://ift.tt/2gMdGxF
Scholar : These new articles for Norwegian Archaeological Review are available online
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Discovery of New Antimalarial Agents: Second-Generation Dual Inhibitors against FP-2 and PfDHFR via Fragments Assembely
Publication date: Available online 16 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Wenhua Chen, Zhenghui Huang, Wanyan Wang, Fei Mao, Longfei Guan, Yun Tang, Hualiang Jiang, Jian Li, Jin Huang, Lubin Jiang, Jin Zhu
Malaria parasites are a leading cause of worldwide mortality from infectious disease. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) play vital roles, which are absolutely essential, in the parasite life cycle. In this study, based on the structures of uniform fragments of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the discovery of 24, which showed high potency against FP-2 (IC50=10.0 µM), PfDHFR (IC50= 84.1 nM), P. falciparum 3D7 (IC50= 53.1 nM), clinical isolated strains Fab9 (IC50= 14.2 nM) and GB4 (IC50= 23.4 nM). The in vivo inhibition assays against P. berghei in 10 days indicated 24 had a more beneficial effect on the growth inhibition of P. berghei than artemisinin and an identical effect with pyrimethamine. Additionally, 24 moderately inhibited the proliferation of chloroquine-resistant P. falciparum Dd2 strain. Collectively, these data revealed that 24 could be an excellent lead compound as FP-2 and PfDHFR dual inhibitor for the treatment of malaria.
Graphical abstract
http://ift.tt/2ysEfQc
Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor
Publication date: Available online 16 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Simone Bertini, Andrea Chicca, Francesca Gado, Chiara Arena, Daniela Nieri, Maria Digiacomo, Giuseppe Saccomanni, Pingwei Zhao, Mary E. Abood, Marco Macchia, Jürg Ghertsch, Clementina Manera
In this work, we explored the molecular framework of the known CB1R allosteric modulator PSNCBAM-1 with the aim to generate new bioactive analogs and to deepen the structure-activity relationships of this type of compounds. In particular, the introduction of a NH group between the pyridine ring and the phenyl nucleus generated the amino-phenyl-urea derivative SN15b that behaved as a positive allosteric modulator (PAM), increasing the CB1R binding affinity of the orthosteric ligand CP55,940. The functional activity was evaluated using serum response element (SRE) assay, which assesses the CB1R-dependent activation of the MAPK/ERK signaling pathway. SN15b and the biphenyl-urea analog SC4a significantly inhibited the response produced by CP55,940 in the low µM range, thus behaving as negative allosteric modulators (NAMs). The new derivatives presented here provide further insights about the modulation of CB1R binding and functional activity by allosteric ligands.
Graphical abstract
http://ift.tt/2yujofp
Design and synthesis of p-carborane-containing sulfamates as multitarget anti-breast cancer agents
Publication date: Available online 16 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Asako Kaise, Kiminori Ohta, Chinami Shirata, Yasuyuki Endo
The development of multitarget anticancer agents is of high interest to medicinal chemists in terms of overcoming drug resistance and preventing cancer-cell migration. Based on the structure of the potent carborane-containing estrogen BE120, non-steroidal multitarget anti-breast cancer agent candidates 1a–1j were designed and synthesized. Compound 1f shows potent STS-inhibitory activity (IC50 = 1.8 μM), cell-growth-inhibitory (CGI) activity against 39 human cancer cell lines (MG-MID = 2.8 μM), and tubulin-polymerization-inhibitory (TPI) activity. An analysis of the DNA content for MDA-MB-453 breast cancer cells revealed that 1f arrests the cell cycle in the G2/M phase and induces apoptosis. Accordingly, 1f should be a promising therapeutic agent for hormone-dependent breast cancer.
Graphical abstract
http://ift.tt/2ysAHxz
Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation
Publication date: Available online 16 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): María N. Chao, Melissa Storey, Catherine Li, Maricel G. Rodríguez, Florencia Di Salvo, Sergio H. Szajnman, Silvia N.J. Moreno, Roberto Docampo, Juan B. Rodriguez
The obligate intracellular parasite, Trypanosoma cruzi is the etiologic agent of Chagas disease or American trypanosomiasis, which is the most prevalent parasitic disease in the Americas. The present chemotherapy to control this illness is still deficient particularly in the chronic stage of the disease. The ergosterol biosynthesis pathway has received much attention as a molecular target for the development of new drugs for Chagas disease. Especially, inhibitors of the enzymatic activity of squalene synthase were shown to be effective compounds on T. cruzi proliferation in in vitro assays. In the present study we designed, synthesized and evaluated the effect of a number of isosteric analogues of WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, on T. cruzi growth in tissue culture cells. The selenium-containing derivatives turned out to be extremely potent inhibitors of T. cruzi growth. Certainly, 3-phenoxyphenoxyethyl, 4-phenoxyphenoxyethyl, 4-(3-fluorophenoxy)phenoxyethyl, 3-(3-fluorophenoxy)phenoxyethyl selenocyanates and (±)-5-phenoxy-2-(selenocyanatomethyl)-2,3-dihydrobenzofuran arose as relevant members of this family of compounds, which exhibited effective ED50 values of 0.084 µM, 0.11 µM, 0.083, µM, 0.085, and 0.075 µM, respectively. The results indicate that compounds bearing the selenocyanate moiety are at least two orders of magnitude more potent than the corresponding skeleton counterpart bearing the thiocyanate group. Surprisingly, these compounds exhibited excellent selectively index values ranging from 900 to 1,800 making these molecules promising candidates as antiparasitic agents.
Graphical abstract
http://ift.tt/2ysACdf
Benzofuran-Dihydropyridine Hybrids: A new class of potential bone anabolic agents
Publication date: Available online 17 October 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ram K. Modukuri, Dharmendra Choudhary, Sampa Gupta, K. BhaskaraRao, SulekhaAdhikary, Tanuj Sharma, Mohammad Imran Siddiqi, Ritu Trivedi, Koneni V. Sashidhara
A series of novel benzofuran-dihydropyridine hybrids were designed by molecular hybridization approach and evaluated for bone anabolic activities. Among the screened library, ethyl 4-(7-(sec-butyl)-2-(4-methylbenzoyl)benzofuran-5-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (compound 21) significantly enhanced the ALP production and mineralized nodule formation, which are primary requisites in the process of in-vitro osteogenesis. Oral administration of compound 21 at 10 mg.kg-1day-1 for two weeks led to restoration of trabecular bone microarchitecture in drill hole fracture model by significantly increasing BV/TV and Tb.N. Furthermore, histological and molecular studies showed compound 21 triggering the new bone regeneration in a drill hole defect site by increasing BMP expression. Furthermore, molecular modeling studies were performed to gain insight into the binding approach, which revealed that both benzofuran and dihydropyridine moieties are essential to show similar binding interactions to fit into the active site of BMP2 receptor, an important target of the osteogenic agents.Our results suggest that compound 21 stimulates BMP2 synthesis in osteoblast cells that promotes new bone formation (∼40%) at the fracture site which helps in shorten the healing period.
Graphical abstract
http://ift.tt/2ysEdry
Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4
Source:Behavioural Brain Research, Volume 338
Author(s): J. Pearson-Leary, V. Jahagirdar, J. Sage, E.C. McNay
The insulin-regulated glucose transporter, GluT4, is a key molecule in peripheral insulin signaling. Although GluT4 is abundantly expressed in neurons of specific brain regions such as the hippocampus, the functional role of neuronal GluT4 is unclear. Here, we used pharmacological inhibition of GluT4-mediated glucose uptake to determine whether GluT4 mediates insulin-mediated glucose uptake in the hippocampus. Consistent with previous reports, we found that glucose utilization increased in the dorsal hippocampus of male rats during spontaneous alternation (SA), a hippocampally-mediated spatial working memory task. We previously showed that insulin signaling within the hippocampus is required for processing this task, and that administration of exogenous insulin enhances performance. At baseline levels of hippocampal insulin, inhibition of GluT4-mediated glucose uptake did not affect SA performance. However, inhibition of an upstream regulator of GluT4, Akt, did impair SA performance. Conversely, when a memory-enhancing dose of insulin was delivered to the hippocampus prior to SA-testing, inhibition of GluT4-mediated glucose transport prevented cognitive enhancement. These data suggest that baseline hippocampal cognitive processing does not require functional hippocampal GluT4, but that cognitive enhancement by supra-baseline insulin does. Consistent with these findings, we found that in neuronal cell culture, insulin increases glucose utilization in a GluT4-dependent manner. Collectively, these data demonstrate a key role for GluT4 in transducing the procognitive effects of elevated hippocampal insulin.
http://ift.tt/2ysAhqZ
NMDA receptor blockade specifically impedes the acquisition of incentive salience attribution
Source:Behavioural Brain Research, Volume 338
Author(s): Jonathan J. Chow, Joshua S. Beckmann
Glutamatergic signaling plays an important role in learning and memory. Using Pavlovian conditioned approach procedures, the mechanisms that drive stimulus-reward learning and memory have been investigated. However, there are instances where reward-predictive stimuli can function beyond being solely predictive and can be attributed with "motivational value" or incentive salience. Using a Pavlovian conditioned approach procedure consisting of two different but equally predictive stimuli (lever vs. tone) we investigated the role NMDA receptor function has in the attribution of incentive salience. The results revealed that the administration of MK-801, an NMDA receptor antagonist, during acquisition of Pavlovian conditioned approach promoted goal-tracking to a lever stimulus, while control animals learned to sign-track. Moreover, within the same animals, the use of a tone stimulus elicited goal-tracking responses that were unaffected by MK-801 pretreatments. Furthermore, a lever CS that elicited sign-tracking served as a more robust conditioned reinforcer than a tone CS that elicited goal-tracking or a lever CS that elicited goal-tracking via MK-801 pretreatments. Collectively, these results demonstrate that NMDA receptor antagonism can alter the stimulus-reward relationship learned and prevent the attribution of incentive salience, rather than impede general learning.
http://ift.tt/2x2GBny
Head-turning asymmetry: A novel lateralization in rats predicts susceptibility to behavioral despair
Source:Behavioural Brain Research, Volume 338
Author(s): Efe Soyman, Guzin Duygu Yilmaz, Resit Canbeyli
Behavioral markers of laterality reflecting underlying neurobiological asymmetries between the cerebral hemispheres are related to differential susceptibility to mood disorders. In the present study, we investigated the strength and consistency of a novel behavioral lateralization, head-turning asymmetry, and its relation to behavioral despair in adult female Wistar rats. Head-turning biases were determined in a test where water-deprived rats had to turn their head to right or left to gain access to a water dispenser. This procedure was administered 4 times over 8days. Four days after the head-turning test, rats were subjected to two forced swim tests separated by 24h to examine the relationship between head-turning asymmetry and behavioral despair. Rats were administered one more head-turning test session after the second swim test to determine whether behavioral despair induction altered head-turning direction preferences. Results revealed significant correlations among head-turning test sessions indicating head-turning direction preference as measured with our method is a consistent behavioral lateralization. Although most rats were strongly lateralized, there was no bias in either direction at the population level. Importantly, we found that while rats with a left head-turning bias showed a significant increase in the duration of immobility from the first to the second swim test, right-biased rats performed similarly in the two swim tests. Behavioral despair induction did not change head-turning direction preferences. The present findings show that head-turning asymmetries are predictive of mood disorders in rats and may serve as the basis to elucidate the mechanisms relating hemispheric asymmetries to depression in humans.
http://ift.tt/2yujgfV
Impaired cognitive flexibility during sleep deprivation among carriers of the Brain Derived Neurotrophic Factor (BDNF) Val66Met allele
Source:Behavioural Brain Research, Volume 338
Author(s): Leilah K. Grant, Sean W. Cain, Anne-Marie Chang, Richa Saxena, Charles A. Czeisler, Clare Anderson
Accumulating evidence points to a genetic contribution to explain inter-individual vulnerability to sleep deprivation. A functional polymorphism in the BDNF gene, which causes a valine (Val) to methionine (Met) amino acid substitution at Codon 66, has been associated with cognitive impairment, particularly in populations with impaired frontal functioning. We hypothesised that sleep deprivation, which affects frontal function, may lead to cognitive dysfunction in Met allele carriers. To examine this, we investigated, in different BDNF genotypes, the effects of sleep deprivation on cognitive flexibility, as measured by response inhibition using the Stroop Color Naming Task. Thirty healthy, adults of European ancestry, including 12 heterozygous Met allele carriers and 18 Val/Val homozygotes, underwent 30-h of extended wakefulness under constant routine conditions. A computerised Stroop task was administered every 2h. Error rate and reaction times increased with time awake for all individuals. Participants with the Val/Met genotype made more errors on incongruent trials after 20h awake. While Val/Met participants also took significantly longer to respond when inhibiting a prepotent response irrespective of time awake, this was particularly evident during the biological night. Our study shows that carriers of the BDNF Met allele are more vulnerable to the impact of prolonged wakefulness and the biological night on a critical component of executive function, as measured by response inhibition on the Stroop task.
http://ift.tt/2ysE9Ik
Scholar : These new articles for Critical Discourse Studies are available online
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A Study of DSP-7888 Dosing Emulsion in Combination With Immune Checkpoint Inhibitors in Adult Subjects With Advanced Solid Tumors
Interventions: Drug: DSP-7888 Dosing Emulsion; Drug: Nivolumab; Drug: Atezolizumab
Sponsor: Boston Biomedical, Inc
Not yet recruiting
http://ift.tt/2x0G853
Scholar : These new articles for The Law Teacher are available online
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Scholar : These new articles for Critical Inquiry in Language Studies are available online
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Lab-on-a-chip systems for photodynamic therapy investigations
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Michał Chudy, Katarzyna Tokarska, Elżbieta Jastrzębska, Magdalena Bułka, Sławomir Drozdek, Łukasz Lamch, Kazimiera A. Wilk, Zbigniew Brzózka
In recent years photodynamic therapy (PDT) has received widespread attention in cancer treatment due to its smaller surgical trauma, better selectivity towards tumor cells, reduced side effects and possibility of repeatable treatment. Since cancer is the second cause of death worldwide, scientists constantly seek for new potential therapeutic agents including nanotechnology-based photosensitizers used in PDT. The new-designed nanostructures must be carefully studied and well characterized what require analytically useful and powerful tools that enable real progress in nanoscience development. This review describes the current status of PDT investigations using microfluidic Lab-on-a-Chip systems, including recent developments of nanoparticle-based PDT agents, their combinations with different drugs, designs and examples of in vitro applications. This review mainly lays emphasis on biological evaluation of FDA approved photosensitizing agents as well as newly designed nanophotosensitizers. It also highlights the analytical performances of various microfluidic Lab-on-a-chip systems for PDT efficacy analysis on 3D culture and discusses microsystems designs in detail.
http://ift.tt/2zf31T3
Efficient capture, rapid killing and ultrasensitive detection of bacteria by a nano-decorated multi-functional electrode sensor
Publication date: 15 March 2018
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Runrun Wu, Yue Ma, Jianming Pan, Shih-Hui Lee, Jinxin Liu, Hengjia Zhu, Runxin Gu, Kenneth J. Shea, Guoqing Pan
In this work, we demonstrated a nano-decorated porous impedance electrode sensor for efficient capture, rapid killing and ultrasensitive detection of bacteria. The multi-functional sensor was prepared by a facile sonochemical method via in situ deposition of antibacterial prickly Zn-CuO nanoparticles and graphene oxide (GO) nanosheets on a Ni porous electrode. Due to the surface burr-like nanostructures, the nano-decorated impedance sensor exhibited very good bacterial-capture efficiency (70 − 80% in 20min) even at a low concentration of 50 CFU mL−1, rapid antibacterial rate (100% killing in 30min) and high detection sensitivity (as low as 10 CFU mL−1). More importantly, the nano-decorated sensor has proven to be highly effective in quantitative detection of bacteria in a biological sample, for example, a rat blood sample spiked with E. coli. Despite the complexity of blood, the sensor still exhibited excellent detection precision within 30min at bacteria concentrations ranging from 10 − 105 CFU mL−1. The simplicity, rapidity, sensitivity, practicability and multifunctionality of this impedance sensor would greatly facilitate applications in portable medical devices for on-the-spot diagnosis and even the possibility for simultaneous therapy of diseases caused by bacterial infections.
Graphical abstract
http://ift.tt/2ysTV69
A novel three-dimensional carbonized PANI1600@CNTs network for enhanced enzymatic biofuel cell
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Zepeng Kang, Kailong Jiao, Jin Cheng, Ruiyun Peng, Shuqiang Jiao, Zongqian Hu
A novel three-dimensional (3D) carbon composite of PANI1600@CNTs with rhizobium-like structure is prepared by in-situ polymerization of aniline monomers around and along the functionalized carbon nanotubes (CNTs) and then carbonized at 1600°C for enzymatic biofuel cells (EBFCs). The SEM and TEM images clearly show that the carbonized PANI grew seamlessly on the surface of CNTs and presented the rhizobium-like structure. The carbonized PANI acts like conductive "glue" and connects the adjacent tubes together, which can assemble the CNTs into a 3D network. The PANI1600@CNTs composite modified glassy carbon electrodes based on glucose oxidase (GOx) and laccase (Lac) exhibit high electrochemical performance. A glucose//O2 EBFC constitutes of the fabricated anode and cathode performs a maximum power density of 1.12mWcm−2 at 0.45V. Furthermore, three of the fabricated EBFCs in series are able to lightening up a yellow light-emitting diode (LED) whose turn-on voltage is about at 1.8V. This work may be helpful for exploiting novel substrates by carbonizing the composites of conducting polymer with nano materials at high-temperature for immobilization of enzymes in the EBFCs or biosensor fields.
http://ift.tt/2ytjMuu
Versatile on-stage microfluidic system for long term cell culture, micromanipulation and time lapse assays
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Yao-Xiong Huang, Chun-Lan He, Ping Wang, Yan-Ting Pan, Wei-Wei Tuo, Cheng-Can Yao
We report here a versatile on-stage microfluidic cell culture and assay system which is compatible with different microscopes and sensors, can simultaneously perform steps of long term cell culture, high throughput time lapse cell assays/imaging, and cell micromanipulations. With the system, we cultured a variety of cells for different periods of time and monitored their cell morphology, migration and division. We also performed a series non-invasive real time in situ time lapse assays and micromanipulations on different cells. They include: the first time lapse imaging and measurements on the instantaneous variations of morphology, biomechanical properties and the intracellular protein of human red blood cells in responding to pH fluctuation, drug action and electromagnetic radiation; the first continuous time lapse Raman micro-spectroscopy on a CHO cell in different phases of its entire life cycles; the micro-transfection of GFP into B16 cells and the follow up observation of the cell's morphology and expressed GFP fluorescence varying with incubation time and cell generations. The performance of these experiments not only demonstrated the capability of the system, but also proposed a variety of novel methods for obtaining time- and spatially-resolved information about the cellular and molecular heterogeneity and transformation during development or stimulations.
http://ift.tt/2zgiVg4
Enhanced diffusometric immunosensing with grafted gold nanoparticles for detection of diabetic retinopathy biomarker tumor necrosis factor-α
Publication date: 15 March 2018
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Han-Sheng Chuang, Yu-Ju Chen, Hui-Pin Cheng
Diffusometry is sensitive to geometric changes of particles. Target antigens can be detected through diffusivity changes resulting from their immunoreactions by functionalizing particle surface with a specific antibody. Considering that Brownian motion is a self-driven phenomenon, diffusometric immunosensing features several characteristics, such as no-washing steps, rapid detection, high flexibility, and high sensitivity. Until recently, this technique has been applied to many biomedical fields, such as monitoring of microorganism motility and diagnosis of diseases with biomarkers. Despite the abovementioned advantages, diffusivity changes in conventional diffusometry can be compromised at low-abundance antigens because proteins are much smaller than capture particles. To overcome such restriction, we present an improved diffusometric immunosensing technique by grafting additional gold nanoparticles (AuNPs) to capture particles to enhance size changes. A diabetic retinopathy (DR) biomarker, tumor necrosis factor-α was selected to evaluate the proposed immunosensing technique. Spherical AuNPs showed better enhancement than rod-like AuNPs during measurement. Limit of detection was improved by at least 100-fold down to 10pg/mL. A dichotomous method was also developed to enable rapid detection and avoid tedious calibration. The relationship of concentrations between the two solutions used can be explicitly determined by comparing diffusivity of an unknown concentration of target molecules with that of a reference solution. Minimum discernible concentration reached as low as twofold higher or lower than basal concentration. Tear samples were collected from four volunteers, including three healthy subjects and one proliferative DR patient to prove the concept in diagnosis of the disease. All data showed good agreement with preset conditions. The technique eventually provides an insight into rapid diagnoses of diseases in the early stage.
Graphical abstract
http://ift.tt/2yrYLR5
Rechargeable, flexible and mediator-free biosupercapacitor based on transparent ITO nanoparticle modified electrodes acting in µM glucose containing buffers
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Tim Bobrowski, Elena González Arribas, Roland Ludwig, Miguel D. Toscano, Sergey Shleev, Wolfgang Schuhmann
We present a transparent and flexible self-charging biosupercapacitor based on an optimised mediator- and membrane-free enzymatic glucose/oxygen biofuel cell. Indium tin oxide (ITO) nanoparticles were spray-coated on transparent conducting ITO supports resulting in a flocculent, porous and nanostructured electrode surface. By this, high capacitive currents caused by an increased electrochemical double layer as well as enhanced catalytic currents due to a higher number of immobilised enzyme molecules were obtained. After a chemical pre-treatment with a silane derivative, bilirubin oxidase from Myrothecium verrucaria was immobilized onto the ITO nanostructured electrode surface under formation of a biocathode, while bioanodes were obtained by either immobilisation of cellobiose dehydrogenase from Corynascus thermophilus or soluble PQQ-dependent glucose dehydrogenase from Acinetobacter calcoaceticus. The latter showed a lower apparent KM value for glucose conversion and higher catalytic currents at µM glucose concentrations. Applying the optimised device as a biosupercapacitor in a discontinuous charge/discharge mode led to a generated power output of 0.030mW/cm2 at 50µM glucose, simulating the glucose concentration in human tears. This represents an enhancement by a factor of 350 compared to the power density obtained from the continuously operating biofuel cell with a maximum power output of 0.086µW/cm2 under the same conditions. After 17h of charging/discharging cycles a remarkable current enhancement was still measured. The entire device was transferred to flexible materials and applied for powering a flexible display showing its potential applicability as an intermittent power source in smart contact lenses.
http://ift.tt/2yrG2oD
3D spongy graphene-modified screen-printed sensors for the voltammetric determination of the narcotic drug codeine
Publication date: 15 March 2018
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Mona A. Mohamed, Dalia M. El-Gendy, Nashaat Ahmed, Craig E. Banks, Nageh K. Allam
Adenine-functionalized spongy graphene (FSG) composite, fabricated via a facile and green synthetic method, has been explored as a potential electrocatalyst toward the electroanalytical sensing of codeine phosphate (COD). The synthesized composite is characterized using Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, X-ray powder diffraction, UV−vis absorption spectroscopy, scanning electron microscopy, high resolution transmission electron microscopy (HRTEM), and thermogravimetric analysis. The FSG was electrically wired via modification upon screen-printed (macro electrode) sensors, which behave as a hybrid electrode material for the sensitive and selective codeine phosphate (COD) determination in the presence of paracetamol (PAR) and caffeine (CAF). The FSG- modified sensor showed an excellent electrocatalytic response towards the sensing of COD with a wide linear response range of 2.0 × 10−8–2.0 × 10−4M and a detection limit (LOD) of 5.8 × 10−9M, indicating its potential for the sensing of COD in clinical samples and pharmaceutical formulations.
Graphical abstract
http://ift.tt/2zgj436
Ginsenoside Rg3 ameliorated HFD-induced hepatic steatosis through downregulation of STAT5-PPAR{gamma}
Healthy expansion of adipose tissue maintains metabolic homeostasis by storing excess chemical energy in increased fat mass. The STAT5-PPAR gamma pathway reportedly regulates adipocyte differentiation, lipid metabolism and adipogenesis. Ginsenoside Rg3 is one of the diverse groups of steroidal saponins, the major active components of ginseng, which have demonstrated pharmacological properties. In this study, we evaluated the therapeutic effects of ginsenoside Rg3 under pathological conditions in vitro and in vivo. We examined the effects of ginsenoside Rg3 on glucose level, insulin sensitivity and lipogenesis in high-fat diet-fed C57BL/6 mice. Ginsenoside Rg3 was also applied to the pre-adipocyte cell line 3T3-L1 to assess the impact on lipogenesis. Ginsenoside Rg3 reduced epididymal white adipose tissue (eWAT) size and hepatic steatosis, and the amount of triglycerides (TGs) in both eWAT and liver. Similar to the murine model, Rg3-treated 3T3-L1 cells showed a reduction in lipid accumulation and amount of total TGs. Ginsenoside Rg3 regulates the expression of PPAR gamma though STAT5 in vitro and in vivo. According to our results, lipid metabolism-related genes were downregulated in the high-fat mice and 3T3-L1 cell line. Rg3 shows potential for the amelioration of obesity-induced pathology, acting though STAT5-PPAR gamma to facilitate the healthy functioning of adipose tissue. This is the first report of evidence that obesity-induced insulin resistance and lipotoxicity can be treated with ginsenoside Rg3, which acts though the STAT5-PPAR gamma pathway in vivo and in vitro.
http://ift.tt/2ytLaKw
Optogenetic Activation of the Infralimbic Cortex Suppresses the Return of Appetitive Pavlovian-Conditioned Responding Following Extinction
http://ift.tt/2gLsJYH
Critical Language Areas Show Increased Functional Connectivity in Human Cortex
http://ift.tt/2iiQL0F
Shared and Disorder-Specific Neurocomputational Mechanisms of Decision-Making in Autism Spectrum Disorder and Obsessive-Compulsive Disorder
http://ift.tt/2gLaEKn
Knockout Mice for Dyslexia Susceptibility Gene Homologs KIAA0319 and KIAA0319L have Unaffected Neuronal Migration but Display Abnormal Auditory Processing
http://ift.tt/2ih8YLY
A Modulatory Effect of Brief Passive Exposure to Non-linguistic Sounds on Intrinsic Functional Connectivity: Relevance to Cognitive Performance
http://ift.tt/2gLAD4o
Oxytocin Fails to Recruit Serotonergic Neurotransmission in the Autistic Brain
http://ift.tt/2iiQJpz
Differential Contributions of Default and Dorsal Attention Networks to Remembering Thoughts and External Stimuli From Real-Life Events
http://ift.tt/2gKAKgs
BOLD Activity During Correct-Answer Feedback in Cued Recall Predicts Subsequent Retrieval Performance: An fMRI Investigation Using a Partial Trial Design
http://ift.tt/2ih8XaS
Segregated Excitatory–Inhibitory Recurrent Subnetworks in Layer 5 of the Rat Frontal Cortex
http://ift.tt/2gKlu38
Photocatalytic decomposition of methanol over La/TiO 2 materials
Abstract
Lanthanum-modified TiO2 photocatalysts (0.2–1.5 wt% La) were investigated in the methanol decomposition in an aqueous solution. The photocatalysts were prepared by the common sol-gel method followed by calcination. The structural (X-ray diffraction, Raman, X-ray photoelectron spectroscopy), textural (N2 physisorption), and optical properties (diffuse reflectance spectroscopy, photoelectrochemical measurements) of all synthetized nanomaterials were correlated with photocatalytic activity. Both pure TiO2 and La-doped TiO2 photocatalysts proved higher yields of hydrogen in comparison to photolysis. The photocatalyst with optimal amount of lanthanum (0.2 wt% La) showed almost two times higher amount of hydrogen produced at the same time as in the presence of pure TiO2. The photocatalytic activity increased with both increasing photocurrent response and decreasing amount of lattice and surface O species. It has been shown that both direct and indirect mechanisms of methanol photocatalytic oxidation participate in the production of hydrogen. Both direct and indirect mechanisms take part in the formation of hydrogen.
http://ift.tt/2yuEnjX
Frequency dependent hub role of the dorsal and ventral right anterior insula
Source:NeuroImage, Volume 165
Author(s): Yifeng Wang, Lixia Zhu, Qijun Zou, Qian Cui, Wei Liao, Xujun Duan, Bharat Biswal, Huafu Chen
The right anterior insula (rAI) plays a crucial role in generating adaptive behavior by orchestrating multiple brain networks. Based on functional separation findings of the insula and spectral fingerprints theory of cognitive functions, we hypothesize that the hub role of the rAI is region and frequency dependent. Using the Human Connectome Project dataset and backtracking approach, we segregate the rAI into dorsal and ventral parts at frequency bands from slow 6 to slow 3, indicating the frequency dependent functional separation of the rAI. Functional connectivity analysis shows that, within lower than 0.198 Hz frequency range, the dorsal and ventral parts of rAI form a complementary system to synchronize with externally and internally-oriented networks. Moreover, the relationship between the dorsal and ventral rAIs predicts the relationship between anti-correlated networks associated with the dorsal rAI at slow 6 and slow 5, suggesting a frequency dependent regulation of the rAI to brain networks. These findings could improve our understanding of the rAI by supporting the region and frequency dependent function of rAI and its essential role in coordinating brain systems relevant to internal and external environments.
http://ift.tt/2kVUPVt
Nonfunctioning adrenal incidentaloma affecting central blood pressure and arterial stiffness parameters
Abstract
Purpose
Recently, cardiovascular risk is thought to be increased in patients with nonfunctioning adrenal incidentaloma (NFAI). There are no sufficient studies in the literature to evaluate this situation in NFAI patients without cardiovascular risk. The objective of this study is to compare peripheral and central blood pressure and arterial stiffness between patients with NFAI and healthy volunteers (of a similar age, gender and body mass index as the NFAI group) who have no traditional cardiovascular risk factors and autonomous cortisol secretion, with pulse wave analysis (PWA).
Methods
In this cross-sectional study, we evaluated 35 NFAI patients who have no traditional cardiovascular risk factors and 35 healthy volunteers. PWA was performed in the participants of similar gender, age and body mass index, with a Mobil-O-Graph PWA/ABPM (I.E.M. GmBH, Stolberg, Germany) device. Radiological and biochemical data were obtained retrospectively in the NFAI group.
Results
In our study, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), central SBP, central DBP, peripheral vascular resistance, augmentation pressure (AP), heart rate-corrected augmentation index (Aix@75) and pulse wave velocity (PWV) values were significantly higher in the NFAI group compared to the control group. In addition, peripheral and central blood pressure and arterial stiffness parameters were correlated with age and duration of NFAI diagnosis of more than 1 year.
Conclusions
NFAIs are known as cardiometabolically innocent, but in our study, both peripheral and central blood pressure values and arterial stiffness parameters were negatively affected in patients diagnosed with NFAI who have no traditional cardiovascular risk factors. These patients are at risk of cardiovascular diseases.
http://ift.tt/2gL4slz
Immunohistochemical evaluation of molecular radiotherapy target expression in neuroblastoma tissue
Abstract
Purpose
Neuroblastoma may be treated with molecular radiotherapy, 131I meta-Iodobenzylguanidine and 177Lu Lutetium DOTATATE, directed at distinct molecular targets: Noradrenaline Transporter Molecule (NAT) and Somatostatin Receptor (SSTR2), respectively. This study used immunohistochemistry to evaluate target expression in archival neuroblastoma tissue, to determine whether it might facilitate clinical use of molecular radiotherapy.
Methods
Tissue bank samples of formalin fixed paraffin embedded neuroblastoma tissue from patients for whom clinical outcome data were available were sectioned and stained with haematoxylin and eosin, and monoclonal antibodies directed against NAT and SSTR2. Sections were examined blinded to clinical information and scored for the percentage and intensity of tumour cells stained. These data were analysed in conjunction with clinical data.
Results
Tissue from 75 patients was examined. Target expression scores varied widely between patients: NAT median 45%, inter-quartile range 25% - 65%; and SSTR2 median 55%, interquartile range 30% – 80%; and in some cases heterogeneity of expression between different parts of a tumour was observed. A weak positive correlation was observed between the expression scores of the different targets: correlation coefficient = 0.23, p = 0.05. MYCN amplified tumours had lower SSTR2 scores: mean difference 23% confidence interval 8% - 39%, p < 0.01. Survival did not differ by scores.
Conclusions
As expression of both targets is variable and heterogeneous, imaging assessment of both may yield more clinical information than either alone. The clinical value of immunohistochemical assessment of target expression requires prospective evaluation. Variable target expression within a patient may contribute to treatment failure.
http://ift.tt/2ihKuCz
Static and dynamic 18 F–FET PET for the characterization of gliomas defined by IDH and 1p/19q status
Abstract
Purpose
The molecular features isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion have gained major importance for both glioma typing and prognosis and have, therefore, been integrated in the World Health Organization (WHO) classification in 2016. The aim of this study was to characterize static and dynamic O-(2-18F-fluoroethyl)-L-tyrosine (18F–FET) PET parameters in gliomas with or without IDH mutation or 1p/19q co-deletion.
Methods
Ninety patients with newly diagnosed and untreated gliomas with a static and dynamic 18F–FET PET scan prior to evaluation of tumor tissue according to the 2016 WHO classification were identified retrospectively. Mean and maximum tumor-to-brain ratios (TBRmean/max), as well as dynamic parameters (time-to-peak and slope) of 18F–FET uptake were calculated.
Results
Sixteen (18%) oligodendrogliomas (IDH mutated, 1p/19q co-deleted), 27 (30%) astrocytomas (IDH mutated only), and 47 (52%) glioblastomas (IDH wild type only) were identified. TBRmean, TBRmax, TTP and slope discriminated between IDH mutated astrocytomas and IDH wild type glioblastomas (P < 0.01). TBRmean showed the best diagnostic performance (cut-off 1.95; sensitivity, 89%; specificity, 67%; accuracy, 81%). None of the parameters discriminated between oligodendrogliomas (IDH mutated, 1p/19q co-deleted) and glioblastomas or astrocytomas. Furthermore, TBRmean, TBRmax, TTP, and slope discriminated between gliomas with and without IDH mutation (p < 0.01). The best diagnostic performance was obtained for the combination of TTP with TBRmax or slope (accuracy, 73%).
Conclusion
Data suggest that static and dynamic 18F–FET PET parameters may allow determining non-invasively the IDH mutation status. However, IDH mutated and 1p/19q co-deleted oligodendrogliomas cannot be differentiated from glioblastomas and astrocytomas by 18F–FET PET.
http://ift.tt/2gL1OMn
Nonfunctioning adrenal incidentaloma affecting central blood pressure and arterial stiffness parameters
Abstract
Purpose
Recently, cardiovascular risk is thought to be increased in patients with nonfunctioning adrenal incidentaloma (NFAI). There are no sufficient studies in the literature to evaluate this situation in NFAI patients without cardiovascular risk. The objective of this study is to compare peripheral and central blood pressure and arterial stiffness between patients with NFAI and healthy volunteers (of a similar age, gender and body mass index as the NFAI group) who have no traditional cardiovascular risk factors and autonomous cortisol secretion, with pulse wave analysis (PWA).
Methods
In this cross-sectional study, we evaluated 35 NFAI patients who have no traditional cardiovascular risk factors and 35 healthy volunteers. PWA was performed in the participants of similar gender, age and body mass index, with a Mobil-O-Graph PWA/ABPM (I.E.M. GmBH, Stolberg, Germany) device. Radiological and biochemical data were obtained retrospectively in the NFAI group.
Results
In our study, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), central SBP, central DBP, peripheral vascular resistance, augmentation pressure (AP), heart rate-corrected augmentation index (Aix@75) and pulse wave velocity (PWV) values were significantly higher in the NFAI group compared to the control group. In addition, peripheral and central blood pressure and arterial stiffness parameters were correlated with age and duration of NFAI diagnosis of more than 1 year.
Conclusions
NFAIs are known as cardiometabolically innocent, but in our study, both peripheral and central blood pressure values and arterial stiffness parameters were negatively affected in patients diagnosed with NFAI who have no traditional cardiovascular risk factors. These patients are at risk of cardiovascular diseases.
http://ift.tt/2gL4slz
Datasets on the statistical properties of the first 3000 squared positive integers
Source:Data in Brief, Volume 15
Author(s): Hilary I. Okagbue, Muminu O. Adamu, Pelumi E. Oguntunde, Abiodun A. Opanuga, Ayodele A. Adebiyi, Sheila A. Bishop
The data in this article are as a result of a quest to uncover alternative research routes of deepening researchers' understanding of integers apart from the traditional number theory approach. Hence, the article contains the statistical properties of the digits sum of the first 3000 squared positive integers. The data describes the various statistical tools applied to reveal different statistical and random nature of the digits sum of the first 3000 squared positive integers. Digits sum here implies the sum of all the digits that make up the individual integer.
http://ift.tt/2kT1os1
Forecasting the outcome of a time-varying Bernoulli process: Data from a laboratory experiment
Source:Data in Brief, Volume 15
Author(s): Mel W. Khaw, Luminita Stevens, Michael Woodford
The data presented in this article are related to the research article entitled "Discrete Adjustment to a Changing Environment: Experimental Evidence" (Khaw et al., 2017) [1]. We present data from a laboratory experiment that asks subjects to forecast the outcome of a time-varying Bernoulli process. On a computer program, subjects draw rings with replacement from a virtual box containing green and red rings in an unknown proportion. Subjects provide their estimates of the probability of drawing a green ring. They are rewarded for their participation and for the accuracy of their estimates. The actual probability of drawing a green ring is initially drawn from a uniform distribution. It then changes intermittently throughout the session, and each subsequent probability is an independent draw from the uniform distribution. Each session involves 1000 ring draws. The dataset contains the values of the underlying probability, the sequence of ring draws that are realized, and the subjects' estimates and response times. The dataset contains the performance of 11 subjects who each completed 10 sessions over the course of several days.
http://ift.tt/2xNfG3u
Massive Left-sided Congestive Colitis Due to Idiopathic Inferior Mesenteric Arteriovenous Malformation
Journal of Clinical Imaging Science 2017 7(1):40-40
Arteriovenous malformations (AVM) of the inferior mesenteric artery are rare. They may be primary (congenital or idiopathic) or secondary (acquired) after trauma or of iatrogenic origin. Of the abdominal AVM, the inferior mesenteric trunk is the least commonly involved. Most reported cases are of iatrogenic origin, resulting from colon surgery. Only 17 cases have been described and published in the literature. The objective of this work is to make known a case treated in our center. We present a case of 73-year old male, who came to the emergency service with symptoms of abdominal distension, pain lasting 48 hours along with months of diarrhoea. CT scan and an abdominal CT angiography showed a massive left-sided congestive colitis due to idiopathic inferior mesenteric arteriovenous malformation. In our case, the decision was to carry out the treatment in two stages. Embolisation was performed in the first stage in order to decrease the blood flow and the risk of intraoperative bleeding, followed by resective surgery of the affected colon.
http://ift.tt/2yoikwc
Snapping Pes Anserinus and the Diagnostic Utility of Dynamic Ultrasound
Journal of Clinical Imaging Science 2017 7(1):39-39
Snapping pes anserinus syndrome is an often encountered cause of medial knee snapping. It results from impingement and translation of the gracilis tendon or semitendinosus tendon over the osseous structures of the knee during active flexion and extension. Ultrasonography is often the diagnostic imaging test of choice in cases of mechanical snapping. We report 2 cases of painful snapping pes anserinus and highlight the value of dynamic ultrasound in making an accurate diagnosis so as to direct care.
http://ift.tt/2yqSAfW
Randomized study of etirinotecan pegol versus irinotecan as second-line treatment for metastatic colorectal cancer
Abstract
Purpose
Etirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor designed to provide sustained exposure to SN-38 (active metabolite of irinotecan). This phase II study compared EP versus irinotecan as second-line treatment for KRAS-mutant, irinotecan-naïve, metastatic colorectal cancer (mCRC).
Methods
Patients were randomized to EP 145 mg/m2 or irinotecan 350 mg/m2 Q21d until disease progression/unacceptable toxicity. The primary endpoint was progression-free survival (PFS) with response determined by central radiologic review (RECIST version 1.1).
Results
The study was terminated before completing accrual due to evolving standards of care. Eighty-three patients were randomized. Median PFS was longer with EP versus irinotecan (4.0 versus 2.8 months, respectively; HR 0.65; 95% CI 0.40–1.04; P = 0.07). Six-month PFS rates were 32.8 and 15.4%, respectively. Median OS was 9.6 and 8.4 months in EP and irinotecan arms, respectively (HR 0.91; 95% CI 0.56–1.49). ORRs were 10 and 5%, respectively (P = 0.676); median DOR was significantly longer in EP arm (7.9 versus 1.4 months; P = 0.018). The most common grade-3/4 adverse events for EP and irinotecan were diarrhea (21 vs 20%), neutropenia (10 vs 22%), abdominal pain (14 vs 5%), nausea (14 vs 2%), and vomiting (12 vs 7%), respectively.
Conclusion
EP is active and safe for second-line treatment of KRAS-mutant, irinotecan-naïve mCRC.
http://ift.tt/2gpq3mC
Determination of the human cytochrome P450 monooxygenase catalyzing the enantioselective oxidation of 2,2′,3,5′,6-pentachlorobiphenyl (PCB 95) and 2,2′,3,4,4′,5′,6-heptachlorobiphenyl (PCB 183)
Abstract
2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) and 2,2′,3,4,4′,5′,6-heptachlorobiphenyl (PCB 183) possess axial chirality and form the aS and aR enantiomers. The enantiomers of these congeners have been reported to accumulate in the human body enantioselectively via unknown mechanisms. In this study, we determined the cytochrome P450 (CYP) monooxygenase responsible for the enantioselective oxidization of PCB 95 and PCB 183, using a recombinant human CYP monooxygenase. We evaluated 13 CYP monooxygenases, namely CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, CYP3A4, CYP3A5, CYP4F2, and aromatase (CYP19), and revealed that CYP2A6 preferably oxidizes aS-PCB 95 enantioselectively; however, it did not oxidize PCB 183. The enantiomer composition was elevated from 0.5 (racemate) to 0.54. In addition, following incubation with CYP2A6, the enantiomer fraction (EF) of PCB 95 demonstrated a time-dependent increase.
http://ift.tt/2x1FEfc
Evaluation of leafy vegetables as bioindicators of gaseous mercury pollution in sewage-irrigated areas
Abstract
Mercury (Hg) can evaporate and enter the plants through the stomata of plant leaves, which will cause a serious threat to local food safety and human health. For the risk assessment, this study aimed to investigate the concentration and accumulation of total gaseous mercury (TGM) in five typical leafy vegetables (Chinese chives (Allium tuberosum Rottler), amaranth (Amaranthus mangostanus L.), rape (Brassica campestris L.), lettuce (Lactuca sativa L.), and spinach (Spinacia oleracea L.)) grown on sewage-irrigated areas in Tianjin, China. The following three sites were chosen to biomonitor Hg pollution: a paddy field receiving sewage irrigation (industrial and urban sewage effluents) for the last 30 years, a vegetable field receiving sewage irrigation for 15 years, and a grass field which did not receive sewage irrigation in history. Results showed that the total Hg levels in the paddy (0.65 mg kg−1) and vegetation fields (0.42 mg kg−1) were significantly higher than the local background level (0.073 mg kg−1) and the China national soil environment quality standard for Hg in grade I (0.30 mg kg−1). The TGM levels in ambient air were significantly higher in the paddy (71.3 ng m−3) and vegetable fields (39.2 ng m−3) relative to the control (9.4 ng m−3) and previously reported levels (1.45 ng m−3), indicating severe Hg pollution in the atmospheric environment of the sewage-irrigated areas. Furthermore, gaseous mercury was the dominant form of Hg uptake in the leaves or irreversibly bound to leaves. The comparison of Hg uptake levels among the five vegetables showed that the gradient of Hg accumulation followed the order spinach > red amaranth > Chinese chives > rape > lettuce. These results suggest that gaseous Hg exposure in the sewage-irrigated areas is a dominant Hg uptake route in leafy vegetables and may pose a potential threat to agricultural food safety and human health.
http://ift.tt/2ysLWWs
An inverse association between serum resistin levels and n-3 polyunsaturated fatty acids intake was strongest in the SNP-420 G/G genotype in the Japanese cohort: The Toon Genome Study
Abstract
Objective
Resistin is secreted from monocytes/macrophages and is associated with insulin resistance, inflammation, and cardiovascular diseases. In the Japanese cohort, serum resistin is tightly associated with a single nucleotide polymorphism (SNP) at -420 (rs1862513) in the promoter region of the human resistin gene. However, interactions between SNP-420 and environmental factors remain to be elucidated. The aim of this study was to investigate the association between serum resistin levels and nutrient intake, and the effect of SNP-420 on this association.
Design, Participants, and Measurements
The Toon Genome Study is a cohort study of Japanese community-dwelling subjects. A total of 1981 participants were cross-sectionally analyzed. Each nutrient intake was assessed using the semiquantitative food frequency questionnaire, and categorized into the quartiles (Q1-Q4). Serum resistin was measured by ELISA.
Results
Serum resistin tended to be inversely associated with fish intake and positively associated with meat intake after adjustment for age, sex, BMI, and energy intake. Serum resistin was inversely associated with n-3 polyunsaturated fatty acids (PUFA) intake after adjustment for age, sex, BMI, and energy intake (Q1 12.5, Q2 12.5, Q3 12.2, Q4 11.5 ng/ml; P for trend=0.007). This inverse association was strongest in the G/G genotype of SNP-420, followed by C/G and C/C (G/G, Q1 18.9, Q2 19.5, Q3 18.4, Q4 14.5 ng/ml, P=0.001; C/G, 14.4, 13.3, 13.1, 12.9, P=0.015; C/C, 9.5, 9.5, 9.2, 8.8, P=0.020; P for interaction=0.004).
Conclusions
The inverse association between serum resistin and n-3 PUFA intake was strongest in SNP-420 G/G genotype in the Japanese cohort.
This article is protected by copyright. All rights reserved.
http://ift.tt/2yrwjyx
Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution
Abstract
Purpose
Autoimmune diseases are typically associated with immune checkpoints blockade. This study aims at assessing, in real-life clinical practice, the prevalence and impact of thyroid disorders induced by immune checkpoint inhibitors.
Methods
52 patients (30 F; age 61 ± 13 years) with advanced melanoma treated with ipilimumab (3 mg/kg i.v./3 weeks; 4 doses) were included. For disease progression, 29 (16 F) of them received nivolumab (3 mg/kg i.v./2 weeks) or pembrolizumab (2 mg/kg i.v./3 weeks). Thyroid function and autoimmunity were assessed before, after 6 weeks, at the end of ipilimumab, as well as before and every 3 months during nivolumab/pembrolizumab treatment.
Results
During ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1 associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7 patients (3 F) developed hypothyroidism with severe manifestations in 6 of them; 3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean follow-up after anti-CTLA4 inhibitors treatment was 36 ± 28 months. Thyroid disorders occurred 45.1 ± 20.8 and 151 ± 67 days after the initiation of CTLA4 and PD1 inhibitors, respectively. Autoimmune disorders and BRAF mutation were associated with a better clinical response to CTLA4 followed by PD1 treatment.
Conclusions
Immune checkpoint blockade is burdened by a high incidence of autoimmune thyroid dysfunction, which is often severe. Therefore, early and careful monitoring and, eventually, treatment are crucial to prevent the negative impact of thyroid dysfunction on the clinical outcome.
http://ift.tt/2x2rhHh
Determining the Effects of PEI Adsorption on the Permeability of DPPC/BMP Membranes under Osmotic Stress
Publication date: Available online 17 October 2017
Source:Acta Biomaterialia
Author(s): Scott R. Clark, Keel Yong Lee, Hoyoung Lee, Jawahar Khetan, Hyun Chang Kim, Yun Hwa Choi, Kwanwoo Shin, You-Yeon Won
Polycations are used for a number of biological applications, including antibiotics and gene therapy. One aspect of the use of polycation gene carriers such as polyethylenemine (PEI) in gene therapy that is not well understood is their ability to escape from the vesicles they are internalized in. Here, in an attempt to gain a better understanding of PEI interaction with endosomal lipids under osmotic stress, we performed investigations using monolayers and vesicles derived from a mixture of neutral and negative lipids (1,2-dipalmitoylphosphatidylcholine (DPPC) and bis(monoacylglycero)phosphate (BMP), respectively). X-ray reflectivity (XR) and Langmuir trough measurements confirmed PEI adsorption to the negatively charged membrane. Confocal microscopy imaging indicated that PEI adsorption actually increases the overall integrity of the DPPC/BMP vesicle against osmotic stresses while also causing overall deformation and permeabilization of the lipid membrane, thus leading to leakage of contents from the interior of the vesicle. These confocal microscopy observations were also supported by data gathered by dynamic light scattering (DLS).SignificanceIn recent decades, researchers have investigated polyamine-based gene delivery systems as useful alternatives to viral gene carriers. One step that is crucial to the performance of polyamine gene carriers such as polyethylenemine (PEI) is escape from late endosomal vesicles during intracellular delivery. However, the ability of polyamine/DNA polyplexes to effectively escape from endosomes is a little-understood part of the gene therapy techniques that use these polyplexes. Here, we performed investigations using monolayers and vesicles derived from a mixture of neutral and negative lipids (1,2-dipalmitoylphosphatidylcholine (DPPC) and bis(monoacylglycero)phosphate (BMP), respectively) as model systems for late endosomes in order to examine the interactions of PEI with the DPPC/BMP membranes and study the subsequent effects on the stability and permeability of these membranes.
Graphical abstract
http://ift.tt/2yvklpV
Δευτέρα 16 Οκτωβρίου 2017
Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14 C-microtracer and therapeutic dose in cancer patients
Abstract
Introduction
Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo.
Purpose
Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F po) of this novel compound, which is the aim of this study.
Methods
Six patients received an oral therapeutic dose of 300 mg niraparib, followed by a 15-min intravenous infusion of 100 µg 14C-niraparib with a radioactivity of approximately 100 nCi. The niraparib therapeutic dose was measured in plasma using a validated liquid chromatography–tandem mass spectrometry method, whereas the total 14C-radioactivity and 14C-niraparib plasma levels were measured by accelerator mass spectrometry and a validated high performance liquid chromatography assay with AMS.
Results
The F po of niraparib was determined to be 72.7% in humans.
http://ift.tt/2xKbP25
Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC)
Abstract
Purpose
Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T-DM1 PK and evaluate the impact of patient characteristics on T-DM1 PK in previously treated patients with HER2-positive advanced gastric cancer (AGC).
Methods
Following T-DM1 weekly or every three weeks dosing, T-DM1 concentration measurements (n = 780) were collected from 136 patients in the GATSBY (NCT01641939) study and analyzed using nonlinear mixed effects modeling. The influence of demographic, baseline laboratory, and disease characteristics on T-DM1 PK was examined.
Results
T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment. The final population model estimated linear clearance (CL) of 0.79 L/day, volume of distribution in the central compartment (V c) of 4.48 L, distribution clearance (Q) of 0.62 L/day, volume of distribution in the peripheral compartment (V p) of 1.49 L, nonlinear CL of 2.06 L/day, and KM of 1.63 μg/mL. Parameter uncertainty was low to moderate for fixed effects, except KM (estimated with poor precision). Patients with high body weight and low baseline trastuzumab concentrations had significantly faster linear CL; those with higher body weight had significantly larger V c.
Conclusions
In a HER2-positive AGC population, T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Baseline body weight and trastuzumab concentration were identified as significant covariates for T-DM1 PK in a HER2-positive AGC population.
http://ift.tt/2ytKG7u
Hereditary persistence of hemoglobin F is protective against red cell sickling. A case report and brief review
Publication date: Available online 16 October 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Alexandra Sokolova, Anton Mararenko, Alexander Rozin, Alida Podrumar, Vladimir Gotlieb
Fetal hemoglobin (HbF) is a physiologic protein tetramer that is crucial for a developing fetus to survive in utero. Maternal hemoglobin has a relatively lower affinity for oxygen, and thus allows for an efficient transfer of oxygen from maternal to fetal blood. In addition to fulfilling a critical physiologic role, HbF is also known to alleviate symptoms of sickle-cell disease (SCD). The concentration of HbF depends on several factors. HbF is elevated in inherited conditions, such as hereditary persistence of HbF, hereditary spherocytosis, and thalassemia. The level of HbF is also increased in acquired states, such as pregnancy, aplastic anemia, thyrotoxicosis, hepatoma, myeloproliferative disorders, or hypoplastic myelodysplastic syndrome. It has been identified that some genetic loci have significant influence on HbF levels. The XmnI polymorphism, the HMIP locus, and the BCL11A gene are responsible for 45% of variations in HbF levels. Although SCD has been well described in the subpopulations of Africa, it is less common in the subpopulations of India. We describe a case of SCD, in which a patient with high HbF level presented at a very late age (27 years old). We presume the patient's inherently elevated HbF levels were able to compensate for the hypoxic episodes associated with SCD. The onset of symptoms was delayed as a result of elevated HbF levels.
http://ift.tt/2yvbVPl
Anemia in Patient with Primary Hyperoxaluria and Bone Marrow Involvement by Oxalate Crystals
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Vitaliy Mykytiv, Fiz Campoy Garcia
We present a rare case of anaemia secondary to bone marrow infiltration by oxalate crystals and renal failure in a patient diagnosed with primary hyperoxaluria. In our case, the anaemia was recovered after the double liver and kidney transplantation, the latter was performed on two occasions after the failure of the first graft.
http://ift.tt/2yOwZBr
Beyond Patents: Assessing the Value and Impact of Research Investments: Proceedings of a Workshop–in Brief.
Companies know exactly what they spend on research, but knowing exactly what they get for their money is a more difficult question to answer. Without a good way to measure value, research can be viewed as a cost that can be cut to boost near-term earnings. The number of patents is one metric for measuring the value of research, but that information is not necessarily useful without knowing the business value of those patents in the marketplace. What other metrics serve to highlight the value of research and innovation? On June 27 and 28, 2017, the Government-University-Industry Research Roundtable held a meeting to explore these issues. This publication briefly summarizes the presentations and discussions from the meeting.
http://ift.tt/2zfNsL3
Evaluation of Health in Pregnancy grants in Scotland: a natural experiment using routine data.
'Health in Pregnancy' grants were not associated with higher birthweight but seem to have influenced maternal health-seeking behaviour.
http://ift.tt/2zw5RnM
Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use.
Drug overdose, driven largely by overdose related to the use of opioids, is now the leading cause of unintentional injury death in the United States. The ongoing opioid crisis lies at the intersection of two public health challenges: reducing the burden of suffering from pain and containing the rising toll of the harms that can arise from the use of opioid medications. Chronic pain and opioid use disorder both represent complex human conditions affecting millions of Americans and causing untold disability and loss of function. In the context of the growing opioid problem, the U.S. Food and Drug Administration (FDA) launched an Opioids Action Plan in early 2016. As part of this plan, the FDA asked the National Academies of Sciences, Engineering, and Medicine to convene a committee to update the state of the science on pain research, care, and education and to identify actions the FDA and others can take to respond to the opioid epidemic, with a particular focus on informing FDA's development of a formal method for incorporating individual and societal considerations into its risk-benefit framework for opioid approval and monitoring.
http://ift.tt/2zewYCT
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Publication date: September 2017 Source: Free Radical Biology and Medicine, Volume 110 Author(s): Lucía Fernández-del-Río, Anish Nag, Elen...
