Inhibition of Bcl-2/xl with ABT-263 selectively kills senescent Type II pneumocytes and reverses persistent pulmonary fibrosis induced by ionizing radiation in mice

Publication date: Available online 4 March 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jin Pan, Deguan Li, Yanfeng Xu, Junling Zhang, Yueying Wang, Mengyi Chen, Shuai Lin, Lan Huang, Eun Joo Chung, Deborah E. Citrin, Yingying Wang, Martin Hauer-Jensen, Daohong Zhou, Aimin Meng
PurposeIonizing radiation (IR)-induced pulmonary fibrosis (PF) is an irreversible and severe late effect of thoracic radiotherapy. The goal of this study was to determine whether clearance of senescent cells with ABT-263, a senolytic drug that can selectively kill senescent cells, can reverse PF.Methods and MaterialsC57BL/6J mice were exposed to a single dose of 17 Gy on the right side of the thorax. Sixteen weeks after IR, they were treated with 2 cycles of vehicle or ABT-263 (50 mg/kg/day for 5 days per cycle) by gavage. The effects of ABT-263 on IR-induced increases in senescent cells, elevation in the expression of selective inflammatory cytokines, matrix metalloproteinases (Mmps) and tissue inhibitors of Mmps (Timps), and the severity of the tissue injury and fibrosis in the irradiated lungs were evaluated 3 weeks after the last treatment, in comparison with the changes observed in the irradiated lungs before the treatment or after vehicle treatment.ResultsThe results show that 16 weeks after exposure of C57BL/6 mice to a single dose of 17 Gy thoracic irradiation resulted in persistent pulmonary fibrosis associated with a significant increase in senescent cells. Treatment of the irradiated mice with ABT-263 after they had developed persistent pulmonary fibrosis reduced senescent cells and reversed the disease.ConclusionsTo our knowledge, this is the first study to demonstrate that PF can be reserved by a senolytic drug such as ABT-263 after it becomes a progressive disease. Therefore, ABT-263 has the potential to be developed as a new treatment for PF.

Teaser

Ionizing radiation (IR)-induced pulmonary fibrosis (PF) is an irreversible and severe late effect of thoracic radiotherapy. Our studies show that ABT-263, a specific Bcl-2/xl inhibitor and a newly identified senolytic drug that can selectively kill senescent cells, could reverse PF even when the pulmonary fibrosis had already became persistent in mice after thoracic irradiation. This finding suggests that ABT-263 has the potential to be used as an effective treatment for PF.


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Interim 18FDG PET/CT during chemo-radiotherapy in the management of head-neck cancer patients: a systematic review

Publication date: Available online 4 March 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Cristina Garibaldi, Sara Ronchi, Marta Cremonesi, Laura Gilardi, Laura Travaini, Mahila Ferrari, Daniela Alterio, Johannes H.A.M. Kaanders, Delia Ciardo, Roberto Orecchia, Barbara Alicja Jereczek-Fossa, Chiara Maria Grana
Positron-Emission-Tomography (PET) is an imaging modality widely applied in oncology for tumor staging, volume delineation in radiotherapy planning, and therapy response assessment. ¹⁸F-fluorodeoxyglucose PET combined with Computed Tomography (¹⁸F-FDG-PET/CT) plays a significant role in the management of locally advanced head-neck cancer patients in the pre-treatment setting to predict outcome and prognosis and after chemo-radiotherapy (CRT) to assess tumor response. This review aims to evaluate the use of FDG-PET acquired during CRT, ad interim FDG (FDGint), in order to identify tumor response at an early stage, modify the treatment plan if necessary or setup alternative strategies to enhance the therapeutic ratio. Most of the works confirmed the value of FDGint in predicting the response to CRT, while a few highlighted the poor predictive value of FDGint compared to FDG acquired two-four months after the end of CRT, which was well correlated with local and regional control and survival. Such findings deserve to be further analyzed in a more numerous and homogeneous series according to the tumor site and CRT schedules. The best time to assess tumor response during RT remains a matter of debate, although two weeks seem most favorable, still providing opportunity to adapt the treatment strategy.



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Outcomes of Routine Intensity Modulated Radiotherapy Quality Assurance in a large Head and Neck Cancer Center

Publication date: Available online 4 March 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Isuru Amarasena, Ieta D'Costa, Tsien Fua, Albert Tiong, Vaughan Geddes, Phillip Tran, Chen Liu, June Corry
This is a retrospective analysis of a prospective database analysing an IMRT QA programme utilised in routine clinical practice at a large HNC center. The programme resulted in significant percentage of Major changes that were implemented and the time required for the QA process was less than expected. This study can inform discussion on optimal RT QA processes in routine clinical practice.



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Long-term growth decline in Toona ciliata in a moist tropical forest in Bangladesh: Impact of global warming

Publication date: April 2017
Source:Acta Oecologica, Volume 80
Author(s): Mizanur Rahman, Rofiqul Islam, Mahmuda Islam
Tropical forests are carbon rich ecosystems and small changes in tropical forest tree growth substantially influence the global carbon cycle. Forest monitoring studies report inconsistent growth changes in tropical forest trees over the past decades. Most of the studies highlighted changes in the forest level carbon gain, neglecting the species-specific growth changes which ultimately determine community-level responses. Tree-ring analysis can provide historical data on species-specific tree growth with annual resolution. Such studies are inadequate in Bangladesh, which is one of the most climate sensitive regions in the tropics. In this study, we investigated long-term growth rates of Toona ciliata in a moist tropical forest of Bangladesh by using tree-ring analysis. We sampled 50 trees of varying size, obtained increment cores from these trees and measured tree-ring width. Analyses of growth patterns revealed size-dependent growth increments. After correcting for the effect of tree size on tree growth (ontogenetic changes) by two different methods we found declining growth rates in T. ciliata from 1960 to 2013. Standardized ring-width index (RWI) was strongly negatively correlated with annual mean and maximum temperatures suggesting that rising temperature might cause the observed growth decline in T. ciliata. Assuming that global temperatures will rise at the current rate, the observed growth decline is assumed to continue. The analysis of stable carbon and oxygen isotopes may reveal more insight on the physiological response of this species to future climatic changes.



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Non-mammalian models reveal the role of alternative ligands for thyroid hormone receptors

Publication date: Available online 4 March 2017
Source:Molecular and Cellular Endocrinology
Author(s): Aurea Orozco, Iván Lazcano, Gabriela Hernández-Puga, Aurora Olvera
Thyroid hormones, or THs, are well-known regulators of a wide range of biological processes that occur throughout the lifespan of all vertebrates. THs act through genomic mechanisms mediated by thyroid hormone receptors (TRs). The main product of the thyroid gland is thyroxine or T4, which can be further transformed by different biochemical pathways to produce at least 15 active or inactive molecules. T3, a product of T4 outer-ring deiodination, has been recognized as the main bioactive TH. However, growing evidence has shown that other TH derivatives are able to bind to, and/or activate TRs, to induce thyromimetic effects. The compiled data in this review points to at least two of these TR alternative ligands: TRIAC and T2. Taking this into account, non-mammalian models have proven to be advantageous to explore new TH derivatives with potential novel actions, prompting a re-evaluation of the role and mechanism of action of TR alternative ligands that were previously believed to be inactive. The functional implications of these ligands across different vertebrates may require us to reconsider current established notions of thyroid physiology.



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Facing two faces: Defense activation varies as a function of personal relevance

Publication date: Available online 4 March 2017
Source:Biological Psychology
Author(s): Florian Bublatzky, Georg W. Alpers
It can be unsettling to be watched by a group of people, and when they express anger or hostility, this can prime defensive behavior. In contrast, when others smile at us, this may be comforting. This study tested to which degree the impact of facial expressions (happy, neutral, and angry) varies with the personal relevance of a social situation. Modelling a triadic situation, two faces looked either directly at the participant, faced each other, or they were back to back. Results confirmed that this variation constitutes a gradient of personal relevance (directed frontally > towards > away), as reflected by corresponding defensive startle modulation and autonomic nervous system activity. This gradient was particularly pronounced for angry faces and it was steeper in participants with higher levels of social anxiety. Thus, sender-recipient constellations modulate the processing of facial emotions in favor of adequate behavioral responding (e.g., avoidance) in group settings.



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Automating Cell Detection and Classification in Human Brain Fluorescent Microscopy Images Using Dictionary Learning and Sparse Coding

Publication date: Available online 4 March 2017
Source:Journal of Neuroscience Methods
Author(s): Maryana Alegro, Panagiotis Theofilas, Austin Nguy, Patricia A. Castruita, William Seeley, Helmut Heinsen, Daniela M. Ushizima, Lea T. Grinberg
BackgroundImmunofluorescence (IF) plays a major role in quantifying protein expression in situ and understanding cell function. It is widely applied in assessing disease mechanisms and in drug discovery research. Automation of IF analysis can transform studies using experimental cell models. However, IF analysis of postmortem human tissue relies mostly on manual interaction, often subjected to low-throughput and prone to error, leading to low inter and intra-observer reproducibility. Human postmortem brain samples challenges neuroscientists because of the high level of autofluorescence caused by accumulation of lipofuscin pigment during aging, hindering systematic analyses. We propose a method for automating cell counting and classification in IF microscopy of human postmortem brains. Our algorithm speeds up the quantification task while improving reproducibility.New methodDictionary learning and sparse coding allow for constructing improved cell representations using IF images. These models are input for detection and segmentation methods. Classification occurs by means of color distances between cells and a learned set.ResultsOur method successfully detected and classified cells in 49 human brain images. We evaluated our results regarding true positive, false positive, false negative, precision, recall, false positive rate and F1 score metrics. We also measured user-experience and time saved compared to manual countings.Comparison with existing methodsWe compared our results to four open-access IF-based cell-counting tools available in the literature. Our method showed improved accuracy for all data samples.ConclusionThe proposed method satisfactorily detects and classifies cells from human postmortem brain IF images, with potential to be generalized for applications in other counting tasks.



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Isometric endurance test of the cervical flexor muscles – reliability and normative reference values

Publication date: Available online 4 March 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Jari Ylinen, Petri Salo, Salme Järvenpää, Arja Häkkinen, Riku Nikander
ObjectiveTo obtain reference values for the isometric endurance test (IET) of the cervical flexor muscles, investigate its reproducibility, and compare the results with the maximal isometric strength test (MIST) of the cervical flexor muscles.DesignCross-sectional non-comparative study with single group repeated measurements.MethodsAltogether 219 healthy females aged 20 to 59 years volunteered to participate in the study. The IET was performed in the supine position and MIST seated. The reproducibility was evaluated by the intraclass correlation coefficient (ICC) and an analysis described by Bland and Altman. The relationship between the two measuring methods was evaluated by Pearson's correlation coefficient.ResultsThe mean (SD) IET time was 60 (33) seconds with no significant differences between the age groups of each decade. The ICC for intrarater repeatability was 0.80. However, the Bland-Altman analysis suggested moderate variation in repeated measurements. Pearson's correlation coefficient between the IET and MIST was 0.56.ConclusionNormative reference values for the IET are presented. Although the ICC showed good repeatability, one should consider that the change at follow-up visits has to be considerable to be clinically relevant. The correlation between the endurance time and maximal flexion strength was moderate. Thus IET of the cervical flexor muscles may be used in the clinic like the Biering-Sorenson test has been used to assess fatigue of the trunk extensor muscles.



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Low handgrip strength levels among adolescents in a city in Southern Brazil

Publication date: Available online 4 March 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Diego Augusto Santos Silva, Andreia Pelegrini, João Antônio Chula de Castro, Tiago Rodrigues de Lima, Gabriel Renaldo de Sousa, João Marcos Ferreira de Lima Silva, Edio Luiz Petroski
ObjectiveTo estimate the prevalence of low handgrip strength (HGS) levels and sociodemographic characteristics, health behaviours and body fatness status related in adolescents. Method: Cross-sectional epidemiological study with 636 adolescents aged 14-19 years in a city in southern Brazil. HGS was measured by dynamometer. Sociodemographic and behavioural data were collected using self-report questionnaires. Body mass and height was measured by Body Mass Index. Results: Prevalence of low HGS levels was 47% (63.5% boys, 37.7% girls). Boys aged 14-16 years were more likely to have low HGS levels. Girls who were of higher socioeconomic status and who were less physically active were more likely to have low HGS levels. Overweight girls were less likely to have low HGS levels. Conclusions: High prevalence of low HGS levels was observed in adolescents. Increased HGS levels should be focused on younger boys and normal-weight girls with higher socioeconomic status and lower levels of physical activity.



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The effects of neck mobilization in patients with chronic neck pain: A randomized controlled trial

Publication date: Available online 4 March 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Muhammad Nazim Farooq, Mohammad A. Mohseni-Bandpei, Syed Amir Gilani, Muhammad Ashfaq, Qamar Mahmood
ObjectiveTo determine the effect of mobilization and routine physiotherapy on pain, disability, neck range of motion (ROM) and neck muscle endurance (NME) in patients having chronic mechanical neck pain (NP).MethodsSixty eight patients with chronic mechanical NP were randomly allocated into two groups by using a computer generated random sequence table with 34 patients in the multi-modal mobilization group and 34 patients in the routine physiotherapy group. Baseline values for pain, disability, NME, and neck ROM were recorded using visual analogue scale (VAS), neck disability index (NDI), neck flexor muscle endurance test and universal goniometer respectively, before the treatment. Each patient received 10 treatment sessions over a period of four weeks and at the end of four weeks all the outcome measures were recorded again.ResultsA paired t-test revealed significant pre to post treatment differences for all outcome measures in both groups (p < 0.001 in all instances). An independent t-test revealed statistically significant differences for pain, disability, NME, and neck rotation in favor of the multi-modal mobilization group with a between group difference of 1.57 cm for VAS (p < 0.001), 11.74 points for NDI (p = 0.001), 18.45 seconds for NME (p < 0.001) and 6.06 to 8.24 degrees for neck ROM (p < 0.05).ConclusionThe results suggest that a combination of cervical mobilization with routine physiotherapy is more effective for reducing pain and disability and improving NME and neck ROM in patients with chronic mechanical NP compared to routine physiotherapy alone.



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The effects of clinical Pilates exercises on patients with shoulder pain: A randomized clinical trial

Publication date: Available online 4 March 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Esra Atılgan, Aydan Aytar, Aslıcan Çağlar, Ayça Aytar Tığlı, Gamze Arın, Gökmen Yapalı, Pınar Kısacık, Utku Berberoğlu, Hülya Özlem Şener, Edibe Ünal
AimThe purpose of this study was to determine the effect of Clinical Pilates exercises on patients with shoulder pain.Material and MethodsThirty-three patients, experiencing shoulder pain continuously for at least four weeks were selected as study subjects. The patients were randomly divided into two groups, namely Clinical Pilates exercise (n=17) group and conventional exercise (n=16) group. The patients were treated for five days a week, the total treatment being carried out for 10 days. The assessment of pain and disability amongst the patients were done at the baseline and at the end of the treatment sessions, using Visual Analogue Scale (VAS) and Shoulder Pain and Disability Index (SPADI).ResultsThe clinical Pilates exercise group showed a significant improvement in all scores used for assessment (p<0.05), while the conventional exercise group demonstrated a significant improvement only in the SPADI total score (p<0.05). A comparison of scores for the VAS, SPADI-Pain and SPADI-Total between the two groups, revealed a significant improvement in the Clinical Pilates exercise group (p<0.05).ConclusionIt was demonstrated by the study that Clinical Pilates exercise is an efficient technique for patients experiencing shoulder pain, as it helps reduce pain and disability among them.



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Reliability of Kinematic Measures in Subjects With Anterior Cruciate Ligament Deficiency During Dual-Task Walking

Publication date: Available online 4 March 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Salman Nazary-Moghadam, Mahyar Salavati, Ali Esteki, Behnam Akhbari, Sohrab Keyhani, Afsaneh Zeinalzadeh
ObjectiveTo define the throughout within- and between-day reliability of gait parameters in single - and dual-task conditions in subjects with and without anterior cruciate ligament deficiency (ACLD).MethodsFourteen subjects with ACLD and 14 healthy subjects completed a walking task on a treadmill with three levels of velocity (self-selected, high and low), with or without performing an auditory Stroop task over two sessions each 3-5 days apart. The gait kinematic parameters, including maximum and minimum hip flexion, total hip range of motion, maximum and minimum knee flexion and total knee range of motion were recorded using a motion analysis system. The intraclass correlation coefficient (ICC), the standard error of measurement (SEM), and the coefficient of variation (CV) were used to determine inter- and intrasession reliability of kinematic and cognitive measures.ResultsICCs for ACLD group in dual-task and single task conditions ranged between 0.50 to 0.93 and 0.53 to 0.93, respectively. ICC values for healthy groups in dual-task and single task conditions ranged between 0.36 to 0.90 and 0.39 to 0.87, respectively. When comparing relative reliability across kinematic variables in different velocities, ICC values were generally identical in all three levels of velocity.ConclusionThe findings suggest that dual-tasking could also be applied reliably for the assessment of functional activities in subjects with and without ACLD.



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Postural insoles on gait in children with cerebral palsy: Randomized controlled double-blind clinical trial

Publication date: Available online 4 March 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Hugo Pasin Neto, Luanda André Collange Grecco, Luis Alfredo Braun Ferreira, Natália Almeida Carvalho Duarte, Manuela Galli, Claudia Santos Oliveira
The aim of the present study was to assess the effect of postural insoles on gait performance in children with Cerebral Palsy (CP).Twenty four children between four and 12 years of age were randomly allocated either the control group (n = 12) or experimental group (n = 12).The control group used placebo insoles and the experimental group used postural insoles. Three-dimensional gait analysis was performed under three conditions: barefoot, in shoes and in shoes with insoles. Three evaluations were carried out: 1)immediately following placement of the insoles; 2)after three months of insole use; and 3)one month after suspending insole use. Regarding the immediate effects and after three months use of insole, significant improvements in gait velocity and cadence were found in the experimental group, along with an increase in foot dorsiflexion, a reduction in knee flexion and a reduction in internal rotation. Conversely, these changes were not maintained in the third assessment, one month after withdrawal of the insoles. The use of postural insoles led to improvements in gait performance in children with CP.



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Effect of Movement Control and stabilization Exercises in People with Extension Related Non -Specific Low Back Pain- A pilot Study

Publication date: Available online 4 March 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Sara Salamat, Saeed Talebian, Hosein Bagheri, Nader Maroufi, Mohammad Jafar Shaterzadeh, Gitta Kalbasi, Kieran O'Sullivan
BackgroundExercise is considered an effective treatment strategy for non-specific chronic low back pain (NSCLBP).In spite of the wide use of exercise protocols, it is not clear what type of exercise is more effective in decreasing pain, disability and normalizing muscle activation patterns in people with chronic low back pain.ObjectivesTo assess the effects of two exercise protocols (stabilization vs movement control) on pain and disability scores and the flexion relaxation ratio (FRR) of lumbar multifidus (LM) and iliocostalis lumbarum pars thoracic (ICLT) in people with extension related non-specific chronic low back pain.Study designPilot randomized control trial.Methods32 subjects with active extension pattern chronic low back pain (stabilization group=16, movement control group=16) participated in this study. Treatment groups received 4 weeks of exercise therapy. Outcomes were based on pain score (Numeric rating Scale-NRS), disability (Oswestry Disability Index- ODI) and FRR of the LM and ICLT.ResultsFour people dropped out of the study in each group for reasons unrelated to the protocols of the study. Pain and disability reduced in both groups, with no significant difference between the groups. The FRR of LM did not change in either treatment group after treatment. However, the FRR of ICLT was significantly increased after treatment in the movement control group.ConclusionBoth movement control and stabilization exercises reduced pain and disability in the short-term among people with extension pattern NSCLBP, with no difference in effectiveness between the groups. However, movement control exercises were more effective in normalizing back muscle activation patterns than stabilization exercises.



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Immediate effect of common peroneal nerve electrical stimulation on quadriceps muscle arthrogenic inhibition in patients with knee osteoarthritis

Publication date: Available online 4 March 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Hossein Rafsanjani, Khosro Khademi-Kalantari, Asghar Rezasoltani, Sedigheh Sadat Naimi, Mehri Ghasemi, Shapour Jaberzadeh
ObjectiveTo investigate the immediate effect of electrical stimulation of the common peroneal nerve on the maximum voluntary activation of the quadriceps muscle in patients with knee osteoarthritis.MethodologyFifteen subjects with knee osteoarthritis (mean age: 50.5±13 years) participated in this study. To measure the arthrogenic inhibition ratio of quadriceps, a burst of electrical stimulation was superimposed on the maximum voluntary contraction, and the percentage of change in the force production was computed. The same measurement was also performed with concurrent electrical stimulation of the common peroneal nerve.ResultsAll the patients with knee osteoarthritis showed significant arthrogenic inhibition of the quadriceps muscle. The stimulation of the common peroneal nerve was able to reduce this inhibition and increase the capacity of the muscle to produce a significantly higher knee extension force (p=0.028).ConclusionsElectrical stimulation of the common peroneal nerve concurrent with the maximum voluntary effort can remove the arthrogenic inhibition of the quadriceps muscle in patients with knee osteoarthritis. This finding could have clinical implications in the management of patients with knee disorders.



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Smartphone–based enzymatic biosensor for oral fluid L-lactate detection in one minute using confined multilayer paper reflectometry

Publication date: 15 August 2017
Source:Biosensors and Bioelectronics, Volume 94
Author(s): Donato Calabria, Cristiana Caliceti, Martina Zangheri, Mara Mirasoli, Patrizia Simoni, Aldo Roda
The development of smartphone–based biosensors for point-of-care testing (POCT) applications allows realizing "all in one" instruments, with large potential distribution among the general population. With this respect, paper color-based detection performed by reflectance measurement is the most popular, simple, inexpensive and straightforward method. Despite the large number of scientific publications related to these biosensors, they still suffer from a poor detectability and reproducibility related to inhomogeneity of color development, which leads to low assay reproducibility. To overcome these problems, we propose a smartphone paper-based biosensor, in which all the reagents necessary to complete the analysis are co-entrapped on paper in a "wafer"-like bilayer film of polyelectrolytes (Poly (allyl amine hydrochloride/poly(sodium 4-styrene sulfonate)). Using a 3D printing low-cost technology we fabricated the smartphone-based device that consists in a cover accessory attached to the smartphone and incorporating a light diffuser over the flash to improve the image quality, a mini dark box and a disposable analytical cartridge containing all the reagents necessary for the complete analysis. The biosensor was developed exploiting coupled enzyme reactions for quantifying L-lactate in oral fluid, which is considered a biomarker of poor tissue perfusion, a key element in the management of severe sepsis, septic shock and in sports performance evaluation. The developed method is sensitive, rapid, and it allows detecting L-lactate in oral fluid in the relevant physiological range, with a limit of detection of 0.1mmolL⁻¹. The extreme simplicity of assay execution (no reagents need to be added) and flexibility of fabrication of the device, together with the high assay versatility (any oxidase can be coupled with HRP-based color change reaction) make our approach suitable for the realization of smartphone-based biosensors able to non-invasively detect a large variety of analytes of clinical interest.



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Fundamental studies of adrenal retinoid-X-receptor: Protein isoform, tissue expression, subcellular distribution, and ligand availability

Publication date: Available online 4 March 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Behling Cheng, Fatema H. Al-Shammari, Isra'a A. Ghader, Fatima Sequeira, Jitendra Thakkar, Thazhumpal C. Mathew
Adrenal gland reportedly expresses many nuclear receptors that are known to heterodimerize with retinoid-X-receptor (RXR) for functions, but the information regarding the glandular RXR is not adequate. Studies of rat adrenal homogenate by Western blotting revealed three RXR proteins: RXRα (55kDa), RXRβ (47kDa) and RXR (56kDa). RXRγ was not detectable. After fractionation, RXRα was almost exclusively localized in the nuclear fraction. In comparison, substantial portions of RXRβ and RXR were found in both nuclear and post-nuclear particle fractions, suggesting genomic and non-genomic functions. Cells immunostained for RXRα were primarily localized in zona fasciculata (ZF) and medulla, although some stained cells were found in zona glomerulosa (ZG) and zona reticularis (ZR). In contrast, cells immunostained for RXRβ were concentrated principally in ZG, although some stained cells were seen in ZR, ZF, and medulla (in descending order, qualitatively). Analysis of adrenal lipid extracts by LC/MS did not detect 9-cis-retinoic acid (a potent RXR-ligand) but identified all-trans retinoic acid. Since C20 and C22 polyunsaturated fatty acids (PUFAs) can also activate RXR, subcellular availabilities of unesterified fatty acids were investigated by GC/MS. As results, arachidonic acid (C20:4), adrenic acid (C22:4), docosapentaenoic acid (C22:5), and cervonic acid (C22:6) were detected in the lipids extracted from each subcellular fraction. Thus, the RXR-agonizing PUFAs are available in all the main subcellular compartments considerably. The present findings not only shed light on the adrenal network of RXRs but also provide baseline information for further investigations of RXR heterodimers in the regulation of adrenal steroidogenesis.



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Reorganization of Anterior and Posterior Hippocampal Networks Associated with Memory Performance in Mesial Temporal Lobe Epilepsy

Publication date: Available online 4 March 2017
Source:Clinical Neurophysiology
Author(s): Hong Li, Caihong Ji, Lujia Zhu, Peiyu Huang, Biao Jiang, Xiaojun Xu, Jianzhong Sun, Zhong Chen, Meiping Ding, Minming Zhang, Shuang Wang
ObjectiveTo investigate the pattern of functional demarcation of hippocampal network and its relationship with memory performance in mesial temporal lobe epilepsy (mTLE) with unilateral hippocampal sclerosis.MethodsResting state fMRI data were acquired from fifteen left mTLE patients, fourteen right mTLE patients and twenty healthy subjects. We explore the hippocampal-cortical alterations and corresponding inter-hemispheric functional connectivity (FC) across anterior and posterior hippocampal networks. The association between FC and memory performance was assessed.ResultsLeft mTLE showed increased intra-hemispheric FC in anterior hippocampal networks, including left anterior hippocampal-entorhinal cortex and right anterior hippocampal-orbitofrontal cortex, and decreased inter-hemispheric FC between anterior hippocampus, entorhinal cortex and posterior cingulate cortex. Right mTLE was associated with extensive reduction in inter-hemispheric FC along the areas of anterior and posterior hippocampal networks. Intra-hemispheric FC between left anterior hippocampus and entorhinal cortex was positively correlated with verbal memory in left mTLE. Inter-hemispheric FC between posterior parahippocampal gyrus was negatively correlated with verbal memory in right mTLE.ConclusionsOur findings suggested that left and right mTLE exhibit different neural reorganization patterns of anterior and posterior hippocampal networks associated with verbal memory.SignificanceThe findings may facilitate the characterization of mTLE associated with memory deficit.



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Response to anti-programmed cell death protein-1 antibodies in men treated for platinum refractory germ cell cancer relapsed after high-dose chemotherapy and stem cell transplantation

Publication date: May 2017
Source:European Journal of Cancer, Volume 76
Author(s): Stefanie Zschäbitz, Felix Lasitschka, Boris Hadaschik, Ralf-Dieter Hofheinz, Kathleen Jentsch-Ullrich, Marcus Grüner, Dirk Jäger, Carsten Grüllich
IntroductionTreatment options for patients with platinum refractory metastatic germ cell tumours (GCT) relapsing after high-dose chemotherapy and autologous stem cell transplantation are limited and survival is poor. Antibodies directed against programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) are currently assessed within clinical trials. We present updated data on our experience with checkpoint inhibitors as a compassionate use off-label treatment attempt for highly-pretreated patients with GCT and provide an overview of the current literature on PD-L1 expression in this rare tumour entity.Patients and methodsWe analysed all patients with platinum refractory GCT treated with checkpoint inhibitors at our institutions between 2015 and 2017. Data were retrieved retrospectively from the patient charts.ResultsSeven patients were treated with nivolumab or pembrolizumab. Four patients received single-dose treatment and died shortly afterwards due to tumour progression; the remaining three patients received treatment for at least 6 months. No significant treatment toxicity was observed. Long-term tumour response was achieved in two of the three patients, both of them highly positive for PD-L1 staining.InterpretationWe consider checkpoint inhibition to be efficient in carefully selected patients with platinum refractory GCT. However, predictive markers associated with tumour response are not yet known and larger prospective clinical trials are warranted.



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More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): L. Kandolf Sekulovic, K. Peris, A. Hauschild, A. Stratigos, J.-J. Grob, P. Nathan, R. Dummer, A.-M. Forsea, C. Hoeller, H. Gogas, L. Demidov, C. Lebbe, C. Blank, J. Olah, L. Bastholt, D. Herceg, B. Neyns, R. Vieira, J. Hansson, P. Rutkowski, I. Krajsova, M. Bylaite-Bucinskiene, I. Zalaudek, J. Maric-Brozic, N. Babovic, M. Banjin, K. Putnik, G. Weinlich, V. Todorovic, K. Kirov, J. Ocvirk, A. Zhukavets, M. Kukushkina, L. De La Cruz Merino, A. Ymeri, M. Risteski, C. Garbe
BackgroundDespite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF).Materials and methodsWeb-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes.ResultsThe recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r = 0.662; p < 0.001), health expenditure per capita (r = 0.695; p < 0.001) and the Mackenbach score of health policy performance (r = 0.765; p < 0.001) with the percentage of patients treated with innovative medicines and a number of reimbursed medicines.ConclusionsGreat discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry.



http://ift.tt/2maDBlU

Continuous membrane potential fluctuations in motor cortex and striatum neurons during voluntary forelimb movements and pauses

Publication date: Available online 4 March 2017
Source:Neuroscience Research
Author(s): Satoshi Nonomura, Yoko Fujiwara-Tsukamoto, Takafumi Kajihara, Fumino Fujiyama, Yoshikazu Isomura
Theoretical simulations suggest that spike rate is regulated by varying both membrane potential and its fluctuation. We investigated whether membrane potential fluctuation functionally changes in motor cortex and striatum neurons during discrete forelimb movements and pauses, or at rest, using whole-cell recording in task-performing rats. Membrane potential fluctuation was diminished by task performance, but maintained overall in the alpha/beta and gamma bands during forelimb movements and pauses. By contrast, membrane potential itself was correlated with spike rate in task-related neurons. Thus, membrane potential, but not its fluctuation, is a critical determinant of execution and pausing of discrete movements.



http://ift.tt/2mpjDEz

Redox-responsive mesoporous selenium delivery of doxorubicin targets MCF-7 cells and synergistically enhances its anti- tumor activity

Publication date: Available online 4 March 2017
Source:Acta Biomaterialia
Author(s): Shuang Zhao, Qianqian Yu, Jiali Pan, Yanhui Zhou, Chengwen Cao, Jian-Ming Ouyang, Jie Liu
To reduce the side effects and enhance the anti-tumor activities of anticancer drugs in the clinic, the use of nano mesoporous materials, with mesoporous silica (MSN) being the best-studied, has become an effective method of drug delivery. In this study, we successfully synthesized mesoporous selenium (MSe) nanoparticles and first introduced them to the field of drug delivery. Loading MSe with doxorubicin (DOX) is mainly driven by the physical adsorption mechanism of the mesopores, and our results demonstrated that MSe could synergistically enhance the antitumor activity of DOX. Coating the surface of MSe@DOX with Human serum albumin (HSA) generated a unique redox-responsive nanoparticle (HSA-MSe@DOX) that demonstrated glutathione-dependent drug release, increased tumor-targeting effects and enhanced cellular uptake throug nanoparticle interact with SPARC in MCF-7 cells. In vitro, HSA-MSe@DOX prominently induced cancer cell toxicity by synergistically enhancing the effects of MSe and DOX. Moreover, HSA-MSe@DOX possessed tumor-targeting abilities in tumor-bearing nude mice and not only decreased the side effects associated with DOX, but also enhanced its antitumor activity. Therefore, HSA-MSe@DOX is a promising new drug that warrants further evaluation in the treatments of tumors.Statement of significanceTo reduce the side effects and enhance the anti-tumor activities of anticancer drugs, we successfully synthesized mesoporous selenium (MSe) nanoparticles and first introduced them to the field of drug delivery. Loading MSe with doxorubicin (DOX) is mainly driven by the physical adsorption mechanism of the mesopores. Coating the surface of MSe@DOX with Human serum albumin (HSA) generated a unique redox-responsive nanoparticle (HSA-MSe@DOX) that demonstrated glutathione-dependent drug release, increased tumor-targeting effects and enhanced cellular uptake throug nanoparticle interact with SPARC in MCF-7 cells. In vitro and in vivo, HSA-MSe@DOX possessed tumor-targeting abilities and not only decreased the side effects associated with DOX, but also enhanced its antitumor activity. Therefore, HSA-MSe@DOX is a promising new drug that warrants further evaluation in the treatments of tumors.

Graphical abstract

http://ift.tt/2lKSRSV

Effect of modified flux on MIG arc brazing-fusion welding of aluminum alloy to steel butt joint

Publication date: July 2017
Source:Journal of Materials Processing Technology, Volume 245
Author(s): Guoliang Qin, Yang Ji, Hong Ma, Zhiyong Ao
Pulsed MIG arc brazing-fusion welding process was applied to realize the butt joining of galvanized steel and 5052 aluminum alloy with no enclosed slot or groove adopted. A modified flux mixture was developed to improve the butt joint performance. After applying the modified flux, weld appearance became better and the spreadability of filler metal was also greatly improved. During brazing-fusion welding process, flux floating on the surface of welding pool weakened the surface tension between filler metal and Fe and reduced the evaporation of Zn, which both led to the greatly enhanced spreadability. The analysis of intermetallic compounds (IMCs) at brazed interface showed that Fe3Al was formed at upper side of steel plate, while Fe2Al5 was formed at other areas with the consideration of its lowest Gibbs free energy under certain temperature range. With modified flux, the tensile strength of the joint could reach up to 120MPa, which was about 60% of that of 5052 aluminum alloy base metal. From the fractured surface, two different fracture modes were identified, tear fracture and intergranular fracture, which confirmed that joint fractured in a brittle mode. The crack initiated at the front side of brazed interface due to the thicker IMCs layer, then propagated to the surface before the whole joint failed. The improved spreadability of filler metal on the top and back sides of steel plate due to the application of flux, contributed to the improvement of joint strength.

Graphical abstract

http://ift.tt/2mawrhD

Injury to Perineal Branch of Pudendal Nerve in Women: Outcome from Resection of the Perineal Branches

J reconstr Microsurg
DOI: 10.1055/s-0037-1599130

Background This study describes outcomes from a new surgical approach to treat "anterior" pudendal nerve symptoms in women by resecting the perineal branches of the pudendal nerve (PBPN). Methods Sixteen consecutive female patients with pain in the labia, vestibule, and perineum, who had positive diagnostic pudendal nerve blocks from 2012 through 2015, are included. The PBPN were resected and implanted into the obturator internus muscle through a paralabial incision. The mean age at surgery was 49.5 years (standard deviation [SD] = 11.6 years) and the mean body mass index was 25.7 (SD = 5.8). Out of the 16 patients, mechanisms of injury were episiotomy in 5 (31%), athletic injury in 4 (25%), vulvar vestibulectomy in 5 (31%), and falls in 2 (13%). Of these 16 patients, 4 (25%) experienced urethral symptoms. Outcome measures included Female Sexual Function Index (FSFI), Vulvar Pain Functional Questionnaire (VQ), and Numeric Pain Rating Scale (NPRS). Results Fourteen patients reported their condition pre- and postoperatively. Mean postoperative follow-up was 15 months. The overall FSFI, and arousal, lubrication, orgasm, satisfaction, and pain domains significantly improved (p < 0.05). The VQ also significantly improved (p < 0.001) in 13 (93%) of 14 patients. The NPRS score decreased on average from 8 to 3 (p < 0.0001). All four patients with urethral symptoms were relieved of these symptoms. Conclusion Resection of the PBPN with implantation of the nerve into the obturator internus muscle significantly reduced pain and improved sexual function in women who sustained injury to the PBPN.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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End-to-End versus End-to-Side Microvascular Anastomosis: A Meta-analysis of Free Flap Outcomes

J reconstr Microsurg
DOI: 10.1055/s-0037-1599099

Background Optimal outcomes in microsurgery have been attributed to a range of factors, with performing of end-to-end (ETE) versus end-to-side (ETS) influencing anastomotic complications and flap outcomes. Methods A systematic review of the literature and meta-analysis was undertaken to evaluate the relative risks of anastomotic complications with ETE versus ETS approaches, for arterial and venous anastomoses looking at risk ratios (RRs) for thrombosis and overall flap failure. Results RRs of thrombosis and flap failure in ETS versus ETE venous anastomosis groups were 1.30 (95% confidence interval [CI]: 0.53–3.21) and 1.50 (95% CI: 0.85–2.67), respectively. The RRs of thrombosis and flap failure in ETS versus ETE arterial anastomosis groups were 1.04 (95% CI: 0.32–3.35) and 1.04 (95% CI: 0.72–1.48), respectively. Conclusion Differences in rates of thrombosis and flap failure between ETE and ETS venous and arterial anastomoses are marginal and nonsignificant. As such, the type of anastomotic technique is best decided on a case-by-case basis, dependent on anatomical, surgical, and patient factors.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Surgeon-Based 3D Printing for Microvascular Bone Flaps

J reconstr Microsurg
DOI: 10.1055/s-0037-1600133

Background Three-dimensional (3D) printing has developed as a revolutionary technology with the capacity to design accurate physical models in preoperative planning. We present our experience in surgeon-based design of 3D models, using home 3D software and printing technology for use as an adjunct in vascularized bone transfer. Methods Home 3D printing techniques were used in the design and execution of vascularized bone flap transfers to the upper extremity. Open source imaging software was used to convert preoperative computed tomography scans and create 3D models. These were printed in the surgeon's office as 3D models for the planned reconstruction. Vascularized bone flaps were designed intraoperatively based on the 3D printed models. Results Three-dimensional models were created for intraoperative use in vascularized bone flaps, including (1) medial femoral trochlea (MFT) flap for scaphoid avascular necrosis and nonunion, (2) MFT flap for lunate avascular necrosis and nonunion, (3) medial femoral condyle (MFC) flap for wrist arthrodesis, and (4) free fibula osteocutaneous flap for distal radius septic nonunion. Templates based on the 3D models allowed for the precise and rapid contouring of well-vascularized bone flaps in situ, prior to ligating the donor pedicle. Conclusions Surgeon-based 3D printing is a feasible, innovative technology that allows for the precise and rapid contouring of models that can be created in various configurations for pre- and intraoperative planning. The technology is easy to use, convenient, and highly economical as compared with traditional send-out manufacturing. Surgeon-based 3D printing is a useful adjunct in vascularized bone transfer. Level of Evidence Level IV.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

http://ift.tt/2mok95C

Radiocaesium contamination and dose rate estimation of terrestrial and freshwater wildlife in the exclusion zone of the Fukushima Dai-ichi Nuclear Power Plant accident

Publication date: May 2017
Source:Journal of Environmental Radioactivity, Volume 171
Author(s): Shoichi Fuma, Sadao Ihara, Hiroyuki Takahashi, Osamu Inaba, Youji Sato, Yoshihisa Kubota, Yoshito Watanabe, Isao Kawaguchi, Tatsuo Aono, Haruhi Soeda, Satoshi Yoshida
To characterise the radioactive contamination of terrestrial and freshwater wildlife caused by the Fukushima Dai-ichi Nuclear Power Plant accident, biological samples, namely, fungi, mosses, plants, amphibians, reptiles, insects, molluscs, and earthworms, were collected mainly from the forests of the exclusion zone in the Fukushima Prefecture from 2011 to 2012. Caesium-134 and ¹³⁷Cs were detected by gamma spectrometry in almost all the samples. Fungi, ferns, and mosses accumulated high amounts of radiocaesium, as they did in Chernobyl, with ¹³⁴Cs + ¹³⁷Cs activity concentrations of 10⁴–10⁶ Bq kg⁻¹ fresh mass (FM). Earthworms, amphibians, and the soft tissue of the garden snail Acusta despecta sieboldiana, also had levels as high as 10⁴–10⁵ Bq kg⁻¹ FM of ¹³⁴Cs + ¹³⁷Cs. Most of the estimated total (internal + external) dose rates to herbaceous plants, amphibians, insects, and earthworms were below the corresponding derived consideration reference levels (DCRLs) recommended by the ICRP. This suggests that, in most cases, there was little chance of deleterious effects of ionising radiation on these organisms in the exclusion zone for the first year after the accident, though the dose rates were underestimated mainly due to the lack of consideration of short-lived radionuclides.



http://ift.tt/2lJm6pb

Meeting report: Metastasis Research Society–Chinese Tumor Metastasis Society joint conference on metastasis

Abstract

During September 16th–20th 2016, metastasis experts from around the world convened for the 16th Biennial Congress of the Metastasis Research Society and 12th National Congress of the Chinese Tumor Metastasis Society in Chengdu, China to share most current data covering basic, translational, and clinical metastasis research. Presentations of the more than 40 invited speakers of the main congress and presentations from the associated Young Investigator Satellite Meeting are summarized in this report by session topic. The congress program also included three concurrent short talk sessions, an advocacy forum with Chinese and American metastatic patient advocates, a 'Meet the Professors Roundtable' session for young investigators, and a 'Meet the Editors' session with editors from Cancer Cell and Nature Cell Biology. The goal of integrating expertise and exchanging the latest findings, ideas, and practices in cancer metastasis research was achieved magnificently, thanks to the excellent contributions of many leaders in the field.

http://ift.tt/2mnEsAi

A reflection and a look forward with Dr. Sue Eccles, retired Editor-in-Chief of Clinical and Experimental Metastasis

Abstract

After a lifetime's work devoted to metastasis research, Dr. Sue Eccles recently retired. She was a founding member the Metastasis Research Society in 1984, and has served as Editor-In-Chief of Clinical and Experimental Metastasis from its inception until her retirement, an amazing 32 years of service. Dr. Kate Bakaitis recently talked with Dr. Eccles about her experiences, memories and advice for young investigators.

http://ift.tt/2mZqvFE

Cabergoline for hyperprolactinemia: getting to the heart of it

http://ift.tt/2lqzSlp

Follicle stimulating hormone, its novel association with sex hormone binding globulin in men and postmenopausal women

Abstract

Purpose

Follicle stimulating hormone plays direct roles in a variety of nongonadal tissues and sex hormone binding globulin is becoming the convergence of the crosstalk among metabolic diseases. However, no studies have explored the association between follicle stimulating hormone and sex hormone binding globulin. We aimed to study this association among men and women.

Methods

SPECT-China is a population-based study conducted since 2014. This study included 4206 men and 2842 postmenopausal women. Collected serum was assayed for gonadotropins, sex hormone binding globulin, sex hormones etc. Regression analyses were performed to assess the relationship between sex hormone binding globulin and follicle stimulating hormone and other variables including metabolic factors, thyroid function and sex hormones. Treatment with follicle stimulating hormone at different concentrations of 0, 5, 50 and 100 IU/L for 24 h was performed in HepG2 cells.

Results

In Spearman correlation, sex hormone binding globulin was significantly correlated with FSH, triglycerides, thyroxins, body mass index and blood pressure in men and postmenopausal women (all P < 0.05). In regression analyses, follicle stimulating hormone was a significant predictor of sex hormone binding globulin in men and postmenopausal women (P < 0.05), independent of above variables. Follicle stimulating hormone induced sex hormone binding globulin expression in a dose-dependent fashion in HepG2 cells.

Conclusion

Serum follicle stimulating hormone levels were positively associated with circulating sex hormone binding globulin levels in men and postmenopausal women. This association is independent of age, insulin resistance, hepatic function, lipid profile, thyroid function, adiposity, blood pressure, and endogenous sex hormones.

http://ift.tt/2mR0YPR

Biochemical assessment of disease control in acromegaly: reappraisal of the glucose suppression test in somatostatin analogue (SA) treated patients

Abstract

Background

It is recommended not to measure growth hormone during oral glucose suppression (oral glucose tolerance test) during somatostatin analog treatment in acromegaly. However, we have observed that failure to suppress growth hormone in response to oral glucose tolerance test during somatostatin analog unmasks insufficient disease control and hypothesize that somatostatin analog also induces insufficient growth hormone suppression to mixed meals.

Methods

We therefore compared serum growth hormone levels during two mixed meals in patients with controlled insulin-like growth factor-I levels after either surgery alone (n = 9) or somatostatin analog treatment (n = 9). The patients were unbiasedly matched for gender and insulin-like growth factor-I and studied twice in the following order: (1) during a 6 h growth hormone day curve including two mixed meals and (2) during a 3 h growth hormone profile including 60 min fasting followed by a 2-h oral glucose tolerance test.

Results

During the day curve growth hormone levels were elevated in the somatostatin analog group (P = 0.008) and growth hormone levels 1 h after each meal declined significantly only in the surgery group (P = 0.02). During the oral glucose tolerance test the two groups had similar growth hormone levels prior to the glucose load (P = 0.6), whereas a significant 66% suppression was observed after glucose only in the surgery group (P = 0.001).

Conclusions

(1) Patients controlled by somatostatin analog fail to suppress growth hormone in response to both mixed meals and oral glucose tolerance test (2) This phenomenon is likely to result in elevated serum growth hormone levels during everyday life in somatostatin analog-treated patients, (3) We postulate that measuring growth hormone levels during oral glucose tolerance test is useful to unmask potential somatostatin analog under-treatment in the presence of 'safe' insulin-like growth factor-I levels.

http://ift.tt/2lqgqWd

Cabergoline for hyperprolactinemia: getting to the heart of it

http://ift.tt/2lqzSlp

Follicle stimulating hormone, its novel association with sex hormone binding globulin in men and postmenopausal women

Abstract

Purpose

Follicle stimulating hormone plays direct roles in a variety of nongonadal tissues and sex hormone binding globulin is becoming the convergence of the crosstalk among metabolic diseases. However, no studies have explored the association between follicle stimulating hormone and sex hormone binding globulin. We aimed to study this association among men and women.

Methods

SPECT-China is a population-based study conducted since 2014. This study included 4206 men and 2842 postmenopausal women. Collected serum was assayed for gonadotropins, sex hormone binding globulin, sex hormones etc. Regression analyses were performed to assess the relationship between sex hormone binding globulin and follicle stimulating hormone and other variables including metabolic factors, thyroid function and sex hormones. Treatment with follicle stimulating hormone at different concentrations of 0, 5, 50 and 100 IU/L for 24 h was performed in HepG2 cells.

Results

In Spearman correlation, sex hormone binding globulin was significantly correlated with FSH, triglycerides, thyroxins, body mass index and blood pressure in men and postmenopausal women (all P < 0.05). In regression analyses, follicle stimulating hormone was a significant predictor of sex hormone binding globulin in men and postmenopausal women (P < 0.05), independent of above variables. Follicle stimulating hormone induced sex hormone binding globulin expression in a dose-dependent fashion in HepG2 cells.

Conclusion

Serum follicle stimulating hormone levels were positively associated with circulating sex hormone binding globulin levels in men and postmenopausal women. This association is independent of age, insulin resistance, hepatic function, lipid profile, thyroid function, adiposity, blood pressure, and endogenous sex hormones.

http://ift.tt/2mR0YPR

Biochemical assessment of disease control in acromegaly: reappraisal of the glucose suppression test in somatostatin analogue (SA) treated patients

Abstract

Background

It is recommended not to measure growth hormone during oral glucose suppression (oral glucose tolerance test) during somatostatin analog treatment in acromegaly. However, we have observed that failure to suppress growth hormone in response to oral glucose tolerance test during somatostatin analog unmasks insufficient disease control and hypothesize that somatostatin analog also induces insufficient growth hormone suppression to mixed meals.

Methods

We therefore compared serum growth hormone levels during two mixed meals in patients with controlled insulin-like growth factor-I levels after either surgery alone (n = 9) or somatostatin analog treatment (n = 9). The patients were unbiasedly matched for gender and insulin-like growth factor-I and studied twice in the following order: (1) during a 6 h growth hormone day curve including two mixed meals and (2) during a 3 h growth hormone profile including 60 min fasting followed by a 2-h oral glucose tolerance test.

Results

During the day curve growth hormone levels were elevated in the somatostatin analog group (P = 0.008) and growth hormone levels 1 h after each meal declined significantly only in the surgery group (P = 0.02). During the oral glucose tolerance test the two groups had similar growth hormone levels prior to the glucose load (P = 0.6), whereas a significant 66% suppression was observed after glucose only in the surgery group (P = 0.001).

Conclusions

(1) Patients controlled by somatostatin analog fail to suppress growth hormone in response to both mixed meals and oral glucose tolerance test (2) This phenomenon is likely to result in elevated serum growth hormone levels during everyday life in somatostatin analog-treated patients, (3) We postulate that measuring growth hormone levels during oral glucose tolerance test is useful to unmask potential somatostatin analog under-treatment in the presence of 'safe' insulin-like growth factor-I levels.

http://ift.tt/2lqgqWd

CO 2 laser for the treatment of diabetic foot ulcers with exposed bone. A consecutive series of type 2 diabetic patients

Abstract

Aim

The treatment of foot ulcers with exposed bone is challenging, because of the risk of infection and of difficulties in the development of granulation tissue. A CO₂ laser beam could be used to produce discontinuities in periosteum, allowing the exposure of blood containing multipotent stem cells, capable of initiating the healing process. The local application of platelet-rich plasma (PRP) has been proposed as a therapeutic tool for accelerating healing in foot ulcers, including those in patients with diabetes. Aim of the present pilot, proof-of-concept study is the assessment of the therapeutic potential of CO₂ laser treatment, either alone or combined with PRP, in the treatment of diabetic foot ulcers with exposed bone.

Methods

We performed a pilot, uncontrolled 3-month observation study on a consecutive series of 9 type two diabetic patients and foot ulcers with exposed bone. A CO₂-laser was used for producing nine discontinuities on periosteum for each cm², by directing the focused laser beam on the bone until bleeding. The procedure was repeated up to 6 times, at a distance of 1 week and ulcers assessed weekly until the end of the study (3 months). In the last 5 of the 14 patients, the treatment described above was associated with PRP.

Results

Of the nine patients treated, four healed, and one more patient developed granulation tissue covering entirely bone surface. Out of the four patients who did not heal, one underwent minor amputation. Among the five patients treated with a combination of CO₂ laser and PRP, two healed within 3 months, and two more patients developed granulation tissue covering entirely bone surface; the fifth patient did not show any improvement and underwent amputation.

Conclusions

The present pilot experience represents a novelty in this field showing a possible use of CO₂-laser in the treatment of diabetic foot ulcers.

http://ift.tt/2mQSSqa

Immunotherapy for type 1 diabetes

Abstract

Introduction

Although many approaches have been tested to overcome the insulin dependence caused by the pancreatic β-cells destruction observed in individuals affected by type 1 diabetes (T1D), medical research has largely failed to halt the onset or to reverse T1D.

Methods

In this work, the state of the art of immunotherapy will be examined, and the most important achievement in the field will be critically discussed. Particularly, we will focus on the clinical aspect, thus avoiding the tedious preclinical work done in NOD mice, which has been so poorly translated to the bedside.

Conclusions

Stem cell therapies achieved thus this far the most promising results, while immune ablation and standard immunosuppressants did not maintain the premises of preclinical results. The next step will be to generate a feasible and safe clinical approach in order to cure the thousands of patients affected by T1D.

http://ift.tt/2lqmm1f

Pharyngitis in the Wake of an Invasive Dental Procedure

Publication date: Available online 3 March 2017
Source:The Journal of Emergency Medicine
Author(s): Erica Simon, Brit Long, Craig Pedersen




http://ift.tt/2mn1HdS

The Role of Early Focused Cardiac Ultrasound in a Not-So-Typical Presentation of Takotsubo Cardiomyopathy: A Case Report

Publication date: Available online 3 March 2017
Source:The Journal of Emergency Medicine
Author(s): Jithin G. Varghese, Qurat-ul-ain Jelani, Stuart Zarich, Brooks Walsh
BackgroundFocused cardiac ultrasound (FoCUS) can be extremely helpful in identifying unexpected diagnoses that can significantly alter treatment options. The diagnosis of Takotsubo cardiomyopathy (TCM) may be difficult to identify.Case ReportWe describe a 47-year-old woman who presented to the emergency department (ED) with atypical features of TCM. Her clinical features included being a premenopausal woman with mild chest pain with a lack of identifiable emotional or physical stressors or significant electrocardiographic changes. Initial findings on FoCUS were consistent with TCM, with these findings replicated on repeat bedside echo performed in the ED by the cardiology fellow. A subsequent comprehensive echo showed marked improvement of the TCM pattern within 24 hours.Why Should an Emergency Physician Be Aware of This?TCM may present in younger women or men, without obvious preceding physical or emotional stressors and with nonspecific ECG findings. FoCUS performed in the ED may suggest a diagnosis of TCM in patients with chest pain or dyspnea of uncertain etiology. The performance of FoCUS, as highlighted by this case report, can lead to timely intervention and follow-up of a variety of cardiac conditions.



http://ift.tt/2lIblU7

Spontaneous Hemothorax, A Rare Face of Vertebral Osteochondroma

Publication date: Available online 3 March 2017
Source:The Journal of Emergency Medicine
Author(s): Sarah Sainte, Herbert Decaluwé, Peter Vanbrabant
BackgroundOsteochondroma is the most common benign tumor of the bone. It is usually asymptomatic, but complications may result from mechanical injury to adjacent anatomic structures, such as the diaphragm and lung, when located intrathoracically.Case ReportWe report the unusual occurrence of a large hemothorax and lacerated right diaphragm in a 41-year-old woman caused by vertebral osteochondroma affecting the eleventh thoracic vertebra. Thoracoscopic exploration with resection of the osteochondroma and repair of the diaphragm was performed.Why Should an Emergency Physician Be Aware of This?Spontaneous hemothorax is a potential life-threatening condition when the initial diagnosis is postponed and hemodynamic instability and hypovolemic shock occurs. Osteochondroma as a cause of spontaneous hemothorax is uncommon but may require urgent surgical intervention with video-assisted thoracoscopic surgery of thoracotomy to control the hemorrhage and prevent recurrence.



http://ift.tt/2mmYkDD

Effects of Student-Performed Point-of-Care Ultrasound on Physician Diagnosis and Management of Patients in the Emergency Department

Publication date: Available online 3 March 2017
Source:The Journal of Emergency Medicine
Author(s): Daniel S. Udrea, Andrew Sumnicht, Deanna Lo, Logan Villarreal, Stephanie Gondra, Richard Chyan, Audra Wisham, Vi Am Dinh
BackgroundDespite the increasing integration of ultrasound training into medical education, there is an inadequate body of research demonstrating the benefits and practicality of medical student–performed point-of-care ultrasound (SP-POCUS) in the clinical setting.ObjectivesThe primary purpose of this study was to evaluate the effects that SP-POCUS can have on physician diagnosis and management of patients in the emergency department, with a secondary purpose of evaluating the diagnostic accuracy of SP-POCUS.MethodsSP-POCUS examinations were performed in the emergency department by medical students who completed year one of a 4-year medical school curriculum with integrated ultrasound training. Scans were evaluated by an emergency physician who then completed a survey to record any changes in diagnosis and management.ResultsA total of 641 scans were performed on the 482 patients enrolled in this study. SP-POCUS resulted in a change in management in 17.3% of scans performed. For 12.4% of scans, SP-POCUS discovered a new diagnosis. SP-POCUS reduced time to disposition 33.5% of the time. Because of SP-POCUS, physicians avoided ordering an additional imaging study for 53.0% of the scans performed. There was 94.7% physician agreement with SP-POCUS diagnosis.ConclusionsThis study showed that SP-POCUS is feasible and may potentially have a meaningful impact on physician diagnosis and management of patients in the emergency department. In addition, the implementation of SP-POCUS could serve as an ideal method of developing ultrasound skills in medical school while positively impacting patient care.



http://ift.tt/2lI1kX9

Impact of low-level laser therapy on hyposalivation, salivary pH, and quality of life in head and neck cancer patients post-radiotherapy

Abstract

Late effects of radiotherapy for head and neck cancer treatment have been increasingly investigated due to its impact on patients' quality of life. The purpose of this study was to evaluate the effect of low-level laser therapy on hyposalivation, low salivary pH, and quality of life in head and neck cancer patients post-radiotherapy. Twenty-nine patients with radiation-induced xerostomia received laser sessions twice a week, during 3 months (24 sessions). For this, a continuous wave Indium-Gallium-Aluminium-Phosphorus diode laser device was used punctually on the major salivary glands (808 nm, 0.75 W/cm², 30 mW, illuminated area 0.04 cm², 7.5 J/cm², 10 s, 0.3 J). Six extraoral points were illuminated on each parotid gland and three on each submandibular gland, as well as two intraoral points on each sublingual gland. Stimulated and unstimulated salivary flow rate, pH (two scales with different gradations), and quality of life (University Of Washington Quality of Life Questionnaire for Patients with Head and Neck Cancer) were assessed at baseline and at the end of the treatment. There were significant increases in both mean salivary flow rates (unstimulated: p = 0.0012; stimulated: p < 0.0001), mean pH values (p = 0.0002 and p = 0.0004), and mean score from the quality of life questionnaire (p < 0.0001). Low-level laser therapy seems to be effective to mitigate salivary hypofunction and increase salivary pH of patients submitted to radiotherapy for head and neck cancer, thereby leading to an improvement in quality of life.

http://ift.tt/2m5QvBA

Response Inhibition and Internet Gaming Disorder: A Meta-analysis

Publication date: August 2017
Source:Addictive Behaviors, Volume 71
Author(s): Evangelia Argyriou, Christopher B. Davison, Tayla T.C. Lee
Previous research has demonstrated that Internet Gaming Disorder (IGD) has multiple negative effects in psychological functioning and health. This makes the identification of its underpinnings, such as response inhibition, essential for the development of relevant interventions that target these core features of the disorder resulting in more effective treatment. Several empirical studies have evaluated the relationship between response inhibition deficits and IGD using neurocognitive tasks, but provided mixed results. In this study, we conducted a meta-analysis of studies using three neurocognitive tasks, the Go/No Go, the Stroop, and the Stop-Signal tasks, to integrate existing research and estimate the magnitude of this relationship. We found a medium overall effect size (d=0.56, 95% CI [0.32, 0.80]) indicating that compared with healthy individuals, individuals with IGD are more likely to exhibit impaired response inhibition. This finding is in alignment with literature on inhibition and addictive and impulsive behaviors, as well as with neuroimaging research. Theoretical implications regarding the conceptualization of IGD as a clinical disorder, shared commonalities with externalizing psychopathology, and clinical implications for treatment are discussed.



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Development and validation of a model to predict blood alcohol concentrations: Updating the NHTSA equation

Publication date: August 2017
Source:Addictive Behaviors, Volume 71
Author(s): Yiqi Zhang, Changxu Wu, Jingyan Wan
ObjectsTo date, multiple models have been developed to estimate blood or breath alcohol concentration (BAC/BrAC). Several factors have been identified that affect the discrepancy between BACs/BrACs and retrospective estimation (eBAC) with existing equations. To the best of our knowledge, a model to quantify the effects of factors on the discrepancy between BAC/BrAC and eBAC is still nonexistent. The goal of this work was to develop a model to provide a more accurate retrospective estimation of breath alcohol concentration (eBAC).MethodA laboratory study with alcohol consumption and a driving task was conducted with 30 participants (17 male and 13 female) to explore the factors that may contribute to the discrepancy between BrAC and eBAC obtained with existing models. A new eBAC model was developed to improve the estimation of BrAC by modeling effects of gender, weight, and the delay of BrAC measurement on the discrepancy. The validity of the model was tested and established with the data from the experiment conducted in this study and two published research studies, and compared with existing eBAC models.ResultsResults of the model validity examination indicated that the developed model had higher R squares and lower root-mean-squared errors (RMSE) in estimating BrAC in three experiments compared with the existing eBAC models, including the NHTSA equation, the Matthew equation, the Lewis equation, the Watson equation, and the Forrest equation.ConclusionThe developed eBAC model had a better performance of BrAC estimation compared with existing eBAC models. The validation of the model with the data from three empirical studies indicated a high level of generalizability in estimating BrAC.



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Label and label-free based surface-enhanced Raman scattering for pathogen bacteria detection: A review

Publication date: 15 August 2017
Source:Biosensors and Bioelectronics, Volume 94
Author(s): Yu Liu, Haibo Zhou, Ziwei Hu, Guangxia Yu, Danting Yang, Jinshun Zhao
Rapid, accurate detection of pathogen bacteria is a highly topical research area for the sake of food safety and public health. Surface-enhanced Raman scattering (SERS) is being considered as a powerful and attractive technique for pathogen bacteria detection, due to its sensitivity, high speed, comparatively low cost, multiplexing ability and portability. This contribution aims to give a comprehensive overview of SERS as a technique for rapid detection of pathogen bacteria based on label and label-free strategies. A brief tutorial on SERS is given first of all. Then we summarize the recent trends and developments of label and label-free based SERS applied to detection of pathogen bacteria, including the relatively complete interpretation of SERS spectra. In addition, multifunctional SERS platforms for pathogen bacteria in matrix are discussed as well. Furthermore, an outlook of the work done and a perspective on the future directions of SERS as a reliable tool for real-time pathogen bacteria detection are given.



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A survey on IVIVC/IVIVR development in the pharmaceutical industry – Past experience and current perspectives

Publication date: 1 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 102
Author(s): M.A. Nguyen, T. Flanagan, M. Brewster, F. Kesisoglou, S. Beato, J. Biewenga, J. Crison, R. Holm, R. Li, E. Mannaert, M. McAllister, M. Mueller-Zsigmondy, U. Muenster, K. Ojala, S. Page, A. Parr, S. Rossenu, P. Timmins, A. Van Peer, A. Vermeulen, P. Langguth
The present work aimed to describe the current status of IVIVC/IVIVR development in the pharmaceutical industry, focusing on the use and perception of specific approaches as well as successful and failed case studies. Two questionnaires have been distributed to 13 EFPIA partners of the Oral Biopharmaceutics Tools Initiative and to the Pharmacokinetics Working Party of the European Medicines Agency in order to capture the perspectives and experiences of industry scientists and agency members, respectively. Responses from ten companies and three European Agencies were received between May 21st 2014 and January 19th 2016. The majority of the companies acknowledged the importance of IVIVC/IVIVR throughout the drug development stages and a well-balanced rate of return on investment. However, the IVIVC/IVIVR approach seemed to be underutilized in regulatory submissions. Four of the ten companies stated to have an internal guidance related to IVIVC/IVIVR modelling, whereas three felt that an overall strategy is not necessary. Successful models mainly served to support formulation development and to provide a better mechanistic understanding. There was not yet much experience with safe-space IVIVRs as well as the use of physiologically based modelling in the field of IVIVC. At the same time, the responses from both industry and agencies indicated that there might be a need for a regulatory framework to guide the application of these novel approaches. The relevance of IVIVC/IVIVR for oral IR drug products was recognized by most of the companies. For IR formulations, relationships other than Level A correlation were more common outcomes among the provided case studies, such as multiple Level C correlation or safe-space IVIVR, which could be successfully used for requesting regulatory flexibility. Compared to the responses from industry scientists, there was a trend towards a higher appreciation of the BCS among the regulators, but a less positive attitude towards the utility of non-compendial dissolution methods for establishing a successful IVIVC/IVIVR. The lack of appropriate in vivo data and regulatory uncertainty were considered the major difficulties in IVIVC/IVIVR development. The results of this survey provide unique insights into current IVIVC/IVIVR practices in the pharmaceutical industry. Pursuing an IVIVC/IVIVR should be generally encouraged, considering its high value from both industry and regulators' perspective.

Graphical abstract

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Neonatal Diabetes and the KATP Channel: From Mutation to Therapy

Publication date: Available online 3 March 2017
Source:Trends in Endocrinology & Metabolism
Author(s): Frances M. Ashcroft, Michael C. Puljung, Natascia Vedovato
Activating mutations in one of the two subunits of the ATP-sensitive potassium (KATP) channel cause neonatal diabetes (ND). This may be either transient or permanent and, in approximately 20% of patients, is associated with neurodevelopmental delay. In most patients, switching from insulin to oral sulfonylurea therapy improves glycemic control and ameliorates some of the neurological disabilities. Here, we review how KATP channel mutations lead to the varied clinical phenotype, how sulfonylureas exert their therapeutic effects, and why their efficacy varies with individual mutations.



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Surrogate end-points for overall survival in 22 neoadjuvant trials of gastro-oesophageal cancers

Publication date: May 2017
Source:European Journal of Cancer, Volume 76
Author(s): Fausto Petrelli, Gianluca Tomasello, Sandro Barni
BackgroundThe surrogacy between disease-free survival (DFS) and overall survival (OS) has been evaluated in patients with gastric cancer who received adjuvant chemotherapy. Similar analyses in patients who have undergone neoadjuvant chemoradiotherapy (CTRT) or chemotherapy (CT) for gastro-oesophageal (GE) cancer have not yet been performed.MethodsWe evaluated the correlation between DFS and pathologic complete response (pCR) with OS in patients with GE carcinomas enrolled in randomised studies. A weighted linear regression analysis was used to evaluate surrogacy. Correlations were evaluated by squared correlation R². Surrogacy of DFS and pCR with OS was assessed through the correlation between end-points and OS (individual-level surrogacy), and between the treatment effects on the end-points (trial-level surrogacy). Correlations were weighted by the number of patients in the intent-to-treat population.ResultsTwenty-two trials were included for a total of 4749 patients that received CTRT or CT for gastric or oesophageal cancers. Treatment effect on surrogates did not correlate with treatment effect on OS (R² = 0.27, and R² = 0.17, for DFS and pCR) at the trial level. In subgroup analysis surrogacy of DFS did not vary according to histology or treatment modality but was good in gastric cancer and poor in oesophageal cancers.ConclusionsDFS and pCR did not correlate with OS, and should not be used as surrogate end-points in patients with GE cancer who have undergone neoadjuvant therapy. OS should still represent the primary end-point to compare treatments in future randomised clinical trials.



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The prognostic and potentially predictive value of the Laurén classification in oesophageal adenocarcinoma

Publication date: May 2017
Source:European Journal of Cancer, Volume 76
Author(s): Rosa T. van der Kaaij, Petur Snaebjornsson, Francine E.M. Voncken, Jolanda M. van Dieren, Edwin P.M. Jansen, Karolina Sikorska, Annemieke Cats, Johanna W. van Sandick
AimTo investigate the histological subtypes of oesophageal adenocarcinoma according to the Laurén classification (intestinal/diffuse/mixed) in relation to tumour response to neoadjuvant treatment, and in relation to patients' survival after potentially curative treatment.MethodsData were collected from all oesophageal adenocarcinoma patients who underwent potentially curative treatment in our institute between 1998 and 2014. Treatment consisted of neoadjuvant chemoradiotherapy (36–50 Gy) followed by an oesophagectomy or definitive chemoradiotherapy (50–50.4 Gy). Clinical data were collected from patient records. All endoscopic biopsies and surgical resection specimens were reassessed to determine the histological subtype (intestinal, diffuse or mixed) and the Mandard tumour regression grade (TRG). The impact of the histological subtypes on survival was determined using a Cox model.ResultsMedian follow-up was 68 months. Diffuse and mixed type cancers accounted for 25% of oesophageal adenocarcinomas. Median overall survival differed significantly between patients with intestinal (n = 121, 39 months), diffuse (n = 28, 18 months) or mixed type (n = 11, 25 months) carcinomas (log rank, p = 0.023). In multivariable analysis, the diffuse type was associated with shorter survival (diffuse versus intestinal: hazard ratios 2.06, p = 0.006). A pathologically (near) complete response (TRG 1 or 2) was seen less frequently in diffuse type than in intestinal type carcinomas (24% versus 60%; p = 0.015).ConclusionsPatients with diffuse type oesophageal adenocarcinomas had a significantly worse prognosis than those with intestinal type carcinomas. Intestinal type carcinomas showed a better response to neoadjuvant chemoradiotherapy than diffuse type carcinomas. These differences call for the exploration of differentiated approaches in the potentially curative treatment of oesophageal adenocarcinomas.



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Accelerated partial breast irradiation using intensity modulated radiotherapy versus whole breast irradiation: Health-related quality of life final analysis from the Florence phase 3 trial

Publication date: May 2017
Source:European Journal of Cancer, Volume 76
Author(s): Icro Meattini, Calogero Saieva, Guido Miccinesi, Isacco Desideri, Giulio Francolini, Vieri Scotti, Livia Marrazzo, Stefania Pallotta, Fiammetta Meacci, Cristina Muntoni, Benedetta Bendinelli, Luis Jose Sanchez, Marco Bernini, Lorenzo Orzalesi, Jacopo Nori, Simonetta Bianchi, Lorenzo Livi
BackgroundAccelerated partial breast irradiation (APBI) represents a valid option for selected early breast cancer (BC). We recently published the 5-year results of the APBI-IMRT-Florence phase 3 randomised trial (NCT02104895), showing a very low rate of disease failure, with acute and early–late toxicity in favour of APBI. We present the early and 2-year follow-up health-related quality of life (HRQoL) results.MethodsEligible patients were women aged more than 40 years with early BC suitable for breast-conserving surgery. APBI consisted of 30 Gy in five fractions delivered with IMRT technique. Standard whole breast irradiation (WBI) consisted of 50 Gy in 25 fractions plus a 10 Gy in five fractions boost on tumour bed. A total of 520 patients were enrolled in the phase 3 trial. Overall, 205 patients (105 APBI and 100 WBI) fully completed all the given questionnaires and were therefore included in the present analysis. As HRQoL assessment, patients were asked to complete the European Organisation for Research and Treatment of Cancer QLQ-C30, and the BR23 questionnaires at the beginning (T0), at the end (T1) and after 2 years from radiation (T2).FindingsNo significant difference between the two arms at QLQ-C30 and BR23 scores emerged at T0. Global health status (p = 0.0001), and most scores of the functional and symptom scales of QLQ-C30 at T1 showed significant differences in favour of the APBI arm. Concerning the BR23 functional and symptom scales, the body image perception, future perspective and breast and arm symptoms were significantly better in the APBI group. Similar significant results emerged at T2: significant differences in favour of APBI emerged for GHS (p = 0.0001), and most functional and symptom QLQ-C30 scales. According to QLQ-BR23 module, among the functional scales, the body image perception and the future perspective were significantly better in the APBI group (p = 0.0001), whereas among the symptom scales significant difference emerged by breast and arm symptoms with better outcomes in APBI arm (p < 0.01).InterpretationEarly BC treated with APBI showed an improved short-term, and 2-year follow-up HRQoL outcome as compared with WBI. Early BC treated with APBI showed an improved short-term, and 2-year follow-up HRQoL outcome as compared with WBI. APBI should be strongly considered in the treatment choice for selected low-risk patients. Mature local control results from ongoing adequately powered randomised trials are awaited.



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Glucose Concentrations Modulate Brain-Derived Neurotrophic Factor Responsiveness of Neurons in the Paraventricular Nucleus of the Hypothalamus

Abstract

The hypothalamic paraventricular nucleus (PVN) is critical for normal energy balance and has been shown to contain high levels of both BDNF and TrkB mRNA. Microinjections of BDNF into the PVN increase energy expenditure, suggesting BDNF plays an important role in energy homeostasis through direct actions in this nucleus. The current studies were undertaken to examine the postsynaptic effects of BDNF on the membrane potential of PVN neurons, and to determine if extracellular glucose concentrations modulated these effects.

We used hypothalamic PVN slices from male Sprague-Dawley rats to perform whole cell current-clamp recordings from PVN neurons. BDNF was bath applied at a concentration of 2 nM and the effects on membrane potential determined. BDNF caused depolarizations in 54% of neurons (n = 25; mean ± standard error of the mean 8.9 ± 1.2 mV), hyperpolarizations in 23% (n = 11; -6.7 ± 1.4 mV), while the remaining cells were unaffected. These effects were maintained in the presence of tetrodotoxin (N = 9; 56% depolarized, 22% hyperpolarized, 22% non-responders), or the GABA_a antagonist bicuculline (N = 12; 42% depolarized, 17% hyperpolarized, 41% non-responders), supporting the conclusion that these effects on membrane potential were postsynaptic.

Current-clamp recordings from PVN neurons next examined effects of BDNF on these neurons at varying extracellular glucose concentrations. Larger proportions of PVN neurons hyperpolarized in response to BDNF as glucose concentrations decreased (10 mM glucose 23% (n = 11) of neurons hyperpolarized whereas at 0.2 mM glucose, 71% showed hyperpolarizing effects (n = 12)).

Our findings reveal that BDNF has direct GABA_A independent effects on PVN neurons, which are modulated by local glucose concentrations. The latter observation further emphasizes the critical importance of using physiologically relevant conditions for study of central pathways involved in the regulation of energy homeostasis.

This article is protected by copyright. All rights reserved.

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6-Hydroxy-5,7-dimethoxy-flavone suppresses the neutrophil respiratory burst via selective PDE4 inhibition to ameliorate acute lung injury

Publication date: Available online 3 March 2017
Source:Free Radical Biology and Medicine
Author(s): Yung-Fong Tsai, Tzu-Chi Chu, Wen-Yi Chang, Yang-Chang Wu, Fang-Rong Chang, Shun-Chin Yang, Tung-Ying Wu, Yu-Ming Hsu, Chun-Yu Chen, Shih-Hsin Chang, Tsong-Long Hwang
Over-activated neutrophils produce enormous oxidative stress and play a key role in the development of acute and chronic inflammatory diseases. 6-Hydroxy-5,7-dimethoxy-flavone (UFM24), a flavone isolated from the Annonaceae Uvaria flexuosa, showed inhibitory effects on human neutrophil activation and salutary effects on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. UFM24 potently inhibited superoxide anion (O2^•−) generation, reactive oxidants, and CD11b expression, but not elastase release, in N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils. However, UFM24 failed to scavenge O2^•− and inhibit the activity of subcellular NADPH oxidase. fMLF-induced phosphorylation of protein kinase B (Akt) was inhibited by UFM24. Noticeably, UFM24 increased cyclic adenosine monophosphate (cAMP) concentration and protein kinase (PK) A activity in activated human neutrophils. PKA inhibitors significantly reversed the inhibitory effects of UFM24, suggesting that the effects of UFM24 were through cAMP/PKA-dependent inhibition of Akt activation. Additionally, activity of cAMP-related phosphodiesterase (PDE)4, but not PDE3 or PDE7, was significantly reduced by UFM24. Furthermore, UFM24 attenuated neutrophil infiltration, myeloperoxidase activity, and pulmonary edema in LPS-induced ALI in mice. In conclusion, our data demonstrated that UFM24 inhibits oxidative burst in human neutrophils through inhibition of PDE4 activity. UFM24 also exhibited significant protection against endotoxin-induced ALI in mice. UFM24 has potential as an anti-inflammatory agent for treating neutrophilic lung damage.

Graphical abstract

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Mechanisms Governing Precise Protein Biotinylation

Publication date: Available online 3 March 2017
Source:Trends in Biochemical Sciences
Author(s): Louise M. Sternicki, Kate L. Wegener, John B. Bruning, Grant W. Booker, Steven W. Polyak
Protein biotinylation is a key post-translational modification found throughout the living world. The covalent attachment of a biotin cofactor onto specific metabolic enzymes is essential for their activity. This modification is distinctive, in that it is carried out by a single enzyme: biotin protein ligase (BPL), an enzyme that is able to biotinylate multiple target substrates without aberrant-off target biotinylation. BPL achieves this target selectivity by recognizing a sequence motif in the context of a highly conserved tertiary structure. One structural class of BPLs has developed an additional 'substrate verification' mechanism to further enable appropriate protein selection. This is crucial for the precise and selective biotinylation required for efficient biotin management, especially in organisms that are auxotrophic for biotin.



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Comparative effect of ZnO NPs, ZnO bulk and ZnSO4 in the antioxidant defences of two plant species growing in two agricultural soils under greenhouse conditions

Publication date: 1 July 2017
Source:Science of The Total Environment, Volume 589
Author(s): Concepción García-Gómez, Ana Obrador, Demetrio González, Mar Babín, María Dolores Fernández
The present study has investigated the toxicity of ZnO NPs to bean (Phaseolus vulgaris) and tomato (Solanum lycopersicon) crops grown to maturity under greenhouse conditions using an acidic (soil pH5.4) and a calcareous soil (soil pH8.3). The potentially available Zn in the soils and the Zn accumulation in the leaves from NPs applied to the soil (3, 20 and 225mgZnkg⁻¹) and changes in the chlorophylls, carotenoids and oxidative stress biomarkers were measured at 15, 30, 60 and 90days and compared with those caused by bulk ZnO and ZnSO4. The available Zn in the soil and the leaf Zn content did not differ among the Zn chemical species, except in the acidic soil at the highest concentration of Zn applied as Zn ions, where the highest values of the two variables were found. The ZnO NPs showed comparable Zn toxicity or biostimulation to their bulk counterparts and Zn salts, irrespective of certain significant differences suggesting a higher activity of the Zn ion. The treatments altered the photosynthetic pigment concentration and induced oxidative stress in plants. ROS formation was observed at Zn plant concentrations ranging from 590 to 760mgkg⁻¹, but the effects on the rest of the parameters were highly dependent on the plant species, exposure time and especially soil type. In general, the effects were higher in the acidic soil than in the calcareous soil for the bean and the opposite for the tomato. The similar uptakes and toxicities of the different Zn forms suggest that the Zn ions derived from the ZnO NPs exerted a preferential toxicity in plants. However, several results obtained in soils treated with NPs at 3mgZnkg⁻¹ soil indicated that may exist other underlying mechanisms related to the intrinsic nanoparticle properties, especially at low NP concentrations.

Graphical abstract

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Study of morphology and electrical properties of indium zinc oxide-modified kenaf fiber

Publication date: June 2017
Source:Industrial Crops and Products, Volume 100
Author(s): Edynoor bin Osman, Toshihiro Moriga, Kei-ichiro Murai, Mohd Warikh bin Abd Rashid
Indium zinc oxide (IZO) was successfully deposited onto kenaf fibers (KFs) by a dip-coating method. The novel aspect of this study was the investigation of the electrical conductivity of the resulting indium zinc oxide-modified kenaf fiber (KF-IZO) by emphasizing on its morphology and the dipping rate used for dip-coating. KF was alkalized using a 5% sodium hydroxide (NaOH) solution. The dipping rate was varied from 1 to 30mm/s. KF-IZO was then annealed at a temperature of 150°C for 4h. A modified four-probe method employing a copper metal attachment plate was used to evaluate the electrical properties of KF-IZO. A dipping rate of 5mm/s, which yielded the highest electrical conductivity of 11.81S/mm, was found to be optimum. Scanning Electron Microscope/Energy Dispersive Using X-Ray (SEM-EDX) analysis of KF-IZO revealed that the IZO film was uniformly coated on the KF substrates, and no significant thermal damage was observed. KF-IZO showed the potential to be used in smart textiles, electrostatic discharge protection, and as a reinforcement in composites.



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Effects and mechanism of diclofenac degradation in aqueous solution by US/Zn0

Publication date: July 2017
Source:Ultrasonics Sonochemistry, Volume 37
Author(s): Ting Huang, Guangming Zhang, Shan Chong, Yucan Liu, Nan Zhang, Shunyan Fang, Jia Zhu
A system of ultrasound radiation coupled with Zn⁰ was applied to degrade diclofenac. The effects of initial pH, dosage of Zn⁰ and ultrasound density were investigated. To further explore the mechanism of the microcosmic reaction, the fresh and used Zn⁰ powders were characterized by SEM, XRD and XPS. Radical scavengers were used to determine the oxidation performance of strong oxidizing free radicals on diclofenac, including hydroxyl radicals and superoxide radicals. The results showed that the optimum removal of diclofenac reached to over 85% at pH of 2.0 in 15min, with Zn⁰ dosage of 0.1g/L and ultrasound density of 0.6W/cm³. TOC removal of 72.6% in 15min and dechlorination efficiency of diclofenac reached 70% in 30min. Characterization results showed that a ZnO membrane was generated on the surface of Zn particles after use. According to the mass spectrometry results, several possible pathways of diclofenac degradation were proposed, and most diclofenac was turned into micro-molecules or CO2 finally. The synergistic effect of US/Zn⁰ in the reactions led to a proposed degradation mechanism in which zinc could directly attack the target contaminant diclofenac because of its good reducibility with the auxiliary functions of ultrasonic irradiation, mechanical shearing and free radical oxidation.



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Exploiting kinetics to unravel the role of a ZnO diluent in the production of CO via oxidizing Zn particles with CO2

Publication date: 29 June 2017
Source:Chemical Engineering Science, Volume 165
Author(s): David Weibel, Zoran R. Jovanovic, Aldo Steinfeld
Direct oxidation of pure Zn particles with CO2 is inhibited by an impervious ZnO scale. The presence of a ZnO diluent surface provides a site for an additional heterogeneous reaction of sublimated Zn that allows for a fast and high conversion of Zn. This is relevant to the efficient production of CO by the oxidation of Zn particles produced by the solar thermal dissociation of ZnO that are generally contaminated by the recombined ZnO. The overall reaction mechanism thus involves the sublimation of Zn(g) from the Zn surface, its transport to the ZnO diluent surface, and its subsequent heterogeneous reaction with CO2 on this surface. To elucidate the most relevant of those elementary steps different kinetic models were tested against a broad set of isothermal thermogravimetric data acquired at different temperatures, CO2-concentrations, and initial ZnO contents. The overall rate was found to be controlled by the transport of Zn(g) to the ZnO diluent surface and the reaction of the chemisorbed CO2 either with Zn(g) or with Zn incorporated from gas phase into the ZnO lattice surface sites. Increasing the initial content of ZnO diluent increases the effectiveness of the heterogeneous reaction at the ZnO diluent surface which facilitates the sublimation of Zn and appears to render the ZnO product scale surrounding unreacted Zn more permeable.

Graphical abstract

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Deactivation in the posterior mid-cingulate cortex reflects perceptual transitions during binocular rivalry: Evidence from simultaneous EEG-fMRI

Publication date: 15 May 2017
Source:NeuroImage, Volume 152
Author(s): Abhrajeet V. Roy, Keith W. Jamison, Sheng He, Stephen A. Engel, Bin He
Binocular rivalry is a phenomenon in which perception spontaneously shifts between two different images that are dichoptically presented to the viewer. By elucidating the cortical networks responsible for these stochastic fluctuations in perception, we can potentially learn much about the neural correlates of visual awareness. We obtained concurrent EEG-fMRI data for a group of 20 healthy human subjects during the continuous presentation of dichoptic visual stimuli. The two eyes' images were tagged with different temporal frequencies so that eye specific steady-state visual evoked potential (SSVEP) signals could be extracted from the EEG data for direct comparison with changes in fMRI BOLD activity associated with binocular rivalry. We additionally included a smooth replay condition that emulated the perceptual transitions experienced during binocular rivalry as a control stimulus. We evaluated a novel SSVEP-informed fMRI analysis in this study in order to delineate the temporal dynamics of rivalry-related BOLD activity from both an electrophysiological and behavioral perspective. In this manner, we assessed BOLD activity during rivalry that was directly correlated with peaks and crosses of the two rivaling, frequency-tagged SSVEP signals, for comparison with BOLD activity associated with subject reported perceptual transitions. Our findings point to a critical role of a right lateralized fronto-parietal network in the processing of bistable stimuli, given that BOLD activity in the right superior/inferior parietal lobules was significantly elevated throughout binocular rivalry and in particular during perceptual transitions, compared with the replay condition. Based on the SSVEP-informed analysis, rivalry was further associated with significantly enhanced BOLD suppression in the posterior mid-cingulate cortex during perceptual transitions, compared with SSVEP crosses. Overall, this work points to a careful interplay between early visual areas, the right posterior parietal cortex and the mid-cingulate cortex in mediating the spontaneous perceptual changes associated with binocular rivalry and has significant implications for future multimodal imaging studies of perception and awareness.



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Characterization of neural entrainment to speech with and without slow spectral energy fluctuations in laminar recordings in monkey A1

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Benedikt Zoefel, Jordi Costa-Faidella, Peter Lakatos, Charles E. Schroeder, Rufin VanRullen
Neural entrainment, the alignment between neural oscillations and rhythmic stimulation, is omnipresent in current theories of speech processing – nevertheless, the underlying neural mechanisms are still largely unknown. Here, we hypothesized that laminar recordings in non-human primates provide us with important insight into these mechanisms, in particular with respect to processing in cortical layers. We presented one monkey with human everyday speech sounds and recorded neural (as current-source density, CSD) oscillations in primary auditory cortex (A1). We observed that the high-excitability phase of neural oscillations was only aligned with those spectral components of speech the recording site was tuned to; the opposite, low-excitability phase was aligned with other spectral components. As low- and high-frequency components in speech alternate, this finding might reflect a particularly efficient way of stimulus processing that includes the preparation of the relevant neuronal populations to the upcoming input. Moreover, presenting speech/noise sounds without systematic fluctuations in amplitude and spectral content and their time-reversed versions, we found significant entrainment in all conditions and cortical layers. When compared with everyday speech, the entrainment in the speech/noise conditions was characterized by a change in the phase relation between neural signal and stimulus and the low-frequency neural phase was dominantly coupled to activity in a lower gamma-band. These results show that neural entrainment in response to speech without slow fluctuations in spectral energy includes a process with specific characteristics that is presumably preserved across species.



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