Alterations in task-induced activity and resting-state fluctuations in visual and DMN areas revealed in long-term meditators

Publication date: 15 July 2016
Source:NeuroImage, Volume 135
Author(s): Aviva Berkovich-Ohana, Michal Harel, Avital Hahamy, Amos Arieli, Rafael Malach
Recently we proposed that the information contained in spontaneously emerging (resting-state) fluctuations may reflect individually unique neuro-cognitive traits. One prediction of this conjecture, termed the "spontaneous trait reactivation" (STR) hypothesis, is that resting-state activity patterns could be diagnostic of unique personalities, talents and life-styles of individuals. Long-term meditators could provide a unique experimental group to test this hypothesis. Using fMRI we found that, during resting-state, the amplitude of spontaneous fluctuations in long-term mindfulness meditation (MM) practitioners was enhanced in the visual cortex and significantly reduced in the DMN compared to naïve controls. Importantly, during a visual recognition memory task, the MM group showed heightened visual cortex responsivity, concomitant with weaker negative responses in Default Mode Network (DMN) areas. This effect was also reflected in the behavioral performance, where MM practitioners performed significantly faster than the control group. Thus, our results uncover opposite changes in the visual and default mode systems in long-term meditators which are revealed during both rest and task. The results support the STR hypothesis and extend it to the domain of local changes in the magnitude of the spontaneous fluctuations.



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Olfactory modulation of affective touch processing — A neurophysiological investigation

Publication date: 15 July 2016
Source:NeuroImage, Volume 135
Author(s): Ilona Croy, Edda Drechsler, Paul Hamilton, Thomas Hummel, Håkan Olausson
Touch can be highly emotional, and depending on the environment, it can be perceived as pleasant and comforting or disgusting and dangerous. Here, we studied the impact of context on the processing of tactile stimuli using a functional magnetic resonance imaging (fMRI) paradigm. This was achieved by embedding tactile stimulation in a variable olfactory environment.Twenty people were scanned with BOLD fMRI while receiving the following stimulus blocks: Slow stroking Touch, Civette odor (feces like), Rose odor, Touch+Civette, and Touch+Rose. Ratings of pleasantness and intensity of tactile stimuli and ratings of disgust and intensity of olfactory stimuli were collected. The impact of the olfactory context on the processing of touch was studied using covariance analyses. Coupling between olfactory processing and somatosensory processing areas was assessed with psychophysiological interaction analysis (PPI).A subjectively disgusting olfactory environment significantly reduced the perceived pleasantness of touch. The touch fMRI activation in the secondary somatosensory cortex, operculum 1 (OP1), was positively correlated with the disgust towards the odors. Decreased pleasantness of touch was related to decreased posterior insula activity. PPI analysis revealed a significant interaction between the OP1, posterior insula, and regions processing the disgust of odors (orbitofrontal cortex and amygdala).We conclude that the disgust evaluation of the olfactory environment moderates neural reactivity in somatosensory regions by upregulation of the OP1 and downregulation of the posterior insula. This adaptive regulation of affective touch processing may facilitate adaptive reaction to a potentially harmful stimulus.



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The influence of visual information on auditory processing in individuals with congenital amusia: An ERP study

Publication date: 15 July 2016
Source:NeuroImage, Volume 135
Author(s): Xuejing Lu, Hao T. Ho, Yanan Sun, Blake W. Johnson, William F. Thompson
While most normal hearing individuals can readily use prosodic information in spoken language to interpret the moods and feelings of conversational partners, people with congenital amusia report that they often rely more on facial expressions and gestures, a strategy that may compensate for deficits in auditory processing. In this investigation, we used EEG to examine the extent to which individuals with congenital amusia draw upon visual information when making auditory or audio-visual judgments. Event-related potentials (ERP) were elicited by a change in pitch (up or down) between two sequential tones paired with a change in spatial position (up or down) between two visually presented dots. The change in dot position was either congruent or incongruent with the change in pitch. Participants were asked to judge (1) the direction of pitch change while ignoring the visual information (AV implicit task), and (2) whether the auditory and visual changes were congruent (AV explicit task). In the AV implicit task, amusic participants performed significantly worse in the incongruent condition than control participants. ERPs showed an enhanced N2–P3 response to incongruent AV pairings for control participants, but not for amusic participants. However when participants were explicitly directed to detect AV congruency, both groups exhibited enhanced N2–P3 responses to incongruent AV pairings. These findings indicate that amusics are capable of extracting information from both modalities in an AV task, but are biased to rely on visual information when it is available, presumably because they have learned that auditory information is unreliable. We conclude that amusic individuals implicitly draw upon visual information when judging auditory information, even though they have the capacity to explicitly recognize conflicts between these two sensory channels.



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Multidirectional and Topography-based Dynamic-scale Varifold Representations with Application to Matching Developing Cortical Surfaces

Publication date: 15 July 2016
Source:NeuroImage, Volume 135
Author(s): Islem Rekik, Gang Li, Weili Lin, Dinggang Shen
The human cerebral cortex is marked by great complexity as well as substantial dynamic changes during early postnatal development. To obtain a fairly comprehensive picture of its age-induced and/or disorder-related cortical changes, one needs to match cortical surfaces to one another, while maximizing their anatomical alignment. Methods that geodesically shoot surfaces into one another as currents (a distribution of oriented normals) and varifolds (a distribution of non-oriented normals) provide an elegant Riemannian framework for generic surface matching and reliable statistical analysis. However, both conventional current and varifold matching methods have two key limitations. First, they only use the normals of the surface to measure its geometry and guide the warping process, which overlooks the importance of the orientations of the inherently convoluted cortical sulcal and gyral folds. Second, the 'conversion' of a surface into a current or a varifold operates at a fixed scale under which geometric surface details will be neglected, which ignores the dynamic scales of cortical foldings. To overcome these limitations and improve varifold-based cortical surface registration, we propose two different strategies. The first strategy decomposes each cortical surface into its normal and tangent varifold representations, by integrating principal curvature direction field into the varifold matching framework, thus providing rich information of the orientation of cortical folding and better characterization of the complex cortical geometry. The second strategy explores the informative cortical geometric features to perform a dynamic-scale measurement of the cortical surface that depends on the local surface topography (e.g., principal curvature), thereby we introduce the concept of a topography-based dynamic-scale varifold. We tested the proposed varifold variants for registering 12 pairs of dynamically developing cortical surfaces from 0 to 6 months of age. Both variants improved the matching accuracy in terms of closeness to the target surface and the goodness of alignment with regional anatomical boundaries, when compared with three state-of-the-art methods: (1) diffeomorphic spectral matching, (2) conventional current-based surface matching, and (3) conventional varifold-based surface matching.



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Development of cortical shape in the human brain from 6 to 24months of age via a novel measure of shape complexity

Publication date: 15 July 2016
Source:NeuroImage, Volume 135
Author(s): Sun Hyung Kim, Ilwoo Lyu, Vladimir S. Fonov, Clement Vachet, Heather C. Hazlett, Rachel G. Smith, Joseph Piven, Stephen R. Dager, Robert C. Mckinstry, John R. Pruett, Alan C. Evans, D. Louis Collins, Kelly N. Botteron, Robert T. Schultz, Guido Gerig, Martin A. Styner
The quantification of local surface morphology in the human cortex is important for examining population differences as well as developmental changes in neurodegenerative or neurodevelopmental disorders. We propose a novel cortical shape measure, referred to as the 'shape complexity index' (SCI), that represents localized shape complexity as the difference between the observed distributions of local surface topology, as quantified by the shape index (SI) measure, to its best fitting simple topological model within a given neighborhood. We apply a relatively small, adaptive geodesic kernel to calculate the SCI. Due to the small size of the kernel, the proposed SCI measure captures fine differences of cortical shape. With this novel cortical feature, we aim to capture comparatively small local surface changes that capture a) the widening versus deepening of sulcal and gyral regions, as well as b) the emergence and development of secondary and tertiary sulci. Current cortical shape measures, such as the gyrification index (GI) or intrinsic curvature measures, investigate the cortical surface at a different scale and are less well suited to capture these particular cortical surface changes. In our experiments, the proposed SCI demonstrates higher complexity in the gyral/sulcal wall regions, lower complexity in wider gyral ridges and lowest complexity in wider sulcal fundus regions. In early postnatal brain development, our experiments show that SCI reveals a pattern of increased cortical shape complexity with age, as well as sexual dimorphisms in the insula, middle cingulate, parieto-occipital sulcal and Broca's regions. Overall, sex differences were greatest at 6months of age and were reduced at 24months, with the difference pattern switching from higher complexity in males at 6months to higher complexity in females at 24months. This is the first study of longitudinal, cortical complexity maturation and sex differences, in the early postnatal period from 6 to 24months of age with fine scale, cortical shape measures. These results provide information that complement previous studies of gyrification index in early brain development.



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Motion and morphometry in clinical and nonclinical populations

Publication date: 15 July 2016
Source:NeuroImage, Volume 135
Author(s): Heath R. Pardoe, Rebecca Kucharsky Hiess, Ruben Kuzniecky
IntroductionThe relationship between participant motion, demographic variables and MRI-derived morphometric estimates was investigated in autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia and healthy controls. Participant motion was estimated using resting state fMRI and used as a proxy measure for motion during T1w MRI acquired in the same session. Analyses were carried out in scans qualitatively assessed as free from motion-related artifact.MethodsWhole brain T1-weighted MRI and resting state fMRI acquisitions from the ABIDE, ADHD-200 and COBRE databases were included in our analyses. Motion was estimated using coregistration of sequential resting state volumes. We investigated if motion is related to diagnosis, age and gender, and scanning site. We further determined if there is a relationship between participant motion and cortical thickness, contrast, and volumetric estimates.Results2141 participants were included in our analyses. Participant motion was higher in all clinical groups compared with healthy controls. Younger (age<20years) and older (age>40years) people move more than individuals aged 20–40years. Increased motion is associated with reduced average cortical thickness (−0.014mm thickness per mm motion, p=0.0014) and cortical contrast (0.77% contrast reduction per mm motion, p=2.16×10⁻⁹) in scans that have been qualitatively assessed as free from motion artifact. Volumetric estimates were also associated with motion, however the relationships were generally weaker than cortical thickness and contrast and were dependent on the segmentation method used.ConclusionsParticipant motion is increased in clinical groups and is systematically associated with morphometric estimates. These findings indicate that accounting for participant motion may be important for improving the statistical validity of morphometric studies.



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Serotonin transporter polymorphism alters citalopram effects on human pain responses to physical pain

Publication date: 15 July 2016
Source:NeuroImage, Volume 135
Author(s): Yina Ma, Chenbo Wang, Siyang Luo, Bingfeng Li, Tor D. Wager, Wenxia Zhang, Yi Rao, Shihui Han
Humans exhibit substantial inter-individual differences in pain perception, which contributes to variability in analgesic efficacy. Individual differences in pain sensitivity have been linked with variation in the serotonin transporter gene (5-HTTLPR), and selective serotonin reuptake inhibitors (SSRIs) such as citalopram have been increasingly used as treatments for multiple pain conditions. We combined genotyping, pharmacological challenge, and neuroimaging during painful electrical stimulation to reveal how serotonin genetics and pharmacology interact to influence pain perception and its underlying neurobiological mechanisms. In a double-blind, placebo-controlled procedure, we acutely administrated citalopram (30mgpo) to short/short (s/s) and long/long (l/l) healthy male 5-HTTLPR homozygotes during functional MRI with painful and non-painful electrical stimulation. 5-HTTLPR genotype modulated citalopram effects on pain-related brain responses in the thalamus, cerebellum, anterior insula, midcingulate cortex and inferior frontal cortex. Specifically, citalopram significantly reduced pain-related brain responses in l/l but not in s/s homozygotes. Moreover, the interaction between 5-HTTLPR genotype and pain-related brain activity was a good predictor of the citalopram-induced reductions in pain reports. The genetic modulations of citalopram effects on brain-wide pain processing were paralleled by significant effects on the Neurological Pain Signature, a multivariate brain pattern validated to be sensitive and specific to physical pain. This work provides neurobiological mechanism by which genetic variation shapes brain responses to pain perception and treatment efficacy. These findings have important implications for the types of individuals for whom serotonergic treatments provide effective pain relief, which is critical for advancing personalized pain treatment.



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Multiple value signals in dopaminergic midbrain and their role in avoidance contexts

Publication date: 15 July 2016
Source:NeuroImage, Volume 135
Author(s): Francesco Rigoli, Benjamin Chew, Peter Dayan, Raymond J. Dolan
The role of dopaminergic brain regions in avoidance behaviour is unclear. Active avoidance requires motivation, and the latter is linked to increased activity in dopaminergic regions. However, avoidance is also often tethered to the prospect of punishment, a state typically characterized by below baseline levels of dopaminergic function. Avoidance has been considered from the perspective of two-factor theories where the prospect of safety is considered to act as a surrogate for reward, leading to dopamine release and enhanced motivational drive. Using fMRI we investigated predictions from two-factor theory by separating the neural representation of a conventional net expected value, which is negative in the case of avoidance, from an adjusted expected value which factors in a possibility of punishment and is larger for both big rewards and big (predictably avoidable) punishments. We show that neural responses in ventral striatum and ventral tegmental area/substantial nigra (VTA/SN) covaried with net expected value. Activity in VTA/SN also covaried with an adjusted expected value, as did activity in anterior insula. Consistent with two-factor theory models, the findings indicate that VTA/SN and insula process an adjusted expected value during avoidance behaviour.



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Reduced posterior parietal cortex activation after training on a visual search task

Publication date: 15 July 2016
Source:NeuroImage, Volume 135
Author(s): Elisenda Bueichekú, Anna Miró-Padilla, María-Ángeles Palomar-García, Noelia Ventura-Campos, María-Antonia Parcet, Alfonso Barrós-Loscertales, César Ávila
Gaining experience on a cognitive task improves behavioral performance and is thought to enhance brain efficiency. Despite the body of literature already published on the effects of training on brain activation, less research has been carried out on visual search attention processes under well controlled conditions. Thirty-six healthy adults divided into trained and control groups completed a pre-post letter-based visual search task fMRI study in one day. Twelve letters were used as targets and ten as distractors. The trained group completed a training session (840 trials) with half the targets between scans. The effects of training were studied at the behavioral and brain levels by controlling for repetition effects using both between-subjects (trained vs. control groups) and within-subject (trained vs. untrained targets) controls. The trained participants reduced their response speed by 31% as a result of training, maintaining their accuracy scores, whereas the control group hardly changed. Neural results revealed that brain changes associated with visual search training were circumscribed to reduced activation in the posterior parietal cortex (PPC) when controlling for group, and they included inferior occipital areas when controlling for targets. The observed behavioral and brain changes are discussed in relation to automatic behavior development. The observed training-related decreases could be associated with increased neural efficiency in specific key regions for task performance.



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Taste intensity modulates effective connectivity from the insular cortex to the thalamus in humans

Publication date: 15 July 2016
Source:NeuroImage, Volume 135
Author(s): Andy Wai Kan Yeung, Hiroki C. Tanabe, Justin Long Kiu Suen, Tazuko K. Goto
Evaluation of taste intensity is one of the most important perceptual abilities in our daily life. In contrast with extensive research findings regarding the spatial representation of taste in the insula and thalamus, little is known about how the thalamus and insula communicate and reciprocally influence their activities for processing taste intensity. To examine this neurophysiological relationship, we investigated the modulatory effect of intensity of saltiness on connections in the network processing taste signals in the human brain. These "effective connectivity" relationships refer to the neurophysiological influence (including direction and strength of influence) of one brain region on another. Healthy adults (N=34), including 17 males and 17 females (mean age=21.3years, SD=2.4; mean body mass index (BMI)=20.2kg/m², SD=2.1) underwent functional magnetic resonance imaging as they tasted three concentrations of sodium chloride solutions. By effective connectivity analysis with dynamic causal modeling, we show that taste intensity enhances top-down signal transmission from the insular cortex to the thalamus. These results are the first to demonstrate the modulatory effect of taste intensity on the taste network in the human brain.



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Cooperative antiproliferative and differentiation-enhancing activity of medicinal plant extracts in acute myeloid leukemia cells

Publication date: August 2016
Source:Biomedicine & Pharmacotherapy, Volume 82
Author(s): Gulzhan T. Zhamanbayeva, Araylim N. Aralbayeva, Maira K. Murzakhmetova, Sultan T. Tuleukhanov, Michael Danilenko
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with poor prognosis and limited treatment options. Sea buckthorn (Hippophae rhamnoides) berries, dog rose (Rosa canina) rosehips, and garden sage (Salvia officinalis) and oregano (Origanum vulgare) aerial parts are widely used in traditional medicine and exhibit antitumor effects in preclinical models. However, these plants remain scarcely tested for antileukemic activity. Here, we show that their water-ethanol leaf extracts reduced the growth and viability of AML cells and, at non-cytotoxic doses, potentiated cell differentiation induced by a low concentration of 1α,25-dihydroxyvitamin D3, the hormonal form of vitamin D, in a cell type-dependent manner. The latter effect was accompanied by upregulation of the vitamin D receptor protein components and its transcriptional activity. Furthermore, at minimally effective doses the extracts cooperated with one another to produce marked cytostatic effects associated with a partial S-phase arrest and a modest induction of apoptosis. In contrast, these combinations only slightly affected the growth and viability of proliferating normal human peripheral blood mononuclear cells. In addition, the extracts strongly inhibited microsomal lipid peroxidation and protected normal erythrocytes against hypoosmotic shock. Our results suggest that further exploration of the enhanced antileukemic effects of the combinations tested here may lead to the development of alternative therapeutic and preventive approaches against AML.

Graphical abstract

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Fish oil prevents colon cancer by modulation of structure and function of mitochondria

Publication date: August 2016
Source:Biomedicine & Pharmacotherapy, Volume 82
Author(s): Navneet Agnihotri, Gayatri Sharma, Isha Rani, Renuka, Archana Bhatnagar
Cancer cells are more susceptible to metabolic perturbations due to impaired electron transport chain (ETC) that promote uncontrolled proliferation. Mitochondria play a pivotal role in bioenergetics and apoptosis, hence are considered as a promising target in tumor cell eradication. Therefore, the present study is designed to elucidate chemopreventive action of fish oil (FO) in combination with corn oil (CO) on mitochondria in colorectal cancer (CRC). Male Wistar rats were divided into groups depending on dietary regimen—Control group, FO+CO(1:1) and FO+CO(2.5:1). These groups were further subdivided depending on whether these received a weekly intraperitoneal injection of ethylenediamine tetra-acetic acid (EDTA) or N,N-dimethylhydrazine dihydrochloride (DMH) for a period of 4 weeks. The animals sacrificed 48h and 16 weeks after EDTA/DMH treatment constituted initiation and post-initiation phase respectively. The structural and functional alterations in mitochondria were evaluated using transmission electron microscopy (TEM) and by assaying electron transport chain (ETC) enzymes. Mitochondrial lipid composition and cholesterol levels were also assessed. DMH treatment led to mitochondrial degeneration, disrupted cristae and a significant decrease in ETC complexes suggestive of metabolic reprogramming. Moreover, an increase in cholesterol and cardiolipin (CL) levels in post-initiation phase led to evasion of apoptosis. FO in both the ratios resulted in stabilization and increase in number of mitochondria, however, FO+CO(2.5:1)+DMH group also exhibited mitophagy and crystolysis alongwith altered dynamics in ETC which facilitated apoptosis. It also decreased cholesterol and CL levels to increase apoptosis. Fish oil targets mitochondria in a dose dependent manner that augments apoptosis and hence attenuates carcinogenesis.



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Inhibition of autophagy sensitizes MDR-phenotype ovarian cancer SKVCR cells to chemotherapy

Publication date: August 2016
Source:Biomedicine & Pharmacotherapy, Volume 82
Author(s): Bing Liang, Xiaodong Liu, Yang Liu, Dejuan Kong, Xiaomei Liu, Rui Zhong, Shumei Ma
Autophagyis an intracellular lysosomal degradation pathway where its primary function is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death.Chemoresistanceis a major challenge in the clinical treatment of ovarian cancer, of which the underlying mechanisms remain unknown.ObjectiveThe aim of the present study was to explore the role of autophagy in vincristine (VCR) resistant ovarian cancer cells.MethodsThe SKOV3 parental cell line and SKVCR, the VCR-resistant ovarian carcinoma cells were used. 3-MA (3-Methyladenine) and CQ (Chloroquine) were also used as autophagy inhibitors. CCK8 (Cell Counting Kit-8) was used to detect cell viability, quantitative real-time PCR and Western blot were used to detect the expressions of mRNA and protein, MDC staining and flow cytometry were used to detect autophagy and apoptosis, respectively.ResultsCompared with parental SKOV3 cells, SKVCR cells showed Multidrug Resistance (MDR). SKVCR cells demonstrated higher autophagy levels than SKOV3 cells, which could be inhibited by 3-MA and CQ. In SKVCR cells, VCR increased apoptosis levels further, 3-MA and CQ inhibited autophagy and potentiated the cytotoxicity by VCR. Moreover, 3-MA and CQ overcame the acquired VCR resistance in SKVCR cells by enhancing VCR-induced cytotoxicity, and promote apoptosis.ConclusionsOur data indicate that autophagy has a protective role in the multi-drug resistant SKVCR cells. The inhibition of autophagy increases the killing effects of VCR by increasing apoptosis and inhibiting autophagy, suggesting a better strategy for the treatment of drug-resistant SKVCR cells.



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Exenatide suppresses 1,2-dimethylhydrazine-induced colon cancer in diabetic mice: Effect on tumor angiogenesis and cell proliferation

Publication date: August 2016
Source:Biomedicine & Pharmacotherapy, Volume 82
Author(s): Mona K. Tawfik, Magda I. Mohamed
Colon cancer is the third leading cause of cancer mortality worldwide, which results from interactions of different factors. It is frequently a pathological consequence of persistent inflammation. Diabetes affects several cancers and is positively correlated with the incidence of colon cancer. This study aimed to study the effect of exenatide in ameliorating inflammation, angiogenesis and cell proliferation in 1,2-dimethyl hydrazine (DMH) induced colorectal carcinoma in diabetic mice. Mice were randomly allocated into six groups, 8 mice each. Group 1: vehicle control group. Group 2: diabetic control group. Group 3: DMH control group: diabetic mice treated with DMH (20mg/kg/week,s.c.) for 15 week. Group 4: DMH-cisplatin group: mice received cisplatin (4mg/kg/week, i.p.). Groups 5 & 6: DMH-exenatide (10 and 20μg/kg) group: mice received exenatide (10 or 20μg/kg/day,s.c.), respectively. The present results highlighted an increase in angiogenic markers and cell proliferation in the DMH-diabetic group in comparison with the control group with greater expression of endothelial marker (CD34) and Ki-67 in colon tissue. Monotherapy with cisplatin or exenatide (10 and 20μg/kg) downregulated these markers to different extents. The current results provided evidence that exenatide represents a promising chemopreventive effect against DMH-induced colon carcinogenesis in diabetic mice, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.



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MiR-769 promoted cell proliferation in human melanoma by suppressing GSK3B expression

Publication date: August 2016
Source:Biomedicine & Pharmacotherapy, Volume 82
Author(s): Hai-jiang Qiu, Xiao-he Lu, Sha-sha Yang, Chen-yin Weng, E-keng Zhang, Fang-chao Chen
MicroRNAs (miRNAs) are short, non-coding RNAs with post-transcriptional regulatory function, playing crucial roles in cancer development and progression of human melanoma. Previous studies have indicated that miR-769 was implicated in diverse biological processes. However, the underlying mechanism of miR-769 in human melanoma has not been intensively investigated. In this present study, we aimed to investigate the role of miR-769 and its target genes in human melanoma. We found that miR-769 expression was strongly increased in human melanoma cells and clinical tissues compared with their corresponding controls. Overexpression of miR-769 promoted cell proliferation in human melanoma cell line A375, whereas miR-769-in reverses the function. Glycogen synthase kinase-3 Beta (GSK3B), a potential target gene of miR-769, and was validated by luciferase assay. Further studies revealed that miR-769 regulated cell proliferation of human melanoma by directly suppressing GSK3B expression and the knockdown of GSK3B expression reversed the effect of miR-769-in on human melanoma cell proliferation. In summary, our data demonstrated that miR-769 might act as a tumor promoter by targeting GSK3B during development of human melanoma.



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Interferon β improves the efficacy of low dose cisplatin by inhibiting NF-κB/p-Akt signaling on HeLa cells

Publication date: August 2016
Source:Biomedicine & Pharmacotherapy, Volume 82
Author(s): Purushoth Ethiraj, Karpagam Veerappan, Shila Samuel, Sundaresan Sivapatham
The purpose of this study was to evaluate the anticancer efficacy of interferon β in combination with low dose of cisplatin on human cervical cancer progression, as well as its principal action mechanism. The combination treatment synergistically potentiated the effect of interferon β on cell growth inhibition and DNA damage on HeLa cells by repressing NF-κB/p-Akt signaling. Synergistic targeting of these pathways has a therapeutic potential. Further, the combination treatment ameliorated the expression of pro-apoptotic Bax, and decreased the expression of anti-apoptotic protein Bcl-2. Additionally, the expression of active PARP was significantly increased and MMP-9 level was decreased in combination group as compared to the expression seen for the treatment with interferon β or cisplatin alone. Results demonstrate that the synergistic inhibitory effects of interferon β and low dose of cisplatin on human cervical cancer cells and also suggest that the inhibition of NF-κB/p-Akt signaling pathway plays a critical role in the anticancer effects of combination treatment along with the induction of PARP. Therefore, the combination of interferon β and cisplatin may be a useful treatment for human cervical cancer, with a greater effectiveness than other treatments.



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Christian Doppler: Austrian Physicist

Christian #Doppler famous for the "Doppler effect" — that the observed frequency of a wave depends on the relative speed of the source and the observer. Here is me at his birthplace in Salzburg

Famous Radiology Blog http://ift.tt/1MM2hKr TeleRad Providers at http://ift.tt/1NgppuI Mail us at sales@teleradproviders.com

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Management and Outcomes of Clinical Stage IIA/B Seminoma: Results from the National Cancer Data Base 1998-2012

Publication date: Available online 8 May 2016
Source:Practical Radiation Oncology
Author(s): Jonathan J. Paly, Chun Chieh Lin, Phillip J. Gray, Christopher L. Hallemeier, Clair Beard, Helmneh Sineshaw, Ahmedin Jemal, Jason A. Efstathiou
Purpose/ObjectiveDisease-specific survival for testicular seminoma approaches 100%, even for those with node-positive disease. We sought to describe modern practice patterns, survival outcomes, and factors associated with postoperative therapy for patients with clinical stage (CS) IIA/B disease.Methods and MaterialsData on patients diagnosed with CS IIA/B seminoma from 1998–2012 were extracted from the National Cancer Data Base. Demographic, clinical, treatment and payer characteristics were evaluated using multivariate regression to identify factors associated with receipt of chemotherapy or radiation therapy (RT) within six months of orchiectomy. Five-year Kaplan-Meier overall survival (OS) by CS and treatment was calculated. A Cox proportional hazards regression for 5-year OS was performed.Results1885 patients were included; 38.5% received chemotherapy and 61.5% received RT. On multivariate analysis, factors associated with receipt of post-orchiectomy RT rather than chemotherapy included CS IIA (OR 3.04, P<0.01) and community treatment setting (OR 1.81-2.76, P<0.01). Reduced likelihood of receiving RT was associated with Medicaid insurance (OR 0.50, P<0.01), more recent year of diagnosis (continuous OR 0.93, P<0.01), and pT3/4 stage (OR 0.47, P<0.01). On multivariate Cox regression, decreased 5-year OS was associated with receipt of chemotherapy in CS IIA patients (HR 13.33, P<0.01) but not in CS IIB patients (HR 1.39, P=0.45). For CS IIA, 5-year OS was 99.4% for orchiectomy and RT versus 91.2% for orchiectomy and chemotherapy (log-rank P<0.01). For CS IIB, 5-year OS was 96.1% for orchiectomy and RT versus 92.8% for orchiectomy and chemotherapy (log-rank P=0.08).ConclusionsConsistent with national guideline recommendations, our analysis supports preferred status for RT in CS IIA. In addition, these data also support use of RT for CS IIB. CS, treatment year, pT stage, insurance, and facility type were associated with type of post-operative therapy. Longer follow-up to account for potential late effects of treatment is needed.



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Interobserver Variability in Radiotherapy Plan Output: Results of a Single-Institution Study

Publication date: Available online 8 May 2016
Source:Practical Radiation Oncology
Author(s): Sean L. Berry, Amanda Boczkowski, Rongtao Ma, James Mechalakos, Margie Hunt
PurposeTo investigate the sources of variability in radiotherapy treatment plan output between planners within a single institution.Materials/Methods40 treatment planners across 5 campuses of the same institution created a plan on copies of the same thoracic esophagus patient CT and structure set. Plans were scored and ranked based on the planner's adherence to ordered list of target dose coverage and normal tissue evaluation criteria. A runs test was used to identify whether any of the studied planner qualities influenced the ranking. Spearman's rank correlation was used to investigate whether plan score correlated with years of experience or planned MU.ResultsThe distribution of scores, ranging from 80.24 to 135.89, was negatively skewed (mean = 128.7, median = 131.5). No statistically significant relationship between plan score and campus (p=0.193), job title (p=0.174), previous outside experience (p=0.611), or number of gantry angles (p=0.156) exists. No statistical correlation between plan score and MU or years of experience was found.ConclusionDespite clear and established critical organ dose criteria and well documented planning guidelines, planning variation still occurs, even among members of the same institution. As plan consistency does not seem to significantly correlate with experience, career path, or campus, investigation into alternate methods beyond additional education and training to reduce this variation, such as knowledge based planning or advanced optimization techniques, is necessary.



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Molecular and neural control of sexually dimorphic social behaviors

Publication date: June 2016
Source:Current Opinion in Neurobiology, Volume 38
Author(s): Taehong Yang, Nirao M Shah
Sexually reproducing animals exhibit sex differences in behavior. Sexual dimorphisms in mating, aggression, and parental care directly contribute to reproductive success of the individual and survival of progeny. In this review, we discuss recent advances in our understanding of the molecular and neural network mechanisms underlying these behaviors in mice. Notable advances include novel insights into the sensory control of social interactions and the identification of molecularly-specified neuronal populations in the brain that control mating, aggression, and parental behaviors. In the case of the latter, these advances mark a watershed because scientists can now focus on discrete neural pathways in an effort to understand how the brain encodes these fundamental social behaviors.



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Ultrasonography in the preoperative difficult airway assessment

Abstract

To evaluate the utility of ultrasound for detection of the difficult intubation in a preoperative setting. PubMed, Ovid, CINAHL Plus Full Text, and Google Scholar searches using ["difficult airway" OR "difficult intubation" OR "difficult laryngoscopy" OR "difficult ventilation"] AND [ultrasonography OR sonography OR ultrasound] without date limitations. Abstracts without publications, case reports, letters, textbooks, unrelated topics, or foreign language articles were excluded. Ancestry references were included from the reviewed articles. Two reviewers independently performed the query. Each study was reviewed using the STARD checklist to assess blinding, incomplete data reporting, subject attrition, and selection of appropriate statistical tests. Ten studies were included. All used convenience sampling of adult subjects requiring direct laryngoscopy in elective surgical settings. One study is retrospective and nine are prospective observational. Populations included non-obese, obese, pregnant, and thyroidectomy patients in the United States, Turkey, Israel, Canada, Portugal, and China. Airway locations scanned are variable using different protocols and patient positioning. The outcome variable is uniformly the Cormack–Lehane Grade. 114 of the 681 total subjects had difficult laryngoscopies. Significance for sonographic prediction of difficult laryngoscopy occurred at three locations: hyomental distance [52.6 ± 5.8 mm (p < 0.01)], anterior tissue at the hyoid bone [16.9 mm (95 % CI 11.9–21.9) and 15.9 ± 2.7 mm (p < 0.0001)], and the thyrohyoid membrane [34.7 mm (95 % CI 28.8–40.7) and 23.9 ± 3.4 mm (p < 0.0001) and 28.25 ± 4.43 mm (p < 0.001)]. The vocal cords and sternal notch levels have conflicting significance. Limitations include the heterogeneous populations and lack of standard scanning protocols.

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Amlodipine Ameliorates Ischemia-Induced Neovascularization in Diabetic Rats through Endothelial Progenitor Cell Mobilization

Objectives. We investigated whether amlodipine could improve angiogenic responses in a diabetic rat model of acute myocardial infarction (AMI) through improving bone marrow endothelial progenitor cell (EPC) mobilization, in the same way as angiotensin converting enzyme inhibitors. Methods. After induction of AMI by coronary artery ligation, diabetic rats were randomly assigned to receive perindopril (2 mgkg−1 day−1), amlodipine (2.5 mgkg−1 day−1), or vehicle by gavage ( per group). Circulating EPC counts before ligation and on days 1, 3, 5, 7, 14, and 28 after AMI were measured in each group. Microvessel density, cardiac function, and cardiac remodeling were assessed 4 weeks after treatment. The signaling pathway related to EPC mobilization was also measured. Results. Circulating EPC count in amlodipine- and perindopril-treated rats peaked at day 7, to an obvious higher level than the control group peak which was reached earlier (at day 5). Rats treated with amlodipine showed improved postischemia neovascularization and cardiac function, together with reduced cardiac remodeling, decreased interstitial fibrosis, and cardiomyocyte apoptosis. Amlodipine treatment also increased cardiac SDF-1/CXCR4 expression and gave rise to activation of VEGF/Akt/eNOS signaling in bone marrow. Conclusions. Amlodipine promotes neovascularization by improving EPC mobilization from bone marrow in diabetic rats after AMI, and activation of VEGF/Akt/eNOS signaling may in part contribute to this.

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Reducing the Cost of the Diagnostic Odyssey in Early Onset Epileptic Encephalopathies

Whole exome sequencing (WES) has revolutionized the way we think about and diagnose epileptic encephalopathies. Multiple recent review articles discuss the benefits of WES and suggest various algorithms to follow for determining the etiology of epileptic encephalopathies. Incorporation of WES in these algorithms is leading to the discovery of new genetic diagnoses of early onset epileptic encephalopathies (EOEEs) at a rapid rate; however, WES is not yet a universally utilized diagnostic tool. Clinical WES may be underutilized due to provider discomfort in ordering the test or perceived costliness. At our hospital WES is not routinely performed for patients with EOEE due to limited insurance reimbursement. In fact for any patient with noncommercial insurance (Medicaid) the institution does not allow sending out WES as this is not "established"/"proven to be highly useful and cost effective"/"approved test" in patients with epilepsy. Recently, we performed WES on four patients from three families and identified novel mutations in known epilepsy genes in all four cases. These patients had State Medicaid as their insurance carrier and were followed up for several years for EOEE while being worked up using the traditional/approved testing methods. Following a recently proposed diagnostic pathway, we analyzed the cost savings (US dollars) that could be accrued if WES was performed earlier in the diagnostic odyssey. This is the first publication that addresses the dollar cost of traditional testing in EOEE as performed in these four cases versus WES and the potential cost savings.

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Critical and direct involvement of the CD23 stalk region in IgE binding

Publication date: Available online 7 May 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Regina Selb, Julia Eckl-Dorna, Teresa E. Twaroch, Christian Lupinek, Andrea Teufelberger, Gerhard Hofer, Margarete Focke-Tejkl, Barbara Gepp, Birgit Linhart, Heimo Breiteneder, Adolf Ellinger, Walter Keller, Kenneth H. Roux, Rudolf Valenta, Verena Niederberger
BackgroundThe low-affinity receptor for IgE, FcεRII (CD23), contributes to allergic inflammation by allergen presentation to T cells, regulation of IgE responses and enhancing trans-epithelial allergen migration.ObjectiveTo investigate the interaction between CD23, chimeric monoclonal human IgE and the corresponding birch pollen allergen, Bet v 1 at a molecular level.MethodsWe expressed four CD23 variants. One variant comprised the full extracellular portion of CD23 including stalk and head domain, one was identical with the first except of an amino acid exchange in the stalk region abolishing the N-linked glycosylation site, and two variants representing the head domain, one complete and one truncated. The four CD23 variants were purified as monomeric and structurally folded proteins as demonstrated by gel filtration and circular dichroism. Using a human monoclonal IgE antibody, the corresponding allergen Bet v 1 and a panel of antibodies specific for peptides spanning the CD23 surface, binding as well as inhibition assays and negative stain electron microscopy were performed.ResultsA hitherto unknown IgE binding site was mapped on the stalk region of CD23 and the non-N-glycosylated monomeric version of CD23 was superior in IgE binding compared to glycosylated CD23. Furthermore, we demonstrated that a therapeutic anti-IgE antibody, omalizumab, which inhibits IgE binding to FcεRI, also inhibited IgE binding to CD23.ConclusionOur results provide a new model for the CD23-IgE interaction. We show that the stalk region of CD23 is crucially involved in IgE binding and that the interaction can be blocked by the therapeutic anti-IgE antibody omalizumab.

Teaser

We provide a new model of interaction between CD23 and IgE by showing a direct involvement of the CD23 stalk region in IgE binding. Furthermore, we demonstrate that a therapeutic anti-IgE antibody, omalizumab, blocks the binding of IgE to CD23.


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Triterpene sapogenin-polyarginine conjugates exhibit promising antibacterial activity against Gram-positive strains

Publication date: Available online 7 May 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Heiya Na, Xiangpeng Li, Cunbin Zou, Chenhong Wang, Chao Wang, Keliang Liu
Triterpene sapogenins are a group of biologically active compounds with antibacterial activity. However, the limited solubility and poor bioavailability of triterpene sapogenins restrict their therapeutic application. Polyarginine peptides are small cationic peptides with high affinities for multiple negatively charged cell membranes and possess moderate antibacterial activities. In this study, we designed and synthesized a series of sapogenin-polyarginine conjugates in which the triterpene sapogenin moiety was covalently appended to the positively charged polyarginine via click chemistry. A clear synergistic effect was found, and the conjugates exhibited potent and selective antibacterial activity against Gram-positive strains. Among them, BAc-R3 was the most promising compound, which was also proven to be nontoxic toward mammalian cells as well as stable in plasma. The mechanism of BAc-R3 primarily involves an interaction with the bacterial membrane, similar to that of antimicrobial peptides (AMPs). This scaffold design opens an avenue for the further development of novel antibiotics comprised of the combination of a peptide and a natural product.

Graphical abstract

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Arabinoamidine synthesis and its inhibition toward β-glucosidase (sweet almonds) in comparison to a library of galactonoamidines

Publication date: Available online 7 May 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Jessica B. Pickens, Susanne Striegler, Qiu-Hua Fan
Aiming at the development of potent inhibitors of β-glucosidases, a small library of galactonoamidines and one arabinoamidine derived in analogy were studied as inhibitors of sweet almond β-glucosidase. The five-membered glycon in arabinoamidine was shown to interact with the proton donor in the active site of the retaining enzyme, but not with the nucleophile. By contrast, the corresponding galactonoamidine with a six-membered glycon and identical aglycon interacts with both hydrolysis-promoting amino acids in the active site and inhibits the enzymatic hydrolysis of β-glucosides in the low nanomolar concentration range. While both inhibitors are competitive, their inhibition ability is more than 37,000-fold different.

Graphical abstract

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Bismuth(III) complexes with 2-acetylpyridine- and 2-benzoylpyridine-derived hydrazones: Antimicrobial and cytotoxic activities and effects on the clonogenic survival of human solid tumor cells

Publication date: Available online 7 May 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Isabella P. Ferreira, Elisa D.L. Piló, Angel A. Recio-Despaigne, Jeferson G. Da Silva, Jonas P. Ramos, Lucas B. Marques, Pedro H.D.M. Prazeres, Jacqueline A. Takahashi, Elaine M. Souza-Fagundes, Willian Rocha, Heloisa Beraldo
Complexes [Bi(2AcPh)Cl2]·0.5H2O (1), [Bi(2AcpClPh)Cl2] (2), [Bi(2AcpNO2Ph)Cl2] (3), [Bi(2AcpOHPh)Cl2]·2H2O (4), [Bi(H2BzPh)Cl3]·2H2O (5), [Bi(H2BzpClPh)Cl3] (6), [Bi(2BzpNO2Ph)Cl2]·2H2O (7) and [Bi(H2BzpOHPh)Cl3]·2H2O (8) were obtained with 2-acetylpyridine phenylhydrazone (H2AcPh), its -para-chloro-phenyl- (H2AcpClPh), -para-nitro-phenyl (H2AcpNO2Ph) and -para-hydroxy-phenyl (H2AcpOHPh) derivatives, as well as with the 2-benzoylpyridine phenylhydrazone analogues (H2BzPh, H2BzpClPh, H2BzpNO2Ph, H2BzpOHPh).Upon coordination to bismuth(III) antibacterial activity against Gram-positive and Gram-negative bacterial strains significantly improved except for complex (4).The cytotoxic effects of the compounds under study were evaluated on HL-60, Jurkat and THP-1 leukemia, and on MCF-7 and HCT-116 solid tumor cells, as well as on non-malignant Vero cells. In general, 2-acetylpyridine-derived hydrazones proved to be more potent and more selective as cytotoxic agents than the corresponding 2-benzoylpyridine-derived counterparts.Exposure of HCT-116 cells to H2AcpClPh, H2AcpNO2Ph and complex (3) led to 99% decrease of the clonogenic survival. The IC50 values of these compounds were three-fold smaller when cells were cultured in soft-agar (3D) than when cells were cultured in monolayer (2D), suggesting that they constitute interesting scaffolds, which should be considered in further studies aiming to develop new drug candidates for the treatment of colon cancer.

Graphical abstract

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A Serine/threonine Kinase PknL, is involved in the adaptive response of Mycobacterium tuberculosis

Publication date: Available online 7 May 2016
Source:Microbiological Research
Author(s): Ahmed Kabir Refaya, Divakar Sharma, Virendra Kumar, Deepa Bisht, Sujatha Narayanan
Mycobacterium tuberculosis adapts itself to various environmental stress conditions to thrive inside the phagosome for establishing a chronic infection. Serine/threonine protein kinases (STPKs) play a major role in the physiology and pathogenesis of Mycobacterium tuberculosis. Some of these STPKs are involved in regulating the growth of the mycobacterium under nutrient stress and starvation conditions. In this study, we have investigated the role of PknL, a STPK in the adaptive responses of M. tuberculosis by conditional inactivation of the gene using antisense technology. The inhibition of PknL in the knockdown strain was validated by RT-PCR. The in vitro growth kinetics of M. tuberculosis strain following inhibition of PknL was found to be bacteriostatic. The knock down strain of PknL exhibited a better survival in pH 5.5 when compared to its growth in pH 7.0. Similarly, it also exhibited more resistance to both SDS(0.01%) and Lysozyme stress (2.5mg/ml), indicating that loss of PknL enhances the growth of mycobacterium under stress conditions. SEM pictographs also represent an increase in the cell length of the knock down strain compared to Wild type stressing its role in cellular integrity. Lastly, the proteome analysis of differentially expressing PknL strains by 2D gel electrophoresis and mass spectrometry identified 19 differentially expressed proteins. Our findings have shown that PknL plays an important role in sensing the host environment and adapting itself in slowing down the growth of the pathogen and persisting within the host.



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Alternatives to overcoming bacterial resistances: state-of-the-art

Publication date: Available online 7 May 2016
Source:Microbiological Research
Author(s): Alessandra C. Rios, Carla G. Moutinho, Flávio C. Pinto, Fernando S. Del Fiol, Angela Jozala, Marco V. Chaud, Marta M.D.C. Vila, José A. Teixeira, Victor M. Balcão
Worldwide, bacterial resistance to chemical antibiotics has reached such a high level that endangers public health. Presently, the adoption of alternative strategies that promote the elimination of resistant microbial strains from the environment is of utmost importance. This review discusses and analyses several (potential) alternative strategies to current chemical antibiotics. Bacteriophage (or phage) therapy, although not new, makes use of strictly lytic phage particles as an alternative, or a complement, in the antimicrobial treatment of bacterial infections. It is being rediscovered as a safe method, because these biological entities devoid of any metabolic machinery do not possess any affinity whatsoever to eukaryotic cells. Lysin therapy is also recognized as an innovative antimicrobial therapeutic option, since the topical administration of preparations containing purified recombinant lysins with amounts in the order of nanograms, in infections caused by Gram-positive bacteria, demonstrated a high therapeutic potential by causing immediate lysis of the target bacterial cells. Additionally, this therapy exhibits the potential to act synergistically when combined with certain chemical antibiotics already available on the market. Another potential alternative antimicrobial therapy is based on the use of antimicrobial peptides (AMPs), amphiphilic polypeptides that cause disruption of the bacterial membrane and can be used in the treatment of bacterial, fungal and viral infections, in the prevention of biofilm formation, and as antitumoral agents. Interestingly, bacteriocins are a common strategy of bacterial defense against other bacterial agents, eliminating the potential opponents of the former and increasing the number of available nutrients in the environment for their own growth. They can be applied in the food industry as biopreservatives and as probiotics, and also in fighting multi-resistant bacterial strains. The use of antibacterial antibodies promises to be extremely safe and effective. Additionally, vaccination emerges as one of the most promising preventive strategies. All these will be tackled in detail in this review paper.



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Posterior Mediastinal Adenomatoid Tumor: A Case Report and Review of the Literature

Adenomatoid tumor is an uncommon benign neoplasm of mesothelial differentiation that distinctively arises in and around the genital organs. In rare instances, it has been described in extragenital locations. There have been only two reports documenting its occurrence in the anterior mediastinum, and no reports documenting its occurrence in the posterior mediastinum. We report the first case of posterior mediastinal adenomatoid tumor. A 37-year-old Caucasian woman presented with symptoms of bronchitis. Imaging studies identified a 2.0 cm posterior mediastinal mass abutting the T9 vertebral body, clinically and radiologically most consistent with schwannoma. Histologic sections revealed a lesion composed of epithelioid cells arranged in cords and luminal profiles embedded in a fibrotic to loose stroma and surrounded by a fibrous pseudocapsule. Lesional cells showed vacuolated eosinophilic cytoplasm and peripherally displaced nuclei with prominent nucleoli. There was focal cytologic atypia but no mitotic figures or necrosis was identified. The lesional cells expressed cytokeratin, calretinin, and nuclear WT1 but were negative for PAX8, TTF1, p53, chromogranin, CD31, and CD34, and Ki67 showed

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Ovatodiolide of Anisomeles indica Exerts the Anticancer Potential on Pancreatic Cancer Cell Lines through STAT3 and NF-κB Regulation

Pancreatic cancer is the eighth leading cause of cancer death worldwide. Patients with pancreatic cancer are normally diagnosed at an advanced stage and present poor survival rate. Ovatodiolide (OV), a bioactive macrocyclic diterpenoid isolated from Anisomeles indica, showed cytotoxicity effects in pancreatic cancer cells by inhibiting cell proliferation and inducing apoptosis. Moreover, not only were cell adhesion and invasion markedly suppressed in a dose-dependent manner, but the mRNA expression of matrix metalloproteinase-9 (MMP-9) and focal adhesion kinase (FAK) was also significantly decreased. Western blot analysis indicated that OV potently suppressed the phosphorylation of STAT-3 and its upstream kinase including ERK1/2, P38, and AKT Ser473. Meanwhile, OV inactivated the nuclear factor kappa B (NF-κB) by inhibiting IκB kinase (IKK α/β) activation and the subsequent suppression of inhibitor of kappa B (IκB) phosphorylation. These results demonstrated that OV could potentially inhibit Mia-PaCa2 cancer cells proliferation and induce apoptosis through modulation of NF-κB and STAT3 pathway. Moreover, OV suppressed cell invasiveness and interfered with cell-matrix adhesion in Mia-PaCa2 cancer cells by reducing MMP-9 and FAK transcription through suppressing NF-κB and STAT3 pathway. Taken together, our findings reveal a new therapeutic and antimetastatic potential of ovatodiolide for pancreatic cancer remedy.

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More Than Needles: The Importance of Explanations and Self-Care Advice in Treating Primary Dysmenorrhea with Acupuncture

Background. Primary dysmenorrhea is a common gynaecological condition. Traditional Chinese medicine (TCM) acupuncturists commonly treat primary dysmenorrhea and dispense specific self-care advice for this condition. The impact of self-care advice on primary dysmenorrhea is unknown. Methods. 19 TCM acupuncture practitioners from New Zealand or Australia and 12 New Zealand women who had recently undergone acupuncture treatment for primary dysmenorrhea as part of a randomised controlled trial participated in this qualitative, pragmatic study. Focus groups and semistructured interviews were used to collect data. These were recorded, transcribed, and analysed using thematic analysis. Results. The overarching theme was that an acupuncture treatment consisted of "more than needles" for both practitioners and participants. Practitioners and participants both discussed the partnership they engaged in during treatment, based on openness and trust. Women felt that the TCM self-care advice was related to positive outcomes for their dysmenorrhea and increased their feelings of control over their menstrual symptoms. Conclusions. Most of the women in this study found improved symptom control and reduced pain. A contributing factor for these improvements may be an increased internal health locus of control and an increase in self-efficacy resulting from the self-care advice given during the clinical trial.

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Pharmacological inhibition of PI3K class III enhances the production of pro- and anti-inflammatory cytokines in dendritic cells stimulated by TLR agonists

Publication date: July 2016
Source:International Immunopharmacology, Volume 36
Author(s): Álvaro Pittini, Cecilia Casaravilla, Judith E. Allen, Álvaro Díaz




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Pharmacological profile of MEDI-551, a novel anti-CD19 antibody, in human CD19 transgenic mice

Publication date: July 2016
Source:International Immunopharmacology, Volume 36
Author(s): Sandra Gallagher, Sean Turman, Isharat Yusuf, Ahmad Akhgar, Yuling Wu, Lorin K. Roskos, Ronald Herbst, Yue Wang
B cell depletion therapy is beneficial for patients with B cell malignancies and autoimmune diseases. CD19, a transmembrane protein, is expressed on a vast majority of normal and neoplastic B cells, making it a suitable target for monoclonal antibody (MAb) mediated immunotherapy. We have developed MEDI-551, an affinity optimized and afucosylated IgG1 MAb targeting human CD19 for B cell depletion. MEDI-551 is currently under investigation in multiple clinical trials. Because MEDI-551 does not cross react with rodent and non-human primate CD19, the pharmacological characteristics of the MAb were evaluated in human CD19 transgenic mice (hCD19 Tg). Here we show that MEDI-551 potently depletes tissue and circulating B cells in hCD19 Tg mice and is more efficacious than the anti-CD19 MAb with intact fucose. The length of B cell depletion depends on MEDI-551 dose; and, B cell recovery in the circulation follows stepwise phenotypic maturation. Furthermore, intravenous (IV) and subcutaneous (SC) administration of MEDI-551 results in comparable efficacy. Lastly, the combination of MEDI-551 with the anti-CD20 MAb, rituximab, further prolongs the duration of B cell depletion. In summary, the pharmacological profile of MEDI-551 presented in hCD19 Tg mice supports further testing of MEDI-551 in clinical trials involving B cell malignancies and autoimmune diseases.



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Anti-tumor and immunomodulatory activities of an exopolysaccharide from Rhizopus nigricans on CT26 tumor-bearing mice

Publication date: July 2016
Source:International Immunopharmacology, Volume 36
Author(s): Lei Zhu, Jianfeng Cao, Guochuang Chen, Yanghui Xu, Jingbo Lu, Fang Fang, Kaoshan Chen
This study was aimed to investigate the anti-tumor and immunomodulatory activities of an exopolysaccharide (EPS) from Rhizopus nigricans. Our results showed EPS could significantly inhibit the tumor growth and increase the immune organs index of CT26 tumor-bearing mice. EPS treatment increased the productions of interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) levels in serum. The increase of percentage of CD8⁺ cytotoxic T cells among total spleen T lymphocyte was also observed. Furthermore, EPS remarkably stimulate spleen lymphocytes proliferation in the absence or presence of mitogens. In addition, we found that EPS had synergistic effect with chemotherapy and improved immunosuppressive effect induced by 5-Fu. In summary, these findings indicated that the antitumor effects of EPS might be partly due to immune function activation and it might have potential to be used in the treatment for colorectal cancer.



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sST2 translation is regulated by FGF2 via an hnRNP A1-mediated IRES-dependent mechanism

Publication date: Available online 8 May 2016
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Michael M. Kunze, Fabienne Benz, Thilo F. Brauß, Sebastian Lampe, Julia E. Weigand, Johannes Braun, Florian M. Richter, Ilka Wittig, Bernhard Brüne, Tobias Schmid
Translation is an energy-intensive process and tightly regulated. Generally, translation is initiated in a cap-dependent manner. Under stress conditions, typically found within the tumor microenvironment in association with e.g. nutrient deprivation or hypoxia, cap-dependent translation decreases, and alternative modes of translation initiation become more important. Specifically, internal ribosome entry sites (IRES) facilitate translation of specific mRNAs under otherwise translation-inhibitory conditions. This mechanism is controlled by IRES trans-acting factors (ITAF), i.e. by RNA-binding proteins, which interact with and determine the activity of selected IRESs. We aimed at characterizing the translational regulation of the IL-33 decoy receptor sST2, which was enhanced by fibroblast growth factor 2 (FGF2). We identified and verified an IRES within the 5'UTR of sST2. Furthermore, we found that MEK/ERK signaling contributes to FGF2-induced, sST2-IRES activation and translation. Determination of the sST2-5'UTR structure by in-line probing followed by deletion analyses identified 23 nucleotides within the sST2-5'UTR to be required for optimal IRES activity. Finally, we show that the RNA-binding protein heterogeneous ribonucleoprotein A1 (hnRNP A1) binds to the sST2-5'UTR, acts as an ITAF, and thus controls the activity of the sST2-IRES and consequently sST2 translation. Specifically, FGF2 enhances nuclear-cytoplasmic translocation of hnRNP A1, which requires intact MEK/ERK activity. In summary, we provide evidence that the sST2-5'UTR contains an IRES element, which is activated by a MEK/ERK-dependent increase in cytoplasmic localization of hnRNP A1 in response to FGF2, enhancing the translation of sST2.



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Thyroid gland invasion in advanced squamous cell carcinoma of the larynx and hypopharynx

Publication date: Available online 7 May 2016
Source:Brazilian Journal of Otorhinolaryngology
Author(s): João Mangussi-Gomes, Fernando Danelon-Leonhardt, Guilherme Figner Moussalem, Nicolas Galat Ahumada, Cleydson Lucena Oliveira, Flávio Carneiro Hojaij
IntroductionSquamous cell carcinoma (SCC) of the larynx and hypopharynx has the potential to invade the thyroid gland. Despite this risk, the proposition of either partial or total thyroidectomy as part of the surgical treatment of all such cases remains controversial.ObjectivesTo evaluate the frequency of invasion of the thyroid gland in patients with advanced laryngeal or hypopharyngeal SCC submitted to total laryngectomy (TL) or pharyngolaryngectomy (TPL) and thyroidectomy; to determine whether clinic-pathological characteristics can predict glandular involvement.MethodsA retrospective case series with chart review, from January 1998 to July 2013, was undertaken in a tertiary care university medical center. An inception cohort of 83 patients with larynx/hypopharynx SCC was considered. All patients had advanced stage disease (clinically T3–T4) and underwent TL or TPL in association with thyroidectomy. Adjuvant therapy was indicated when tumor or neck conditions required. Frequency of thyroid cartilage invasion was calculated; univariate and multivariate analysis of demographic, clinical and pathological characteristics associated with cartilage invasion were performed.ResultsThe overall frequency of invasion of the thyroid gland was 18.1%. Glandular involvement was associated with invasion of the following structures: anterior commissure (OR=5.13; 95% CI 1.07–24.5), subglottis (OR=12.44; 95% CI 1.55–100.00) and cricoid cartilage (OR=15.95; 95% CI 4.23–60.11).ConclusionsInvasion of the thyroid gland is uncommon in the context of laryngopharyngeal SCC. Clinical and pathological features such as invasion of the anterior commissure, subglottis and cricoid cartilage are more associated with glandular invasion.



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Frequent Flyers: The never-ending shift

See all of Lenwood Brown's comics.

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Multiple β-catenin mutations in hepatocellular lesions arising in Abernethy malformation

Publication date: July 2016
Source:Human Pathology, Volume 53
Author(s): Tracy Sorkin, Sandra Strautnieks, Pierre Foskett, Praveen Peddu, Richard J. Thompson, Nigel Heaton, Alberto Quaglia
An 18-year-old man underwent liver transplantation due to an Abernethy malformation associated with multiple hepatocellular nodules including one which was rapidly enlarging and was suspicious for malignant transformation. Analysis of the explanted liver showed a spectrum of multiple hepatocellular nodules ranging in appearance from focal nodular hyperplasia, hepatocellular adenoma and to a well-differentiated hepatocellular neoplasm borderline for hepatocellular carcinoma. Mutational analysis revealed wild-type β-catenin expression in the background liver and some nodules, whilst different variants were present in other lesions irrespective of their morphological appearance. No telomerase reverse transcriptase (TERT) promoter mutation was identified. Abernethy malformations can lead to independent genetic events which can result in β-catenin mutations associated with malignant transformation of hepatocellular nodules. When following up such patients, one must therefore have a high index of suspicion, particularly if radiological surveillance reveals a change in the nature of hepatic lesions.



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The Use of Protein-Protein Interactions for the Analysis of the Associations between PM2.5 and Some Diseases

Nowadays, pollution levels are rapidly increasing all over the world. One of the most important pollutants is PM2.5. It is known that the pollution environment may cause several problems, such as greenhouse effect and acid rain. Among them, the most important problem is that pollutants can induce a number of serious diseases. Some studies have reported that PM2.5 is an important etiologic factor for lung cancer. In this study, we extensively investigate the associations between PM2.5 and 22 disease classes recommended by Goh et al., such as respiratory diseases, cardiovascular diseases, and gastrointestinal diseases. The protein-protein interactions were used to measure the linkage between disease genes and genes that have been reported to be modulated by PM2.5. The results suggest that some diseases, such as diseases related to ear, nose, and throat and gastrointestinal, nutritional, renal, and cardiovascular diseases, are influenced by PM2.5 and some evidences were provided to confirm our results. For example, a total of 18 genes related to cardiovascular diseases are identified to be closely related to PM2.5, and cardiovascular disease relevant gene DSP is significantly related to PM2.5 gene JUP.

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Protein Remote Homology Detection Based on an Ensemble Learning Approach

Protein remote homology detection is one of the central problems in bioinformatics. Although some computational methods have been proposed, the problem is still far from being solved. In this paper, an ensemble classifier for protein remote homology detection, called SVM-Ensemble, was proposed with a weighted voting strategy. SVM-Ensemble combined three basic classifiers based on different feature spaces, including Kmer, ACC, and SC-PseAAC. These features consider the characteristics of proteins from various perspectives, incorporating both the sequence composition and the sequence-order information along the protein sequences. Experimental results on a widely used benchmark dataset showed that the proposed SVM-Ensemble can obviously improve the predictive performance for the protein remote homology detection. Moreover, it achieved the best performance and outperformed other state-of-the-art methods.

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Non parametric directionality analysis - extension for removal of a single common predictor and application to time series.

Publication date: Available online 7 May 2016
Source:Journal of Neuroscience Methods
Author(s): David M. Halliday, Mohd Harizal Senik, Carl Stevenson, Rob Mason
BackgroundThe ability to infer network structure from multivariate neuronal signals is central to computational neuroscience. Directed network analyses typically use parametric approaches based on auto-regressive (AR) models, where networks are constructed from estimates of AR model parameters. However, the validity of using low order AR models for neurophysiological signals has been questioned. A recent article introduced a non parametric approach to estimate directionality in bivariate data, non parametric approaches are free from concerns over model validity.New MethodWe extend the non parametric framework to include measures of directed conditional independence, using scalar measures that decompose the overall partial correlation coefficient summatively by direction, and a set of functions that decompose the partial coherence summatively by direction. A time domain partial correlation function allows both time and frequency views of the data to be constructed. The conditional independence estimates are conditioned on a single predictor.ResultsThe framework is applied to simulated cortical neuron networks and mixtures of Gaussian time series data with known interactions. It is applied to experimental data consisting of local field potential recordings from bilateral hippocampus in anaesthetised rats.Comparison with Existing Method(s). The framework offers a non parametric approach to estimation of directed interactions in multivariate neuronal recordings, and increased flexibility in dealing with both spike train and time series data.ConclusionsThe framework offers a novel alternative non parametric approach to estimate directed interactions in multivariate neuronal recordings, and is applicable to spike train and time series data



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Safety Assessment of Epidural Wire Electrodes for Cough Production in a Chronic Pig Model of Spinal Cord Injury

Publication date: Available online 7 May 2016
Source:Journal of Neuroscience Methods
Author(s): Krzysztof E. Kowalski, Tomasz Kowalski, Anthony F. DiMarco
BackgroundIt is our hypothesis that high intensity spinal cord stimulation (SCS) to restore an effective cough mechanism using wire leads, will result in significant activation of target neurons without tissue injury or electrode corrosion.MethodsAdult mini-pigs underwent chronic spinal cord compression, followed by implantation of parallel wire leads on the dorsal epidural surface of the spinal cord, with stimulation contacts at the T9 and T12, and control electrode contacts at the T2 and T5 levels. After 3 months of daily SCS, airway pressure generation (P), tissue in the area of the stimulating and control electrodes and electrode leads were examined. P was also assessed in acute animals, which served as controls.ResultsMean P at FRC were 54±5cmH2O and 109±11cmH2O in the control and chronically stimulated animals, respectively (p<0.05). There was minimal tissue reaction in the area of the stimulating and control electrodes. All sets of leads revealed no evidence of electrode corrosion.Comparison with existing methodsPrevious porcine models of chronic spinal cord injury (SCI) were developed to study neurological and regenerative outcomes. Our method of chronic SCI porcine model was developed to evaluate the safety of electrical SCS to restore expiratory muscle function.ConclusionChronic SCS with wire lead electrodes results in significant increases in P without evidence of significant adverse tissue reaction, nor evidence of electrode corrosion. This method may be a safe and useful technique to restore a functional cough in spinal cord injured subjects.



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Phage Display for Identification of Serum Biomarkers of Traumatic Brain Injury

Publication date: Available online 7 May 2016
Source:Journal of Neuroscience Methods
Author(s): Sarbani Ghoshal, Vimala Bondada, Kathryn E. Saatman, Rodney P. Guttmann, James W. Geddes
BackgroundThe extent and severity of traumatic brain injuries (TBIs) can be difficult to determine with current diagnostic methods. To address this, there has been increased interest in developing biomarkers to assist in the diagnosis, determination of injury severity, evaluation of recovery and therapeutic efficacy, and prediction of outcomes. Several promising serum TBI biomarkers have been identified using hypothesis-driven approaches, largely examining proteins that are abundant in neurons and non-neural cells in the CNS.New MethodAn unbiased approach, phage display, was used to identify serum TBI biomarkers. In this proof-of-concept study, mice received a TBI using the controlled cortical impact model of TBI (1mm injury depth, 3.5m/s velocity) and phage display was utilized to identify putative serum biomarkers at 6h postinjury.ResultsAn engineered phage which preferentially bound to injured serum was sequenced to identify the 12-mer 'recognizer' peptide expressed on the coat protein. Following synthesis of the recognizer peptide, pull down, and mass spectrometry analysis, the target protein was identified as glial fibrillary acidic protein (GFAP).Comparison with Existing Methods and ConclusionsGFAP has previously been identified as a promising TBI biomarker. The results provide proof of concept regarding the ability of phage display to identify TBI serum biomarkers. This methodology is currently being applied to serum biomarkers of mild TBI.



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MULTICENTRE COMPARISON OF PATIENT AND DETECTOR DOSE FOR X-RAY-GUIDED EMBOLISATIONS OF ARTERIOVENOUS MALFORMATIONS IN THE BRAIN.

MULTICENTRE COMPARISON OF PATIENT AND DETECTOR DOSE FOR X-RAY-GUIDED EMBOLISATIONS OF ARTERIOVENOUS MALFORMATIONS IN THE BRAIN.

Radiat Prot Dosimetry. 2016 May 5;

Authors: Geleijns J, Overvelde ML, Zweers D, Mourik JE

Abstract
Dosimetric benchmarking at four hospitals was performed to investigate incident entrance dose and dose rate on a phantom, and entrance detector dose and dose rate for protocols that are used in routine clinical practice for complex neuroradiological treatment of arteriovenous malformations (AVMs). Measurements were performed with a head phantom that simulates the attenuation and scattering of the human head for the lateral and posteroanterior (PA) views. For fluoroscopy, the measured incident entrance dose rate and entrance detector dose rate were in the range of 44-172 and 0.3-1.3 μGy s(-1), respectively. The pulse rate in fluoroscopy varied between 6.3 and 15 frames per second (fps). For digital subtraction angiography (DSA), incident entrance dose per frame and entrance detector dose per frame were in the range of 744-2800 and 2.6-8.1 μGy/frame, respectively. Optimisation of acquisition parameters such as pulse rate in fluoroscopy, dose per frame in DSA, beam filtration and tube voltage may further improve imaging protocols and lower the patient dose in very complex X-ray-guided embolisations of AVMs in the brain. However, differences in these acquisition parameters observed in this study were relatively small, suggesting that a relatively high degree of optimisation has already been achieved.

PMID: 27154974 [PubMed - as supplied by publisher]

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The Status of the Quality Control in Acupuncture-Neuroimaging Studies

Using neuroimaging techniques to explore the central mechanism of acupuncture gains increasing attention, but the quality control of acupuncture-neuroimaging study remains to be improved. We searched the PubMed Database during 1995 to 2014. The original English articles with neuroimaging scan performed on human beings were included. The data involved quality control including the author, sample size, characteristics of the participant, neuroimaging technology, and acupuncture intervention were extracted and analyzed. The rigorous inclusion and exclusion criteria are important guaranty for the participants' homogeneity. The standard operation process of acupuncture and the stricter requirement for acupuncturist play significant role in quality control. More attention should be paid to the quality control in future studies to improve the reproducibility and reliability of the acupuncture-neuroimaging studies.

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A Comparative Randomized Controlled Clinical Trial on the Effectiveness, Safety, and Tolerability of a Homeopathic Medicinal Product in Children with Sleep Disorders and Restlessness

A prospective, multicenter, randomized, open-label, controlled clinical trial was performed to evaluate the effectiveness and safety of the homeopathic product ZinCyp-3-02 in children with sleep disorders for ≥ one month compared to glycine. Children ≤ six years old received either ZinCyp-3-02 () or comparator glycine (). After treatment for 28 days, total sleep-disorder-associated complaints severity scores decreased in both groups from median 7.0 (out of maximum 11.0) points to 2.0 (ZinCyp-3-02) and 4.0 (glycine) points, respectively, with overall higher odds of showing improvement for ZinCyp-3-02 (odds ratio: 4.45 (95% CI: 2.77–7.14), , POM overall treatment related effect). Absence of individual complaints (time to sleep onset, difficulties maintaining sleep, sleep duration, troubled sleep (somniloquism), physical inactivity after awakening, restlessness for unknown reason, and sleep disorders frequency) at study end were significantly higher with ZinCyp-3-02 (all values

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Antcin K, a Triterpenoid Compound from Antrodia camphorata, Displays Antidiabetic and Antihyperlipidemic Effects via Glucose Transporter 4 and AMP-Activated Protein Kinase Phosphorylation in Muscles

The purpose of this study was to screen firstly the potential effects of antcin K (AnK), the main constituent of the fruiting body of Antrodia camphorata, in vitro and further evaluate the activities and mechanisms in high-fat-diet- (HFD-) induced mice. Following 8-week HFD-induction, mice were treated with AnK, fenofibrate (Feno), metformin (Metf), or vehicle for 4 weeks afterward. In C2C12 myotube cells, the membrane GLUT4 and phospho-Akt expressions were higher in insulin and AnK-treated groups than in the control group. It was observed that AnK-treated mice significantly lowered blood glucose, triglyceride, total cholesterol, and leptin levels in AnK-treated groups. Of interest, AnK at 40 mg/kg/day dosage displayed both antihyperglycemic effect comparable to Metf (300 mg/kg/day) and antihypertriglyceridemic effect comparable to Feno (250 mg/kg/day). The combination of significantly increased skeletal muscular membrane expression levels of glucose transporter 4 (GLUT4) but decreased hepatic glucose-6-phosphatase (G6 Pase) mRNA levels by AnK thus contributed to a decrease in blood glucose levels. Furthermore, AnK enhanced phosphorylation of AMP-activated protein kinase (phospho-AMPK) expressions in the muscle and liver. Moreover, AnK treatment exhibited inhibition of hepatic fatty acid synthase (FAS) but enhancement of fatty acid oxidation peroxisome proliferator-activated receptor α (PPARα) expression coincident with reduced sterol response element binding protein-1c (SREBP-1c) mRNA levels in the liver may contribute to decreased plasma triglycerides, hepatic steatosis, and total cholesterol levels. The present findings indicate that AnK displays an advantageous therapeutic potential for the management of type 2 diabetes and hyperlipidemia.

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Crossed Renal Fusion and an Abdominal Aortic Aneurysm with a Trifurcation

Publication date: Available online 8 May 2016
Source:European Journal of Vascular and Endovascular Surgery
Author(s): T. Lo, A. Chaudhuri




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Infected Aortic Stentgraft Treated with Fresh Cold Stored Arterial Allograft

Publication date: Available online 8 May 2016
Source:European Journal of Vascular and Endovascular Surgery
Author(s): P. Balaz, S. Rokosny




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