Editorial Board

Publication date: 15 February 2018
Source:Journal of Neuroscience Methods, Volume 296





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Detecting Structural and Inflammatory Response after In Vivo Stretch Injury in the Rat Median Nerve via Second Harmonic Generation

Publication date: Available online 14 February 2018
Source:Journal of Neuroscience Methods
Author(s): Matthew J. Gluck, Surabhi Vijayaraghavan, Elaine B. Sinclair, Asad Ashraf, Michael R. Hausman, Paul J. Cagle
BackgroundSecond Harmonic Generation (SHG) microscopy is a promising method for visualizing the collagenous structure of peripheral nerves. Assessing collagen continuity and damage after a stretch injury provides inferential insight into the level of axonal damage present.New MethodsThis study utilizes SHG microscopy after a calibrated in vivo stretch injury of rat median nerves to evaluate collagen continuity at several time points throughout the recovery process. Endoneurial collagen was qualitatively assessed in nerves that were subjected to low strain (LS) and high strain (HS) injuries using SHG microscopy, conventional histology, and immunohistochemistry.ResultsFollowing an in vivo stretch injury, both LS and HS damaged nerves exhibit signs of structural collagen damage in comparison with sham control nerves (SC). Furthermore, LS nerves exhibit signs of full regeneration while HS nerves exhibited signs of only partial regeneration with lasting damage and intra-neural scar formation.Comparison with Existing MethodsSHG observations of structural changes and inflammatory response due to stretch injury were validated upon comparison with conventional histological methodsConclusionsWe propose that SHG microscopy can be utilized to visualize significant structural artifacts in sectioned median nerves following in vivo stretch injury. Based on the findings in this study, we believe that the in vivo application of SHG microscopy should be further investigated as a means for real-time, intra-operative, quantitative assessment of nerve damage.



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Mucuna pruriens (L.) DC chemo sensitize human breast cancer cells via downregulation of prolactin-mediated JAK2/STAT5A signaling

Publication date: 10 May 2018
Source:Journal of Ethnopharmacology, Volume 217
Author(s): Sonam Sinha, Sonal Sharma, Jaykant Vora, Heta Shah, Anshu Srivastava, Neeta Shrivastava
Ethnopharmacological relevanceMucuna pruriens (L.) DC (MP) is an ancient Indian medicinal plant traditionally used to treat Parkinson's disease. L-Dopa (LD), precursor of dopamine is abundantly found in the seeds of MP. L-dopa is a natural inhibitor of prolactin (PRL) hormone which is required to maintain lactation in women but it's over production (hyperprolactinemia) plays critical role in advancement of breast cancer.Aim of the studyWe aim to examine the pharmacological effect of LD and MP on this hyperprolactinemia associated breast cancer and related signaling for effective management of the disease. We also investigated chemo-sensitizing effect of MP on hyperprolactinemia-mediated cisplatin resistance.Materials and methodsMethanolic seed extract of MP were prepared and analysed using HPLC. Effect of LD and MP on the cellular viability of breast cancer cells (T47D, MCF-7, MDA-MB-468 and MDA-MB-231) were evaluated using MTT assay. Further, effect of LD and MP on colony forming potential, DNA damage, cell cycle distribution and apoptosis was determined using agar/agarose method, comet assay and annexin and PI method followed by FACS analysis. To reveal the molecular mechanism involved in the anti-cancer activity of MP, transcriptional and translational level analysis of the key proteins involved in the PRL-mediated signaling, was performed using RT-PCR and western blot analysis. The effect of MP extract on PRL-mediated signaling was validated using dopaminergic agonist bromocriptine. MP extract and cisplatin was given in different combination with appropriate controls to check their effect on chemo-resistivity of breast cancer cells.ResultsOur results demonstrated that MP seed extract has the potential to inhibit cellular proliferation of PRL expressing T47D and MCF-7 breast cancer cells via induction of DNA damage, G1 phase of cell cycle arrest and apoptosis more effectively as compare to LD. Further, MP-mediated anti-cancerous effect was associated with the downregulation of PRL expression, further suppressing the JAK2/STAT5A/Cyclin D1 signaling pathway which has been validated using dopaminergic agonist bromocriptine. Cancer-related hyperprolactinemia confers cisplatin resistance, we observed that MP via PRL inhibition, enhances cisplatin efficacy after their combinatorial treatment in breast cancer cells.ConclusionsCollectively, our study suggests that MP could be recommended as dietary supplement along with the chemotherapeutic agents against breast cancer.

Graphical abstract

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Bu Shen Yi Sui capsule promotes remyelination correlating with Sema3A/NRP-1, LIF/LIFR and Nkx6.2 in mice with experimental autoimmune encephalomyelitis

Publication date: 10 May 2018
Source:Journal of Ethnopharmacology, Volume 217
Author(s): Pei-Yuan Zhao, Yong-Qiang Wang, Xi-Hong Liu, Ying-Jun Zhu, Hui Zhao, Qiu-Xia Zhang, Fang Qi, Jun-Ling Li, Nan Zhang, Yong-Ping Fan, Kang-Ning Li, Yuan-Yuan Zhao, Jian-Feng Lei, Lei Wang
Ethnopharmacological relevanceBu Shen Yi Sui capsule (BSYSC), based on traditional Chinese formula Liu Wei Di Huang pill, is effective for the treatment of multiple sclerosis (MS) in clinical experience and trials. Our previous studies confirmed that BSYSC had the neuroprotective effect in MS and its animal model, experimental autoimmune encephalomyelitis (EAE); however, its mechanism of action was not clear. Thus, the effect of BSYSC on remyelination and the underlying mechanisms were investigated in the EAE mice.Materials and methodsThe EAE model was established by injecting subcutaneously myelin oligodendrocyte protein (MOG) 35–55 in mice. Mice were treated with BSYSC (3.02 g/kg) or vehicle daily by oral gavage for 40 days. The body weight and clinical score of mice were evaluated. Brain was observed by magnetic resonance imaging. The inflammation infiltrate of brain and spinal cord was determined by hematoxylin-eosin staining, while the structure of myelin sheath was visualized by transmission electron microscopy on days 23 and 40 post immunization (dpi), respectively. The protein and mRNA levels of platelets-derived growth factor receptor (PDGFR) α and 2′, 3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) were measured by immunohistochemistry, western blot and quantitative real-time polymerase chain reaction. The protein expressions of semaphorins (Sema) 3A, Neuropilin (NRP) − 1, leukemia inhibitory factor (LIF), LIF receptor (LIFR) and Nkx6.2 were further investigated by western blot.ResultsBSYSC treatment improved the body weight and clinical score of EAE mice, alleviated inflammatory infiltration and nerve fiber injuries. It also protected the ultrastructural integrity of myelin sheath. BSYSC significantly increased expressions of PDGFRα and CNPase in mice with EAE on 40 dpi. Furthermore, BSYSC treatment increased the expressions of LIF, LIFR and Nkx6.2 and reduced Sema3A and NRP-1 in EAE mice on 40 dpi.ConclusionsThe data demonstrated that BSYSC exhibited the neuroprotective effect against EAE by promoting oligodendrocyte progenitor cells (OPCs) proliferation and differentiation, thus facilitating remyelination. Sema3A/NRP-1, LIF/LIFR and Nkx6.2 are likely contributed to the effects of BSYSC on OPCs.

Graphical abstract

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Anti-nociceptive effect of methanol extract of leaves of Senna singueana in mice

Publication date: 10 May 2018
Source:Journal of Ethnopharmacology, Volume 217
Author(s): Hailemichael Zeru Hishe, Tamrat Abate Ambech, Mebrahtom Gebrelibanos Hiben, Biruk Sintayehu Fanta
Ethnopharmacological RelevanceSenna singueana (Del.) Lock (Fabaceae) is a shrub or tree found in Ethiopia and other African countries. It has been traditionally used for different conditions including treatment of pain conditions in humans and animals. Although various reports are available in the literature claiming different activities of the plant, scientific studies supporting analgesic potential of S. singueana are lacking and the present study aimed to investigate the antinociceptive effect of methanol extract of leaves of S. singueana in mice.Materials and MethodsAnti-nociceptive activity of S. singueana (200 mg/kg and 400 mg/kg, p.o) was investigated using acetic acid-induced writhing, formalin-induced paw licking, and hot plate tests. Acute oral toxicity was determined using a slightly modified guideline (423) of the Organization for Economic Cooperation and Development.ResultsS. singueana extract increased the percentage of inhibition of writhing response and licking response (neurogenic and inflammatory phase) in acetic acid-induced writhing and formalin-induced paw licking tests, respectively. It also significantly (p ≤ 0.05) increased the percentage of mean maximal effect (%MPE) compared to control group in the hot-plate test. In all models, the combination of S. singueana with either diclofenac or morphine produced statistically significant increase (p ≤ 0.05) in the percentage of inhibition of writhing, paw licking, and %MPE compared to single treatment groups. It was also found that the 400 mg/kg extract produced higher antinociceptive effects (p ≤ 0.05) compared to the 200 mg/kg.ConclusionS. singueana leaves may have analgesic effect that is mediated through both peripheral and central mechanisms and could be used as adjuvant treatment to the modern analgesics.

Graphical abstract

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Breast cancer amelioration by Butea monosperma in-vitro and in-vivo

Publication date: 10 May 2018
Source:Journal of Ethnopharmacology, Volume 217
Author(s): Prachi Karia, Kirti V. Patel, Shri S.P. Rathod
Ethnopharmacological relevanceButea monosperma belonging to family Fabaceae is used in the Indian traditional medicine (Ayurveda) for various ailments including abdominal tumors and possess anti-estrogenic activity.Aim of the studyThe present study is aimed at investigating the chemo-preventive potential of Butea monosperma in breast cancer and elucidating it's mechanism of action by assessing its effect on key processes like apoptosis, angiogenesis and metastasis.MethodsCytotoxic potential of methanol extract of Butea monosperma flower (MEBM) was tested in MCF-7 (estrogen receptor positive), MDA-MB-231 (triple negative) and MDA-MB-453 (HER2 positive) human breast cancer cells by MTT assay. Chemo-preventive potential was evaluated in-vivo in Methylnitrosourea (MNU) induced mammary cancer in nulliparous Sprague-Dawley rats. The mechanism for anticancer potential was screened by in-vitro studies involving Annexin V- FITC assay (apoptosis), Chick Chorioallantoic Membrane assay (angiogenesis) and Migration assay (metastasis). Statistical analysis was done by one way and two way ANOVA (for Growth Rate and feed consumption efficiency) followed by post hoc Bonferroni's test with P value < 0.05.ResultsIt is observed that the exposure of MEBM, at various concentrations and time intervals to different cell lines, resulted in decreased cell proliferation. The IC50 value of MCF-7 cells was found significantly less than that of MDA-MB-231 and MDA-MB-453 cells, which indicated that the extract of said medicinal plant were more potent inhibitors of estrogen positive breast cancer cells than other types of breast cancer cells in vitro. Corroborative evidences were acquired in MNU actuated mammary carcinogenesis where MEBM constricted tumor parameters, decreased expression of estrogen and progesterone, nucleic acid content and increased latency period. MEBM also induced apoptosis, inhibited angiogenesis and metastasis in-vitro.ConclusionSelective cytotoxic activity in MCF-7 estrogen positive breast cancer cells and inhibition of growth of mammary carcinoma in-vivo by methanol extract of Butea monosperma flowers (MEBM) suggests chemo-prevention through modulation of estrogen and progesterone receptor, apoptotic, anti-angiogenesis and anti-metastatic activity.

Graphical abstract

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Concurrent use of Chinese herbal medicine among hormone users and its association with ischemic stroke risk: A population-based study

Publication date: 24 April 2018
Source:Journal of Ethnopharmacology, Volume 216
Author(s): Shu-Hui Wen, Wei-Chuan Chang, Mun-Kun Hong, Hsien-Chang Wu
Ethnopharmacological relevancePrevious studies had indicated that hormone therapy (HT) may increase the risk of ischemic stroke (IS) in menopausal women. However, little is known about the benefits and risks of use of Chinese herbal medicine (CHM) in conditions related to hormone use. The aim of this study is to explore the risk of IS in menopausal women treated with HT and CHM.Materials and methodsA total of 32,441 menopausal women without surgical menopause aged 40–65 years were selected from 2003 to 2010 using the 2-million random samples of the National Health Insurance Research Database in Taiwan. According to the medication usage of HT and CHM, we divided the current and recent users into two groups: an HT use-only group (n = 4989) and an HT/CHM group (n = 9265). Propensity-score matching samples (4079 pairs) were further created to deal with confounding by indication. The adjusted hazard ratios (HR) of IS were estimated by the robust Cox proportional hazards model.ResultsThe incidence rate of IS in the HT/CHM group was significantly lower than in the HT group (4.5 vs. 12.8 per 1000 person-year, p < 0.001). Multivariate analysis results indicated that additional CHM use had a lower risk of IS compared to the HT group (HR = 0.3; 95% confidence interval [CI], 0.21–0.43). Further subgroup analyses and sensitivity analyses had similar findings.ConclusionWe found that combined use of HT and CHM was associated with a lower risk of IS. Further study is needed to examine possible mechanism underlying this association.

Graphical abstract

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Table of contents

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Masthead

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Open Access: Is There a Predator at the Door?

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A common brain network among state, trait, and pathological anxiety from whole-brain functional connectivity

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Yu Takagi, Yuki Sakai, Yoshinari Abe, Seiji Nishida, Ben J. Harrison, Ignacio Martínez-Zalacaín, Carles Soriano-Mas, Jin Narumoto, Saori C. Tanaka
Anxiety is one of the most common mental states of humans. Although it drives us to avoid frightening situations and to achieve our goals, it may also impose significant suffering and burden if it becomes extreme. Because we experience anxiety in a variety of forms, previous studies investigated neural substrates of anxiety in a variety of ways. These studies revealed that individuals with high state, trait, or pathological anxiety showed altered neural substrates. However, no studies have directly investigated whether the different dimensions of anxiety share a common neural substrate, despite its theoretical and practical importance. Here, we investigated a brain network of anxiety shared by different dimensions of anxiety in a unified analytical framework using functional magnetic resonance imaging (fMRI). We analyzed different datasets in a single scale, which was defined by an anxiety-related brain network derived from whole brain. We first conducted the anxiety provocation task with healthy participants who tended to feel anxiety related to obsessive-compulsive disorder (OCD) in their daily life. We found a common state anxiety brain network across participants (1585 trials obtained from 10 participants). Then, using the resting-state fMRI in combination with the participants' behavioral trait anxiety scale scores (879 participants from the Human Connectome Project), we demonstrated that trait anxiety shared the same brain network as state anxiety. Furthermore, the brain network between common to state and trait anxiety could detect patients with OCD, which is characterized by pathological anxiety-driven behaviors (174 participants from multi-site datasets). Our findings provide direct evidence that different dimensions of anxiety have a substantial biological inter-relationship. Our results also provide a biologically defined dimension of anxiety, which may promote further investigation of various human characteristics, including psychiatric disorders, from the perspective of anxiety.



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Spatial coherence of oriented white matter microstructure: Applications to white matter regions associated with genetic similarity

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Haraldur T. Hallgrímsson, Matthew Cieslak, Luca Foschini, Scott T. Grafton, Ambuj K. Singh
We present a method to discover differences between populations with respect to the spatial coherence of their oriented white matter microstructure in arbitrarily shaped white matter regions. This method is applied to diffusion MRI scans of a subset of the Human Connectome Project dataset: 57 pairs of monozygotic and 52 pairs of dizygotic twins. After controlling for morphological similarity between twins, we identify 3.7% of all white matter as being associated with genetic similarity (35.1 k voxels, p<10−4, false discovery rate 1.5%), 75% of which spatially clusters into twenty-two contiguous white matter regions. Furthermore, we show that the orientation similarity within these regions generalizes to a subset of 47 pairs of non-twin siblings, and show that these siblings are on average as similar as dizygotic twins. The regions are located in deep white matter including the superior longitudinal fasciculus, the optic radiations, the middle cerebellar peduncle, the corticospinal tract, and within the anterior temporal lobe, as well as the cerebellum, brain stem, and amygdalae.These results extend previous work using undirected fractional anisotrophy for measuring putative heritable influences in white matter. Our multidirectional extension better accounts for crossing fiber connections within voxels. This bottom up approach has at its basis a novel measurement of coherence within neighboring voxel dyads between subjects, and avoids some of the fundamental ambiguities encountered with tractographic approaches to white matter analysis that estimate global connectivity.



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Spontaneous activity forms a foundation for odor-evoked activation maps in the rat olfactory bulb

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Garth J. Thompson, Basavaraju G. Sanganahalli, Keeley L. Baker, Peter Herman, Gordon M. Shepherd, Justus V. Verhagen, Fahmeed Hyder
Fluctuations in spontaneous activity have been observed by many neuroimaging techniques, but because these resting-state changes are not evoked by stimuli, it is difficult to determine how they relate to task-evoked activations. We conducted multi-modal neuroimaging scans of the rat olfactory bulb, both with and without odor, to examine interaction between spontaneous and evoked activities. Independent component analysis of spontaneous fluctuations revealed resting-state networks, and odor-evoked changes revealed activation maps. We constructed simulated activation maps using resting-state networks that were highly correlated to evoked activation maps. Simulated activation maps derived by intrinsic optical signal (IOS), which covers the dorsal portion of the glomerular sheet, significantly differentiated one odor's evoked activation map from the other two. To test the hypothesis that spontaneous activity of the entire glomerular sheet is relevant for representing odor-evoked activations, we used functional magnetic resonance imaging (fMRI) to map the entire glomerular sheet. In contrast to the IOS results, the fMRI-derived simulated activation maps significantly differentiated all three odors' evoked activation maps. Importantly, no evoked activation maps could be significantly differentiated using simulated activation maps produced using phase-randomized resting-state networks. Given that some highly organized resting-state networks did not correlate with any odors' evoked activation maps, we posit that these resting-state networks may characterize evoked activation maps associated with odors not studied. These results emphasize that fluctuations in spontaneous activity form a foundation for active processing, signifying the relevance of resting-state mapping to functional neuroimaging.



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Improved estimation of subject-level functional connectivity using full and partial correlation with empirical Bayes shrinkage

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Amanda F. Mejia, Mary Beth Nebel, Anita D. Barber, Ann S. Choe, James J. Pekar, Brian S. Caffo, Martin A. Lindquist
Reliability of subject-level resting-state functional connectivity (FC) is determined in part by the statistical techniques employed in its estimation. Methods that pool information across subjects to inform estimation of subject-level effects (e.g., Bayesian approaches) have been shown to enhance reliability of subject-level FC. However, fully Bayesian approaches are computationally demanding, while empirical Bayesian approaches typically rely on using repeated measures to estimate the variance components in the model. Here, we avoid the need for repeated measures by proposing a novel measurement error model for FC describing the different sources of variance and error, which we use to perform empirical Bayes shrinkage of subject-level FC towards the group average. In addition, since the traditional intra-class correlation coefficient (ICC) is inappropriate for biased estimates, we propose a new reliability measure denoted the mean squared error intra-class correlation coefficient (ICCMSE) to properly assess the reliability of the resulting (biased) estimates. We apply the proposed techniques to test-retest resting-state fMRI data on 461 subjects from the Human Connectome Project to estimate connectivity between 100 regions identified through independent components analysis (ICA). We consider both correlation and partial correlation as the measure of FC and assess the benefit of shrinkage for each measure, as well as the effects of scan duration. We find that shrinkage estimates of subject-level FC exhibit substantially greater reliability than traditional estimates across various scan durations, even for the most reliable connections and regardless of connectivity measure. Additionally, we find partial correlation reliability to be highly sensitive to the choice of penalty term, and to be generally worse than that of full correlations except for certain connections and a narrow range of penalty values. This suggests that the penalty needs to be chosen carefully when using partial correlations.



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Cooperation makes two less-creative individuals turn into a highly-creative pair

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Hua Xue, Kelong Lu, Ning Hao
This study aimed to investigate which type of group (e.g., consisting of less-creative or highly-creative individuals) would perform better in solving creativity problems, and explore the underlying inter-brain neural correlates between team members. A preliminary test (an alternative-uses task) was performed to rank individuals' level of creativity, and divide participants into three types of dyads: high-high (two highly-creative individuals), low-low (two less-creative individuals), and high-low (one highly-creative and one less-creative individual). Dyads were then asked to solve a realistic presented problem (RPP; a typical creativity problem) during which a functional near-infrared spectroscopy (fNIRS)-based hyperscanning device was used to record the variation of interpersonal brain synchronization (IBS). Results revealed that less-creative individuals, while working together, would perform as well as highly-creative individuals. The low-low dyads showed higher levels of cooperation behaviour than the other two types of dyads. The fNIRS results revealed increased IBS only for low-low dyads at PFC (prefrontal cortex) and rTPJ (right temporal-parietal junction) brain regions during RPP task performance. In the rDLPFC (right dorsolateral prefrontal cortex), the IBS in the low-low dyads was stronger than that of high-high and high-low dyads. In the rTPJ, the IBS in the low-low dyads was only stronger than that of the high-low dyads. Besides, the IBS at rDLPFC and rTPJ regions in the low-low dyads was positively correlated with their cooperation behaviour and group creative performance. These findings indicated when two less-creative individuals worked on a creativity problem together, they tended to cooperate with each other (indicated by both behaviour index and increased IBS at rDLPFC and rTPJ), which benefited their creative performance.



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Rule activation and ventromedial prefrontal engagement support accurate stopping in self-paced learning

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Sean R. O'Bryan, Eric Walden, Michael J. Serra, Tyler Davis
When weighing evidence for a decision, individuals are continually faced with the choice of whether to gather more information or act on what has already been learned. The present experiment employed a self-paced category learning task and fMRI to examine the neural mechanisms underlying stopping of information search and how they contribute to choice accuracy. Participants learned to classify triads of face, object, and scene cues into one of two categories using a rule based on one of the stimulus dimensions. After each trial, participants were given the option to explicitly solve the rule or continue learning. Representational similarity analysis (RSA) was used to examine activation of rule-relevant information on trials leading up to a decision to solve the rule. We found that activation of rule-relevant information increased leading up to participants' stopping decisions. Stopping was associated with widespread activation that included medial prefrontal cortex and visual association areas. Engagement of ventromedial prefrontal cortex (vmPFC) was associated with accurate stopping, and activation in this region was functionally coupled with signal in dorsolateral prefrontal cortex (dlPFC). Results suggest that activating rule information when deciding whether to stop an information search increases choice accuracy, and that the response profile of vmPFC during such decisions may provide an index of effective learning.



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Neural correlates of novelty and appropriateness processing in externally induced constraint relaxation

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Furong Huang, Shuang Tang, Pei Sun, Jing Luo
Novelty and appropriateness are considered the two fundamental features of creative thinking, including insight problem solving, which can be performed through chunk decomposition and constraint relaxation. Based on a previous study that separated the neural bases of novelty and appropriateness in chunk decomposition, in this study, we used event-related functional magnetic resonance imaging (fMRI) to further dissociate these mechanisms in constraint relaxation. Participants were guided to mentally represent the method of problem solving according to the externally provided solutions that were elaborately prepared in advance and systematically varied in their novelty and appropriateness for the given problem situation. The results showed that novelty processing was completed by the temporoparietal junction (TPJ) and regions in the executive system (dorsolateral prefrontal cortex [DLPFC]), whereas appropriateness processing was completed by the TPJ and regions in the episodic memory (hippocampus), emotion (amygdala), and reward systems (orbitofrontal cortex [OFC]). These results likely indicate that appropriateness processing can result in a more memorable and richer experience than novelty processing in constraint relaxation. The shared and distinct neural mechanisms of the features of novelty and appropriateness in constraint relaxation are discussed, enriching the representation of the change theory of insight.



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Errors can elicit an error positivity in the absence of an error negativity: Evidence for independent systems of human error monitoring

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Francesco Di Gregorio, Martin E. Maier, Marco Steinhauser
Errors in human behavior elicit a cascade of brain activity related to performance monitoring and error detection. Whereas the early error-related negativity (Ne/ERN) has been assumed to reflect a fast mismatch or prediction error signal in the medial frontal cortex, the later error positivity (Pe) is viewed as a correlate of conscious error processing. A still open question is whether these components represent two independent systems of error monitoring that rely on different types of information to detect an error. Here, we investigated the prediction that the Ne/ERN but not the Pe requires a representation of the correct response to emerge. To this end, we created a condition in which no information about the correct response was available while error detection was still possible. We hypothesized that a Pe, but no Ne/ERN should be obtained in this case. Participants had to classify targets but ignore flankers that were always associated with an incorrect response. Targets but not flankers were masked with varying target-masking intervals. Crucially, on some trials no target at all was presented, thus preventing the representation of a correct response and the emergence of an Ne/ERN. However, because flankers were easily visible and responses to the flankers were always incorrect, detection of these flanker errors was still possible. In line with predictions of a multiple-systems account, we observed a robust Pe in the absence of an Ne/ERN for these errors. Moreover, this Pe relied on the same neural activity as that on trials with a visible target, as revealed by multivariate pattern analysis. These findings demonstrate that the mechanisms reflected by the two components use different types of information to detect errors, providing evidence for independent systems of human error monitoring.



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The dynamics of human cognition: Increasing global integration coupled with decreasing segregation found using iEEG

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Josephine Cruzat, Gustavo Deco, Adrià Tauste-Campo, Alessandro Principe, Albert Costa, Morten L. Kringelbach, Rodrigo Rocamora
Cognitive processing requires the ability to flexibly integrate and process information across large brain networks. How do brain networks dynamically reorganize to allow broad communication between many different brain regions in order to integrate information? We record neural activity from 12 epileptic patients using intracranial EEG while performing three cognitive tasks. We assess how the functional connectivity between different brain areas changes to facilitate communication across them. At the topological level, this facilitation is characterized by measures of integration and segregation. Across all patients, we found significant increases in integration and decreases in segregation during cognitive processing, especially in the gamma band (50–90 Hz). We also found higher levels of global synchronization and functional connectivity during task execution, again particularly in the gamma band. More importantly, functional connectivity modulations were not caused by changes in the level of the underlying oscillations. Instead, these modulations were caused by a rearrangement of the mutual synchronization between the different nodes as proposed by the "Communication Through Coherence" Theory.



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Differences in steady-state glutamate levels and variability between ‘non-task-active’ conditions: Evidence from 1H fMRS of the prefrontal cortex

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Jonathan Lynn, Eric A. Woodcock, Chaitali Anand, Dalal Khatib, Jeffrey A. Stanley
Proton functional magnetic resonance spectroscopy (¹H fMRS) is a noninvasive neuroimaging technique capable of detecting dynamic changes in glutamate related to task-related demands at a temporal resolution under 1 min. Several recent ¹H fMRS studies demonstrated elevated steady-state levels of glutamate of 2% or greater during different 'task-active' conditions, relative to a 'non-task-active' control condition. However, the 'control' condition from these studies does vary with respect to the degree of constraining behavior, which may lead to different glutamate levels or variability between 'control' conditions. The purpose of this ¹H fMRS study was to compare the steady-state levels and variability of glutamate in the left dorsolateral prefrontal cortex (dlPFC) of 16 healthy adults across four different putative 'non-task-active' conditions: relaxed with eyes closed, passive visual fixation crosshair, visual flashing checkerboard, and finger tapping. Results showed significantly lower glutamate levels during the passive visual fixation crosshair than the visual flashing checkerboard and the finger tapping conditions. Moreover, glutamate was significantly less variable during the passive visual fixation crosshair and the visual flashing checkerboard than the relaxed eyes closed condition. Of the four conditions, the passive visual fixation crosshair condition demonstrated the lowest and least variable glutamate levels potentially reflecting the least dlPFC engagement, but greatest behavioral constraint. These results emphasize the importance of selecting a proper 'control' condition to reflect accurately a 'non-task-active' steady-state level of glutamate with minimal variability during ¹H MRS investigations.



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Quantification of anisotropy and orientation in 3D electron microscopy and diffusion tensor imaging in injured rat brain

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Raimo A. Salo, Ilya Belevich, Eppu Manninen, Eija Jokitalo, Olli Gröhn, Alejandra Sierra
Diffusion tensor imaging (DTI) reveals microstructural features of grey and white matter non-invasively. The contrast produced by DTI, however, is not fully understood and requires further validation. We used serial block-face scanning electron microscopy (SBEM) to acquire tissue metrics, i.e., anisotropy and orientation, using three-dimensional Fourier transform-based (3D-FT) analysis, to correlate with fractional anisotropy and orientation in DTI. SBEM produces high-resolution 3D data at the mesoscopic scale with good contrast of cellular membranes. We analysed selected samples from cingulum, corpus callosum, and perilesional cortex of sham-operated and traumatic brain injury (TBI) rats. Principal orientations produced by DTI and 3D-FT in all samples were in good agreement. Anisotropy values showed similar patterns of change in corresponding DTI and 3D-FT parameters in sham-operated and TBI rats. While DTI and 3D-FT anisotropy values were similar in grey matter, 3D-FT anisotropy values were consistently lower than fractional anisotropy values from DTI in white matter. We also evaluated the effect of resolution in 3D-FT analysis. Despite small angular differences in grey matter samples, lower resolution datasets provided reliable results, allowing for analysis of larger fields of view. Overall, 3D SBEM allows for more sophisticated validation studies of diffusion imaging contrast from a tissue microstructural perspective.



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Vascular reactivity in small cerebral perforating arteries with 7 T phase contrast MRI – A proof of concept study

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Lennart J. Geurts, Alex A. Bhogal, Jeroen C.W. Siero, Peter R. Luijten, Geert Jan Biessels, Jaco J.M. Zwanenburg
Existing cerebrovascular reactivity (CVR) techniques assess flow reactivity in either the largest cerebral vessels or at the level of the parenchyma. We examined the ability of 2D phase contrast MRI at 7 T to measure CVR in small cerebral perforating arteries.Blood flow velocity in perforators was measured in 10 healthy volunteers (mean age 26 years) using a 7 T MR scanner, using phase contrast acquisitions in the semioval center (CSO), the basal ganglia (BG) and the middle cerebral artery (MCA). Changes in flow velocity in response to a hypercapnic breathing challenge were assessed, and expressed as the percentual increase of flow velocity as a function of the increase in end tidal partial pressure of CO2.The hypercapnic challenge increased (fit ± standard error) flow velocity by 0.7 ± 0.3%/mmHg in the CSO (P < 0.01). Moreover, the number of detected perforators (mean [range]) increased from 63 [27–88] to 108 [61–178] (P < 0.001). In the BG, the hypercapnic challenge increased flow velocity by 1.6 ± 0.5%/mmHg (P < 0.001), and the number of detected perforators increased from 48 [24–66] to 63 [32–91] (P < 0.01). The flow in the MCA increased by 5.2 ± 1.4%/mmHg (P < 0.01).Small vessel specific reactivity can now be measured in perforators of the CSO and BG, using 2D phase contrast at 7 T.

Graphical abstract

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Motivational effects on the processing of delayed intentions in the anterior prefrontal cortex

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Jovita Bruening, Vera U. Ludwig, Lena M. Paschke, Henrik Walter, Christine Stelzel
Delaying intentions bears the risk of interference from distracting activities during the delay interval. Motivation can increase intention retrieval success but little is known about the underlying brain mechanisms. Here, we investigated whether motivational incentives (monetary reward) modulate the processing of delayed intentions in the anterior prefrontal cortex (aPFC), known to be crucial for intention processing. Using a mixed blocked and event-related functional Magnetic Resonance Imaging design, we specifically tested whether reward affects intention processing in the aPFC in a transient or in a sustained manner and whether this is related to individual differences in retrieval success.We found a generalized effect of reward on both correct intention retrieval and ongoing task performance. Fronto-parietal regions including bilateral lateral aPFC showed sustained activity increases in rewarded compared to non-rewarded blocks as well as transient reward-related activity during the storage phase. Additionally, individual differences in reward-related performance benefits were related to the degree of transient signal increases in right lateral aPFC, specifically during intention encoding.This suggests that the ability to integrate motivational relevance into the encoding of future intentions is crucial for successful intention retrieval in addition to general increases in processing effort. Bilateral aPFC is central to these motivation-cognition interactions.



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Impacts of simultaneous multislice acquisition on sensitivity and specificity in fMRI

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Benjamin B. Risk, Mary C. Kociuba, Daniel B. Rowe
Simultaneous multislice (SMS) imaging can be used to decrease the time between acquisition of fMRI volumes, which can increase sensitivity by facilitating the removal of higher-frequency artifacts and boosting effective sample size. The technique requires an additional processing step in which the slices are separated, or unaliased, to recover the whole brain volume. However, this may result in signal "leakage" between aliased locations, i.e., slice "leakage," and lead to spurious activation (decreased specificity). SMS can also lead to noise amplification, which can reduce the benefits of decreased repetition time. In this study, we evaluate the original slice-GRAPPA (no leak block) reconstruction algorithm and acceleration factor (AF = 8) used in the fMRI data in the young adult Human Connectome Project (HCP). We also evaluate split slice-GRAPPA (leak block), which can reduce slice leakage. We use simulations to disentangle higher test statistics into true positives (sensitivity) and false positives (decreased specificity). Slice leakage was greatly decreased by split slice-GRAPPA. Noise amplification was decreased by using moderate acceleration factors (AF = 4). We examined slice leakage in unprocessed fMRI motor task data from the HCP. When data were smoothed, we found evidence of slice leakage in some, but not all, subjects. We also found evidence of SMS noise amplification in unprocessed task and processed resting-state HCP data.



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Somatosensory BOLD fMRI reveals close link between salient blood pressure changes and the murine neuromatrix

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Henning Matthias Reimann, Mihail Todiras, Russ Hodge, Till Huelnhagen, Jason Michael Millward, Robert Turner, Erdmann Seeliger, Michael Bader, Andreas Pohlmann, Thoralf Niendorf
The neuromatrix, or "pain matrix", is a network of cortical brain areas which is activated by noxious as well as salient somatosensory stimulation. This has been studied in mice and humans using blood oxygenation level-dependent (BOLD) fMRI. Here we demonstrate that BOLD effects observed in the murine neuromatrix in response to salient somatosensory stimuli are prone to reflect mean arterial blood pressure (MABP) changes, rather than neural activity. We show that a standard electrostimulus typically used in murine somatosensory fMRI can induce substantial elevations in MABP. Equivalent drug-induced MABP changes — without somatosensory stimulation — evoked BOLD patterns in the neuromatrix strikingly similar to those evoked by electrostimulation. This constitutes a serious caveat for murine fMRI. The regional specificity of these BOLD patterns can be attributed to the co-localization of the neuromatrix with large draining veins. Based on these findings we propose a cardiovascular support mechanism whereby abrupt elevations in MABP provide additional energy supply to the neuromatrix and other essential brain areas in fight-or-flight situations.



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Protection against summer solar lentigo over-pigmentation with a SPF30 daily cream

Abstract

Background/purpose

The aim of this study was to measure lentigines' pigmentation over a long period of time and evaluate if summer over-pigmentation can be avoided by the use a SPF30 day skin cream.

Methods

Seventeen healthy female volunteers aged 50 and over and presenting lentigines participated in the study from spring to summer. Throughout the study, all subjects applied a SPF30 daily skin cream to only one hand. Color measurements of the target lesions were performed with a chromameter and with a color-calibrated camera. Target lesions were also imaged with in vivo reflectance confocal microscopy (RCM). A specific procedure for re-registering the images was developed to ensure that the same papillae were measured over time.

Results

Both color measurement methods, chromametry and color-calibrated camera, showed that lentigines treated over time with the SPF30 day skin cream were significantly lighter than the non-treated lentigines. The RCM images showed a decrease in the papillary contrast for the treated lentigines.

Conclusion

This study shows that this over-pigmentation can be avoided using a SPF30 day skin cream. Moreover, we have demonstrated that very fine re-registration of the RCM images is possible and ensures a more robust analysis.

http://ift.tt/2o36MYw

Hyperglycemia and risk of adverse outcomes following microvascular reconstruction of oncologic head and neck defects

Publication date: April 2018
Source:Oral Oncology, Volume 79
Author(s): Anaeze C. Offodile, Hsuan-Yu Chou, Jennifer An-Jou Lin, Charles Yuen Yung Loh, Kai-Ping Chang, Mario A. Aycart, Huang-Kai Kao
IntroductionOur aim is to examine the correlation between perioperative hyperglycemia and post-operative outcomes following microvascular reconstruction of head and neck defects.Patients and methodsRetrospective review of a prospectively collected database of 350 consecutive patients who underwent microvascular reconstruction of malignant head and neck defects over a 2 year period. The relationship between perioperative hyperglycemia (≥ 180 mg/dL) and the incidence of the following complications was evaluated: flap loss, flap-related complications and surgical site infections (SSI). Sub-group analysis based on timing of hyperglycemia was also performed.ResultsWe identified 313 patients (89.4%) in the normoglycemic group and 37 patients (10.6%) in the hyperglycemic group. Baseline demographics, tumor stage, operative variable were comparable. There were no significant differences in flap-related complications and overall mortality. SSI were significantly higher in the hyperglycemic cohort (48% vs. 28%, p = 0.01). On multivariate analysis, hyperglycemia [OR 2.07; 95% CI, 1.87–4.89], perioperative insulin administration [OR 4.805; 95% CI, 2.18–10.60], prolonged operative time [OR 1.003; 95% CI, 1.002–1.025] and higher Charlson co-morbidity indices [II: OR 2.286 & III: OR 2.284] were independent predictors of SSI. On sub-group analysis, only patients with early (POD 1) post-operative hyperglycemia had a significant OR for SSI (OR 1.88; 95% CI, 1.07–3.29).ConclusionOur findings suggest that perioperative hyperglycemia, specifically during the first 24 h post-operatively, is associated with SSI in microvascular head and neck reconstruction. This association highlights the need for strict screening of head and neck patients for hyperglycemia especially in the immediate post-operative period.



http://ift.tt/2EHwR93

Saturation reduces in-vitro leakage of monomers from composites

Publication date: Available online 14 February 2018
Source:Dental Materials
Author(s): Stevan M. Cokic, Radu C. Duca, Jan De Munck, Peter Hoet, Bart Van Meerbeek, Mario Smet, Lode Godderis, Kirsten L. Van Landuyt
ObjectiveAccurate knowledge of the quantity of released monomers from composites is important. To evaluate the elution of monomers, polymerized composites are typically immersed in an extraction solvent. The objective was to determine whether the volume of extraction solvent and the immersion time influences monomer leachability from dental composite materials.MethodsComposite disks of two commercial composites, (Filtek Supreme XTE, 3M ESPE and G-aenial Universal Flo, GC) were prepared. The disks (n=10) were placed in a glass vial with 1ml, 2ml or 3ml of extraction solvent (100% ethanol with deuterated diethylphalate as internal standard). After either 7 or 30 days at 37°C, the supernatant was collected and the amount of released monomers (BisEMA, BisGMA, UDMA, TEGDMA) and bisphenol A was measured with liquid chromatography mass spectroscopy.ResultsFor both tested composites, the highest amount of released monomers was measured after sample incubation in 3ml, while the lowest amount was measured in 1ml of extraction solvent. Furthermore, 30 days did not result in much more monomer release compared to 7 days, and for most monomers, there was no statistically significant difference in release between 7 and 30 days.SignificanceRelease kinetics in in-vitro experiments are also influenced by saturation of the extraction solvent with the leached monomers. This is important as it is unlikely that saturation can be reached in an in-vivo situation, where saliva (or pulpal fluid) is continuously refreshed. Saturation of the extraction solvent can be avoided in-vitro by refreshing the extraction medium after equal time intervals.



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Targeting RORs nuclear receptors by novel synthetic steroidal inverse agonists for autoimmune disorders

Publication date: Available online 15 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Matteo Dal Pra, Davide Carta, Gyorgy Szabadkai, Matteo Suman, Yahima Frión-Herrera, Nicola Paccagnella, Giulia Castellani, Sara De Martin, Maria Grazia Ferlin
Designing novel inverse agonists of NR RORγt still represents a challenge for the pharmaceutical community to develop therapeutics for treating immune diseases. By exploring the structure of NRs natural ligands, the representative arotenoid ligands and RORs specific ligands share some chemical homologies which can be exploited to design a novel molecular structure characterized by a polycyclic core bearing a polar head and a hydrophobic tail. Compound MG 2778 (8), a cyclopenta[a]phenantrene derivative, was identified as lead compound which was chemically modified at position 2 in order to obtain a small library for preliminary SARs. Cell viability and estrogenic activity of compounds 7, 8, 19a, 30, 31 and 32 were evaluated to attest selectivity. The selected 7, 8, 19a and 31 compounds were assayed in a Gal4 UAS-Luc co-transfection system in order to determine their ability to modulate RORγt activity in a cellular environment. They were evaluated as inverse agonists taken ursolic acid as reference compound. The potency of compounds was lower than that of ursolic acid, but their efficacy was similar. Compound 19a was the most active, significantly reducing RORγt activity at low micromolar concentrations.

Graphical abstract

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Pharmacophore Requirements for HIV-1 Reverse Transcriptase Inhibitors that Selectively “Freeze” the Pre-Translocated Complex During the Polymerization Catalytic Cycle

Publication date: Available online 14 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Cyrus M. Lacbay, Michael Menni, Jean A. Bernatchez, Matthias Götte, Youla S. Tsantrizos
Reverse transcriptase (RT) is responsible for replicating the HIV-1 genome and is a validated therapeutic target for the treatment of HIV infections. During each cycle of the RT-catalyzed DNA polymerization process, inorganic pyrophosphate is released as the by-product of nucleotide incorporation. Small molecules were identified that act as bioisosteres of pyrophosphate and can selectively freeze the catalytic cycle of HIV-1 RT at the pre-translocated stage of the DNA- or RNA-template-primer-enzyme complex.

Graphical abstract

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Novel 4-aminoquinazoline derivatives induce growth inhibition, cell cycle arrest and apoptosis via PI3Kα inhibition

Publication date: Available online 13 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Yan-Hua Fan, Huai-Wei Ding, Dan-Dan Liu, Hong-Rui Song, Yong-Nan Xu, Jian Wang
Phosphatidylinositol 3-kinase (PI3K) signaling pathway has diverse functions, including the regulation of cellular survival, proliferation, cell cycle, migration, angiogenesis and apoptosis. Among class I PI3Ks (PI3Kα, β, γ, δ), the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in a large portion of human cancers. Therefore, the inhibition of PI3Kα has been considered as a promising target for the development of a therapeutic treatment of cancer. In this study, we designed and synthesized a series of 4-aminoquinazoline derivatives and evaluated their antiproliferative activities against six cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638, A549 and MCF-7. Compound 6b with the most potent antiproliferative activity and without obvious cytotoxicity to human normal cells was selected for further biological evaluation. PI3K kinase assay showed that 6b has selectivity for PI3Kα distinguished from other isoforms. The western blot assay and PI3K kinase assay indicated that 6b effectively inhibited cell proliferation via suppression of PI3Kα kinase activity with an IC50 of 13.6 nM and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 6b caused G1 cell cycle arrest owing to the inhibition of PI3K signaling and induced apoptosis via mitochondrial dependent apoptotic pathway. Our findings suggested that 6b has a therapeutic value as an anticancer agent via PI3Kα inhibition.

Graphical abstract

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Investigation of multi-target-directed ligands (MTDLs) with butyrylcholinesterase (BuChE) and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition: the design, synthesis of miconazole analogues targeting Alzheimer’s disease

Publication date: Available online 13 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Xin Lu, Si-yu He, Qi Li, Hongyu Yang, Xueyang Jiang, Hongzhi Lin, Yao Chen, Wei Qu, Feng Feng, Yaoyao Bian, You Zhou, Haopeng Sun
In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer's disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine. Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors. Out of the 12 compounds, 5i and 5j exhibited the best potency in enzymatic evaluation, thus were selected for subsequent behavioral study, in which the two compounds exerted much improved effect than tacrine. Meanwhile, 5i and 5j displayed no apparent hepatotoxicity. The results suggest that miconazole analogue offers an attractive starting point for further development of new BuChE-IDO1 dual-target inhibitors against Alzheimer's disease.

Graphical abstract

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Synthesis of 3-aza[4.4.3]propellanes with high σ1 receptor affinity

Publication date: Available online 15 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Héctor Torres-Gómez, Constantin Daniliuc, Dirk Schepmann, Bernhard Wünsch
In order to obtain rigid σ1 receptor ligands with defined orientation of pharmacophoric elements, the azapropellane scaffold was chosen. Schmidt rearrangement of propellan-8-ones 6 and 10 provided 3-azapropellan-4-ones 7 and 11. Benzylation of the secondary lactams 7 and 11 followed by LiAlH4 reduction furnished the azapropellanes 4a and 4c, respectively. A second hydrophobic element was introduced by transformation of the alcohols 4a into carbamates 4b. The σ1 affinity of the azapropellanes 4 is strongly dependent on the stereochemistry and the substitution pattern in 12-position. anti-configured azapropellanes anti-4a and anti-4b show higher σ1 affinity than their syn-configured counterparts syn-4a and syn-4b. Conversion of the alcohol anti-4a into the carbamate anti-4b led to increased σ1 affinity, but complete removal of the 12-substituent resulted in the highest σ1 affinity (Ki(4c) = 17 nM). It can be concluded that the propellane scaffold alone is able to form strong lipophilic interactions and stabilize the ligand - σ1 receptor complex as does usually the primary hydrophobic region.

Graphical abstract

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VEGFR-2 as a novel predictor of survival in gastric cancer: a systematic review and meta-analysis

Publication date: Available online 14 February 2018
Source:Pathology - Research and Practice
Author(s): Teng Li, Jing Yu, Xinyu Luo, Weiguo Ren, Yue Zhang, Bangwei Cao
BackgroundExpression of VEGFRs may affect cancer prognosis. The aim of this work is to evaluate the prognostic significance of VEGFRs of patients with gastric cancer.MethodsThe databases PubMed, Embase, Web of Science, and Cochrane Library as well as ASCO and ESMO were searched systematically for articles reporting the prognostic significance of tissue VEGFRs in gastric cancer. The statistical analyses were carried out using Stata version 12.0.ResultsA total of 8 articles comprising 950 patients were eligible for meta-analysis. The combined HR of studies evaluating total VEGFRs overexpression was 1.42 (95% CI 1.01-2.00, P = 0.044), suggesting that it had prognosis significance in overall survival of gastric cancer. Subgroup analysis showed that it was VEGFR-2 (HR 1.81, 95%CI 1.31–2.49, P < 0.001) but not VEGFR-3 (HR 0.91, 95%CI 0.45–1.82, P = 0.787) overexpression was associated with an increased risk of median overall survival (mOS) and it can be a potentially predictive biomarker for gastric cancer.ConclusionsVEGFR-2 overexpression is a promising negative prognosis predictor for patients with gastric cancer. The prognosis significance of VEGFR-3 still need further study.



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Loss of p27kip1 expression is associated with poor prognosis in patients with taxane-treated breast cancer

Publication date: Available online 14 February 2018
Source:Pathology - Research and Practice
Author(s): Gi Jeong Kim, Dong-Hoon Kim, Kyueng-Whan Min, Young Hwan Kim, Young Ha Oh
PurposeDecreased expression of p27^kip1 and p57^kip2 is considered as a prognostic indicator in patients with breast cancer receiving adjuvant chemotherapy. Previous in vitro studies have reported that reduced expression of p27^kip1 and p57^kip2 is associated with resistance to taxane, which is one of the most effective chemotherapeutic agents. In this study, we investigated the association of low p27^kip1 and p57^kip2 expression with outcomes in patients with breast cancer.MethodsWe investigated 226 cases of breast cancer from Kangbuk SMC between 2000 and 2005. Levels of p27^kip1 and p57^kip2 expression were evaluated using immunohistochemical staining of tumor tissue microarray specimens. The relationships between the expression levels of the markers and patients' outcomes were analyzed using the Kaplan–Meier method and Cox proportional hazard model.ResultsLow p57^kip2 expression was only associated with negative progesterone receptor status (p = 0.034), whereas p27^kip1 expression was associated with poor prognosis of patients receiving adjuvant chemotherapy (p = 0.005). More detailed analysis revealed that low p27^kip1 expression affects the overall survival rate of patients receiving adjuvant chemotherapy including taxane (p = 0.026), but not that of patients receiving chemotherapy without taxane.ConclusionsLow p27^kip1 expression may be useful to predict overall survival in patients with breast cancer who are treated with taxane. Evaluation of p27^kip1 expression may provide further prognostic information beyond traditional prognostic biomarkers and an understanding of the mechanisms that impart resistance against chemotherapy.



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Prognostic significance of epithelial-mesenchymal transition phenotypes in upper urinary tract urothelial carcinoma

Publication date: Available online 14 February 2018
Source:Pathology - Research and Practice
Author(s): Junhun Cho, Sang Yun Ha, Seok-Hyung Kim, Hyun Hwan Sung, Ghee Young Kwon
Epithelial-mesenchymal transition (EMT) is a process which epithelial cells gain mesenchymal phenotype such as motility and invasiveness. We investigated the role of EMT in upper urinary tract urothelial carcinoma (UTUC). The patient cohort included 93 cases of UTUC treated with radical nephroureterectomy. Tissue microarrays were constructed from formalin-fixed paraffin-embedded tissue blocks. Immunohistochemical staining was performed for E-cadherin, vimentin, and smooth muscle actin to evaluate the EMT status. Interpretation criteria were defined for the staining results and EMT phenotypes were assigned as wild type, incomplete type (loss of E-cadherin and negative for vimentin), and complete type (loss of E-cadherin and positive for vimentin). The loss of E-cadherin and vimentin-expression was observed in 76 (81.7%) and 10 (10.8%) cases, respectively, yielding EMT phenotypes comprised of 17 cases (18.3%) of wild type, 66 cases (71.0%) of incomplete type, and 10 cases (10.8%) of complete types. In survival analyses, wild type showed statistically significant association with longer extra-bladder recurrence free survival (p < 0.001) and overall survival (p < 0.001). In multivariate analyses, complete type was an independent prognostic factor for extra-bladder recurrence free survival and overall survival. EMT phenotype based on the combination of EMT-related markers may provide a useful prognostic marker for UTUC patients.



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Clinicopathological analysis of Large Cell Lung Carcinomas definitely diagnosed according to the New World Health Organization Criteria

Publication date: Available online 14 February 2018
Source:Pathology - Research and Practice
Author(s): Yalan Bi, Yang Qu, Zhiyong Liang, Zichen Liu, Hui Zhang, Xiaolong Liang, Yufeng Luo, Jinling Cao, Haiqing Zhang, Ruie Feng
ObjectiveThe definition of large cell lung carcinoma (LCC) has undergone an extensive modification in the World Health Organization (WHO) Classification (2015). Present study aimed to investigate the clinicopathological characteristics of patients diagnosed as LCC according to current WHO criteria.MethodsLCCs diagnosed based on the previous WHO classification were reevaluated, and 17 cases of LCC were finally identified at Peking Union Medical College Hospital and Beijing Chest Hospital between 2009 and 2015. The clinicopathologic features were examined and EGFR and KRAS mutations were tested. Survival of the patients was analyzed by Kaplan-Meier method.ResultsThe median age of the patients was 64 years (range: 40-78). Most patients were male (64.7%) and about half of the patients were at TNM stage III (47.1%). Morphologically, most cases (70.6%) were classic LCC. All patients were treated by lobectomy plus lymph node dissection, 2 with bi-lobectomy and 1 with complex lobectomy, and the other 2 patients were further treated by partial pericardiotomy. Ten patients received postoperative chemotherapy, while only 3 patients were treated with radiotherapy after surgery. Molecular analysis showed two cases of EGFR mutation (L858R) but without non-overlapping KRAS mutation. The 3-year overall survival rate was 48.4 ± 15.1%. Chemotherapy was the only predictive factor that is associated with the prognosis of the patients (P = 0.003).ConclusionThe clinicopathological characteristics of 17 cases of stringently diagnosed LCC were retrospectively analyzed. LCC in our study showed aggressive behavior with high recurrence and metastasis and poor prognosis. Chemotherapy was only predictive factor that is significantly associated with the prognosis of the patients. Future studies based on a larger series and long term follow-up are still needed to characterize it further.



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MiR-1260b promotes the migration and invasion in non-small cell lung cancer via targeting PTPRK

Publication date: Available online 14 February 2018
Source:Pathology - Research and Practice
Author(s): Limin Xu, Xuting Xu, Huilian Huang, Zhihong Ma, Shuangmei Zhang, Pingping Niu, Yingrong Chen, Jinliang Ping, Ping Lu, Caihua Yu, Lishan Min, Jing Chen, Licheng Dai, Shunli Dong
ObjectiveNon-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases which cause most of cancer-related deaths globally. As our previous study discovered miR-1260b can be regarded as a specific signature for metastasis in NSCLC patients. However, the molecular mechanisms of miR-1260b underlying NSCLC progression and metastasis remain dismal.MethodsThe expression of miR-1260b in NSCLC tissues and cell lines were examined by real-time PCR, the effects of miR-1260b on cell migration, invasion and proliferation were evaluated in vitro. Furthermore, luciferase reporter assay was performed to identify the targets of miR-1260b, and the association between miR-1260b and its target gene was determined by real-time PCR and western blot assay.ResultsThe results showed that miR-1260b was significantly upregulated in NSCLC cell lines. The inhibition of miR-1260b expression decreased the migratory and invasive rates in A549 cells while miR-1260b overexpression had the opposite effect. Furthermore, PTPRK was identified as a direct target of miR-1260b, and PTPRK expression was inversely correlated with miR-1260b in NSCLC cell lines and clinical tissues.ConclusionsThese results suggested that miR-1260b may play an important role in NSCLC metastasis progression and could serve as a putative target for diagnosis and treatment of NSCLC.



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The expression patterns of vestigial like family member 4 genes in zebrafish embryogenesis

Publication date: Available online 14 February 2018
Source:Gene Expression Patterns
Author(s): Chang Xue, Hai Hong Wang, Jun Zhu, Jun Zhou
Transcriptional cofactor Vestigial-like 4 (VGLL4) was considered to take part in the early stage of development. Different from human, three paralogs of vgll4 were found in zebrafish, which were vgll4a, vgll4b and vgll4l. However, the expression patterns of the three paralogs during zebrafish development remains unknown. In this study, we used in situ hybridization to elucidate the temporal and spatial expression of zebrafish vgll4 paralogs during normal embryonic and larval development. Similar expression was shown in certain areas at similar stages for the three paralogs. Expression of vgll4a, vgll4b and vgll4l were all found in pectoral fins and otic vesicles during the early developmental stages. On the other hand, a few differences of the three paralogs expression were found in eyes, pharynx, pharyngeal arches and brain tissues. The expression of vgll4a was weak and ubiquitous, while vgll4b was obviously expressed in brain tissues and vgll4l was clearly restricted to each pair of pharyngeal pouches. What's more, vgll4b and vgll4l had unique expression at mature lateral line neuromasts and forerunner cells respectively. Despite the conservativeness of functional domains, the three paralogs of zebrafish vgll4 shared several similarities and displayed some distinctions in the expression patterns, indicating that they may still have different and exclusive functions, which need to be further explored.



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Dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid in a patient with acquired reactive perforating collagenosis

Abstract

Bullous pemphigoid (BP) is a common autoimmune blistering disorder with unknown etiology. Recently, increasing numbers of BP cases which developed under the medication with dipeptidyl peptidase-4 inhibitors (DPP4i), widely used antihyperglycemic drugs, have been reported in published works. Here, we report a case of DPP4i (teneligliptin)-associated BP that developed in a 70-year-old Japanese man. Interestingly, the patient had acquired reactive perforating collagenosis (ARPC), which is also known to be associated with the onset of BP. In the present case, clinical, histopathological and immunological findings suggested that DPP4i rather than ARPC was associated with the onset of BP.

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Efficacy of low-dose 5-fluorouracil/cisplatin therapy for invasive extramammary Paget's disease

Abstract

Extramammary Paget's disease (EMPD) is one of the cutaneous adenocarcinomas. The effective chemotherapy for advanced EMPD has not been established. This study was designed to evaluate the efficacy of combination 5-fluorouracil (500 mg/body, 7 days/week) and cisplatin (5 mg/body 5 days/week) for invasive EMPD. Seventeen EMPD patients with multiple metastases who visited our dermatology clinic between October 2004 and May 2016 (mean age, 76.9 years; 10 men, seven women) were retrospectively analyzed. Eight EMPD patients underwent low-dose 5-fluorouracil/cisplatin therapy and nine patients chose best supportive care. The average number of treatment cycles was 12.3. All patients had a confirmed response, four (50%) showed a partial response, two (25%) stable disease and two progressive disease. The median times to progression-free and overall survival were 25.0 and 77.4 weeks, respectively. There was no severe (grade 3 and 4) adverse event. Although not significant, the survival of the patients treated with low-dose 5-fluorouracil/cisplatin therapy showed a trend toward improved survival as compared with best supportive care (P = 0.08, log–rank test). This regimen had low risk and relatively high disease control rate, suggesting that this regimen be recommended as one of the treatment options for advanced EMPD.

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Successful treatment of chronic intractable pain with risperidone in a patient with acquired idiopathic generalized anhidrosis

http://ift.tt/2o3WjLM

Pyogenic granuloma-like Kaposi's sarcoma on the first toe

http://ift.tt/2o1QhMq

Cabozantinib in Patients with Advanced Merkel Cell Carcinoma

AbstractBackground.This study sought to determine the efficacy and safety profile of cabozantinib in patients with advanced Merkel cell carcinoma (MCC).Experimental Design.This prospective, phase II, single‐institution trial enrolled patients with platinum‐failure, recurrent/metastatic MCC to receive cabozantinib 60 mg orally daily until disease progression, withdrawal from study, or severe toxicity. The primary endpoint was disease control rate. Secondary endpoints included overall survival (OS), progression‐free survival (PFS), and toxicity. Immunohistochemistry for VEGFR‐2, MET, and HGF expression and next‐generation sequencing of tumor tissue were performed and correlated with outcome.Results.Eight patients were accrued from January 24, 2014, to June 8, 2016. The study was closed prematurely because of toxicity and lack of responses. The most frequent adverse events were grades 1 and 2 and included anorexia, fatigue, nausea, hypothyroidism, and dysgeusia. Two patients developed nonhealing, painful ulcers and tumor‐skin fistula. One patient had stable disease for 8 months. One patient withdrew from the study after 2 weeks of therapy because of adverse events. Three patients required dose reduction because of toxicity. Median PFS and OS were 2.1 and 11.2 months, respectively. No expression of MET, HGF, or VEGFR‐2 was identified in tumor cells by immunohistochemistry of patients' tissue samples.Conclusion.Cabozantinib was poorly tolerated and did not demonstrate activity in patients with recurrent/metastatic, platinum‐failure MCC. It is unclear whether preselection of patients with the specific upregulation or genetic alteration in the targets for cabozantinib would have changed the results of this study. (Clinical trial identification number: NCT02036476)Implications for Practice.This phase II study demonstrated poor tolerability and lack of activity of cabozantinib in an unselected group of patients with advanced Merkel cell carcinoma. Although it is unclear whether preselection of patients with the specific upregulation and genetic alterations in targets for cabozantinib would have changed the results of this study, this would have likely led to an extremely rare patient population that would take many years to accrue.

http://ift.tt/2GfBapc

Evaluation of Treatment Patterns and Survival Outcomes in Elderly Pancreatic Cancer Patients: A Surveillance, Epidemiology, and End Results‐Medicare Analysis

AbstractBackground.Management of pancreatic cancer (PC) in elderly patients is unknown; clinical trials exclude patients with comorbidities and those of extreme age. This study evaluated treatment patterns and survival outcomes in elderly PC patients using linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data.Materials and Methods.Histology codes 8140, 8500, 8010, 8560, 8490, 8000, 8260, 8255, 8261, 8263, 8020, 8050, 8141, 8144, 8210, 8211, or 8262 in Medicare Parts A and B were identified. Data regarding demographic, characteristics, treatments, and vital status between 1998 and 2009 were collected from the SEER. Determinants of treatment receipt and overall survival were examined using logistic regression and Cox proportional hazards models, respectively.Results.A total of 5,975 patients met inclusion. The majority of patients were non‐Hispanic whites (85%) and female (55%). Most cases presented with locoregional stage disease (74%); 41% received only chemotherapy, 30% chemotherapy and surgery, 10% surgery alone, 3% radiation, and 16% no cancer‐directed therapy. Patients with more advanced cancer, older age, and those residing in areas of poverty were more likely to receive no treatment. Among patients 66–74 years of age with locoregional disease, surgery alone (hazard ratio [HR] = 0.54; 95% confidence interval [CI]: 0.39–0.74) and surgery in combination with chemotherapy (HR = 0.69; 95% CI: 0.53–0.91) showed survival benefit as compared with the no treatment group. Among patients ≥75 years of age with locoregional disease, surgery alone (HR = 2.04; 95% CI: 0.87–4.8) or in combination with chemotherapy (HR = 1.59; 95% CI: 0.87–2.91) was not associated with better survival.Conclusion.Treatment modality and survival differs by age and stage. Low socioeconomic status appears to be a major barrier to the receipt of PC therapy among Medicare patients.Implications for Practice.Elderly patients with cancer are under‐represented on clinical trials and usually have comorbid illnesses. The management of elderly patients with pancreatic cancer is unknown, with many retrospective experiences but low sample sizes. Using Surveillance, Epidemiology, and End Results‐Medicare linked data to analyze treatment patterns and survival of elderly patients with pancreatic cancer on a larger population scale, this study highlights treatment patterns and their effect on survival and proposes possible obstacles to access of care in elderly patients with pancreatic cancer other than Medicare coverage.

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The Perils of Single‐Site Genetic Testing for Hereditary Cancer Syndromes in the Era of Next‐Generation Sequencing

AbstractA challenge in counseling patients with a family history suggesting a hereditary cancer syndrome is deciding which genetic tests or panels to order. In this article, we discuss the identification of multiple familial mutations through genetic counseling and panel testing. For patients meeting National Comprehensive Cancer Network criteria for clinical genetic testing, providers should consider expanded panels to provide a more complete assessment of one's genetic risk. The continued use of expanded panel testing in the clinical setting will help inform optimal management of cancer patients, as well as the management of their unaffected family members. The mutation discovered in this case was in the ATM gene. The clinical significance of the mutation, potential therapeutic targets, and proper clinical management are discussed.

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Pantoprazole, an Inhibitor of the Organic Cation Transporter 2, Does Not Ameliorate Cisplatin‐Related Ototoxicity or Nephrotoxicity in Children and Adolescents with Newly Diagnosed Osteosarcoma Treated with Methotrexate, Doxorubicin, and Cisplatin

AbstractLessons Learned. Using a randomized crossover design and continuous variables such as change in hearing threshold and biomarkers of acute renal injury as short‐term endpoints, it was determined that pantoprazole, an organic cation transporter 2 inhibitor, did not ameliorate cisplatin‐associated nephrotoxicity or ototoxicity.Cystatin C is a robust method to estimate glomerular filtration rate in patients with cancer. Using a patient‐reported outcome survey, all patients identified tinnitus and subjective hearing loss occurring "at least rarely" after cycle 1, prior to objective high‐frequency hearing loss measured by audiograms.New therapies that improve outcome with less acute and long‐term toxicity are needed.Background.Organic cation transporter 2 (OCT2), which is a cisplatin uptake transporter expressed on renal tubules and cochlear hair cells but not on osteosarcoma cells, mediates cisplatin uptake. Pantoprazole inhibits OCT2 and could ameliorate cisplatin ototoxicity and nephrotoxicity. Using a randomized crossover design, we evaluated audiograms, urinary acute kidney injury (AKI) biomarkers, and glomerular filtration rate (GFR) estimated from cystatin C (GFRcysC) in patients receiving cisplatin with and without pantoprazole.Materials and Methods.Cisplatin (60 mg/m2 × 2 days per cycle) was administered concurrently with pantoprazole (intravenous [IV], 1.6 mg/kg over 4 hours) on cycles 1 and 2 or cycles 3 and 4 in 12 patients with osteosarcoma (OS) with a median (range) age of 12.8 (5.6–19) years. Audiograms, urinary AKI biomarkers, and serum cystatin C were monitored during each cycle.Results.Pantoprazole had no impact on decrements in hearing threshold at 4–8 kHz, post‐treatment elevation of urinary AKI biomarkers, or GFRcysC (Fig. 1, Table 1). Histological response (percent necrosis) after two cycles was similar with or without pantoprazole. All eight patients with localized OS at diagnosis are alive and in remission; three of four patients with metastases at diagnosis have died.Conclusion.Pantoprazole did not ameliorate cisplatin ototoxicity or nephrotoxicity. The decrease in GFRcysC and increase in N‐acetyl‐ß‐glucosaminidase (NAG) and creatinine demonstrate that these biomarkers can quantify cisplatin glomerular and proximal tubular toxicity. OCT2 inhibition by pantoprazole did not appear to alter antitumor response or survival.

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A Curative‐Intent Trimodality Approach for Isolated Abdominal Nodal Metastases in Metastatic Colorectal Cancer: Update of a Single‐Institutional Experience

AbstractBackground.The purpose of this study was to define survival rates in patients with isolated advanced abdominal nodal metastases secondary to colorectal cancer (CRC), treated with curative‐intent trimodality therapy.Materials and Methods.Sixty‐five patients received trimodality therapy, defined as chemotherapy delivered with external beam radiotherapy (EBRT) followed by lymphadenectomy and intraoperative radiotherapy (IORT). Infusional 5‐fluorouracil was the most common radiosensitizer used (63%, 41 patients). The median dose of EBRT was 50 Gy, and the median dose of IORT was 12.5 Gy. We evaluated time to distant metastasis, toxicities, local failure within the EBRT field, recurrence within the IORT field, and survival.Results.Fifty‐two percent of patients were male; patients' median age was 50.5 years. All patients had an Eastern Cooperative Oncology Group score ≤1. Twenty‐nine patients had right‐sided colon cancer, 22 had left‐sided colon cancer, and 14 had rectal primaries. The median time from initial CRC diagnosis to development of abdominal nodal metastatic disease was 20.6 months (95% confidence interval [CI], 21.2–40.8 months). Seventy‐eight percent (51 patients) had para‐aortic nodal metastases, 15% (10 patients) had mesenteric nodal metastases, and 6% (4 patients) had both. With a median follow‐up of 77.6 months, the median overall survival and 5‐year estimated survival rate were 55.4 months (95% CI, 47.2–80.9 months) and 45%, respectively. The median progression‐free survival was 19.3 months (95% CI, 16.5–32.8 months). Twenty‐six (40%) patients never developed distant disease. The outcome was not affected by disease sidedness or rectal primary. Treatment was well tolerated without grade 3 or 4 toxicities.Conclusion.Trimodality therapy produces sustainable long‐term survival in selected patients with metastatic CRC presenting with isolated retroperitoneal or mesenteric nodal relapse.Implications for Practice.This article reports a unique trimodality approach incorporating external beam radiotherapy with radiosensitizing chemotherapy, surgical resection, and intraoperative radiotherapy provides durable survival benefit with significant curative potential for patients with metastatic colorectal cancer who present with isolated abdominal nodal (mesenteric and/or retroperitoneal) recurrence.

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Panobinostat and Multiple Myeloma in 2018

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Incidence of venous thromboembolism and use of anticoagulation in hematological malignancies: Critical review of the literature

Publication date: April 2018
Source:Critical Reviews in Oncology/Hematology, Volume 124
Author(s): Ombretta Annibali, Mariasanta Napolitano, Giuseppe Avvisati, Sergio Siragusa
Venous Thromboembolism (VTE) frequently complicates the course of hematologic malignancies (HM) and its incidence is similar to that observed in high-risk solid tumors. Despite that, pharmacologic prophylaxis and treatment of VTE in patients with HM is challenging, mainly because a severe thrombocytopenia frequently complicates the course of treatments or may be present since diagnosis, thus increasing the risk of bleeding. Therefore, in this setting, safe and effective methods of VTE prophylaxis and treatment have not been well defined and hematologists generally refer to guidelines produced for cancer patients that give indications on anticoagulation in patients with thrombocytopenia. In this review, besides to summarize the incidence and the available data on prophylaxis and treatment of VTE in HM, we give some advices on how to use antithrombotic drugs in patients with HM according to platelets count.



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Seltene Differentialdiagnose einseitiger, frontotemporaler Cephalgien

Laryngo-Rhino-Otol
DOI: 10.1055/s-0044-100516

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

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Skalenübergreifende Auswertung des Fragebogens zur Erfassung des stimmlichen Selbstkonzepts (FESS)

Laryngo-Rhino-Otol
DOI: 10.1055/s-0044-101837

Hintergrund Der Fragebogen zur Erfassung des stimmlichen Selbstkonzepts (FESS) bildet in drei Skalen das persönliche Erleben der eigenen Stimme ab. Dabei werden die Beziehung zur eigenen Stimme, die Bewusstheit im Umgang mit der Stimme und der Zusammenhang zwischen Stimme und Emotion bestimmt. Für die Auswertung des Fragebogens fehlte bisher eine skalenübergreifende Betrachtungsweise, um eine vereinfachte Interpretation der Ergebnisse zu ermöglichen. Material und Methoden Der FESS Fragebogen wurde bei 536 Lehrkräften eingesetzt und mittels einer Diskriminanz analyse auf gemeinsame Ausprägungsmerkmale in den Skalen untersucht. Für eine differenzierte Betrachtung von Zusammenhängen mit Stimmgesundheit, psychischer und körperlicher Gesundheit wurden ebenfalls der Voice Handicap Index (VHI), der Fragebogen zum arbeitsbezogenen Verhaltens- und Erlebensmuster (AVEM) und der Fragebogen zur gesundheitsbezogenen Lebensqualität (SF-12) herangezogen. Ergebnisse Die Analyse ergab vier verschiedene Gruppen des stimmlichen Selbstkonzepts: die Gruppe 1) mit stimmlich und psychisch gesunden Werten, die Gruppe 2) mit einem eher wenig ausgeprägtem stimmlichen Selbstkonzept und durchschnittlicher psychischer Gesundheit, die Gruppe 3) mit einer hohen Bewusstheit im Umgang mit der Stimme und durchschnittlicher psychischer Gesundheit und die Gruppe 4) mit hohen stimmlichen und psychischen Belastungen. Schlussfolgerung Die Ergebnisse zeigen, dass für eine Gesamtauswertung des Fragebogens zur Erfassung des stimmlichen Selbstkonzepts eine gemeinsame Betrachtung aller drei Skalen in Betracht gezogen werden kann. Die dargestellten Gruppen stellen dafür eine geeignete Herangehensweise zur Unterstützung in der Diagnostik zur Verfügung.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

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Critical role of Zn/Sn ratio to enhance Cu-Zn-Sn-S solar cell efficiency by suppressing detrimental Cu2-xS secondary phase

Publication date: 1 June 2018
Source:Solar Energy Materials and Solar Cells, Volume 179
Author(s): Kulwinder Kaur, Mohit Sood, Naveen Kumar, Heydar Honaryar Nazari, Ganesh Sainadh Gudavalli, Tara P. Dhakal, Mukesh Kumar
The co-existing secondary phases, in off-stoichiometric Cu-Zn-Sn-S (CZTS) solar cells, are one of the main causes of performance gap between earth abundant CZTS and matured Cu-In-Ga-Se (CIGS) solar cells technology. Highly metallic Cu-S based secondary phases provide shunting paths to the current flow and critically affect the device performance. Several chemical etchants have been developed and used to remove conductive Cu2-xS phase from CZTS absorber surface before device fabrication. Present work is mainly focused to tune the Zn/Sn composition ratio in co-sputtered CZTS active layer to suppress the formation of Cu2-xS phase during the growth itself to eliminate the additional step of etching in device fabrication. Significant reduction of Cu2-xS secondary phase was observed with decreased Zn/Sn ratio, which resulted in more than 3 times efficiency enhancement for the final composition. The fabricated solar cell in the stacking order of Ag/ITO/i-ZnO/CdS/CZTS/Mo/SLG with optimum composition showed an efficiency of 6.11% without any antireflection coating. Controlling the Zn/Sn ratio resulted in an effective and virtuous solution to avoid the detrimental secondary phases like Cu2-xS, which conventionally required a chemical etching treatment.

Graphical abstract

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Effects of mine tailing and mixed contamination on metals, trace elements accumulation and histopathology of the chub (Squalius cephalus) tissues: Evidence from three differently contaminated sites in Serbia

Publication date: 30 May 2018
Source:Ecotoxicology and Environmental Safety, Volume 153
Author(s): Božidar Rašković, Vesna Poleksić, Stefan Skorić, Katarina Jovičić, Slađana Spasić, Aleksandar Hegediš, Nebojša Vasić, Mirjana Lenhardt
Chub (Squalius cephalus) specimens were collected in Korenita River seven months after spillover from the waste water of antimony mine tailing pond and compared with chub living in Kruščica reservoir (intended for water supply) and Međuvršje reservoir (influenced by intense emission of industrial, urban and rural wastewater). Concentrations of 15 elements (Al, As, B, Ba, Cd, Cr, Cu, Fe, Hg, Mn, Ni, Pb, Si, Sr, Zn) were determined in muscle, liver and gills of chub by inductively coupled plasma optical spectrometry (ICP-OES) and histopathological alterations in liver and gills were assessed. Chub specimens from Korenita River had higher concentrations of As, Ba and Pb in all three investigated tissues as well as higher total histopathological index values than chub from reservoirs. Specimens from Međuvršje reservoir were characterized by higher values for concentrations of Cu and Si in muscle tissue and higher values for regressive histopathological alterations in gills. Individuals of chub from Kruščica reservoir had the highest concentrations of Fe in liver, Hg in muscle and Sr and Zn in muscle while gills had the lowest value of total histopathological index. The results from the present study showed higher level of histopathological alterations as a result of mine tailing accident. As a result of mixed contamination on the Međuvršje site, histopathological index values of gills were in line with the index value from Korenita River. Increased values for Fe and Sr in chub tissue from Kruščica reservoir could be explained by geological structure of the site which is characterized by magmatic rock rich in Cu, Fe and Ni as well as dominant carbonate sediment complex of marine origin with increased level of Sr.

Graphical abstract

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Decreased short-interval intracortical inhibition correlates with better pinch strength in patients with stroke and good motor recovery

Publication date: Available online 14 February 2018
Source:Brain Stimulation
Author(s): Karina Nocelo Ferreiro de Andrade, Adriana Bastos Conforto
BackgroundDeeper short-interval intracortical inhibition (SICI), a marker of GABAA activity, correlates with better motor performance in patients with moderate to severe hand impairments in the chronic phase after stroke.ObjectivesWe evaluated the correlation between SICI in the affected hemisphere and pinch force of the paretic hand in well-recovered patients. We also investigated the correlation between SICI and pinch force in controls.MethodsTwenty-two subjects were included in the study. SICI was measured with a paired-pulse paradigm. The correlation between lateral pinch strength and SICI was assessed with Spearman's rho.ResultsThere was a significant correlation (rho = 0.69, p = 0.014) between SICI and pinch strength in patients, but not in controls. SICI was significantly deeper in patients with greater hand weakness.ConclusionsThese preliminary findings suggest that decreased GABAA activity in M1AH correlates with better hand motor performance in well-recovered subjects with stroke in the chronic phase.



http://ift.tt/2Et72X9

Age and HIV effects on resting state of the brain in relationship to neurocognitive functioning

Publication date: 15 May 2018
Source:Behavioural Brain Research, Volume 344
Author(s): Anna R. Egbert, Bharat Biswal, Keerthana Karunakaran, Suril Gohel, Agnieszka Pluta, Tomasz Wolak, Bogna Szymańska, Ewa Firląg-Burkacka, Marta Sobańska, Natalia Gawron, Przemysław Bieńkowski, Halina Sienkiewicz-Jarosz, Anna Ścińska-Bieńkowska, Robert Bornstein, Stephen Rao, Emilia Łojek
This study examined the effects of age and HIV infection on the resting state (RS) functional connectivity (FC) of the brain and cognitive functioning. The objective was to evaluate the moderating role of age and HIV on the relationship between RS-FC and cognition. To examine RS-FC we implemented the Independent Component Analysis (ICA) and Regional Homogeneity (ReHo). Neurocognition was evaluated with comprehensive battery of standardized neuropsychological tests. Age and HIV were entered as the independent variables. The independent effects of age, HIV, and interaction effects of age-HIV on RS-fMRI measures (ICA, ReHo) were tested in 108 participants (age M = 42). RS-FC indices that exhibited age-HIV interactions were entered into further analysis. Bivariate correlation analysis was performed between the retained RS-FC indices and T-scores of neurocognitive domains (Attention, Executive, Memory, Psychomotor, Semantic Skills). Multivariate regression modeling determined the impact of age and HIV on these relationships. We found that in the ICA measures, HIV-seropositivity was decreasing RS-FC in the left middle occipital gyrus (p < .001). Age-HIV interaction was observed in the left superior frontal gyrus (LSupFrontG), where FC was decreasing with age in HIV+ (p < .001) and increasing in HIV− (p = .031). ReHo indices did not reveal significant effects. HIV strengthened the relationship between RS-FC in LSupFrontG, Memory and Psychomotor Factor scores. Aging weakened those relationships only in control group. In sum, age-HIV interaction effects are prominent rather in remote than local RS-FC. Seroconversion strengthens relationships between intrinsic brain activity and neurocognition, but no acceleration with years of age was noted in HIV+ individuals.



http://ift.tt/2ErWUhf

Reversal of drug-induced gingival overgrowth by UV-mediated apoptosis of gingival fibroblasts — an in vitro study.

Publication date: May 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 217
Author(s): Casey Ritchhart, Anita Joy
Gingival overgrowth (GO) is an undesirable result of certain drugs like Cyclosporine A (CsA). Histopathology of GO shows hyperplasia of gingival epithelium, expansion of connective tissue with increased collagen, or a combination. Factors such as age, gender, oral hygiene, duration, and dosage also influence onset and severity of GO. One of the mechanisms behind uncontrolled cell proliferation in drug-induced GO is inhibition of apoptotic pathways, with a consequent effect on normal cell turnover. Our objective was to determine if UV photo-treatment would activate apoptosis in the gingival fibroblast component. Human gingival fibroblast cells (HGF-1) were exposed to 200ng/ml or 400ng/ml CsA and maintained for 3, 6, and 9 days, followed by UV radiation for 2, 5, or 10min (N=6). Naïve (no CsA or UV), negative (UV, no CsA), and positive controls (CsA, no UV) were designated. Prior to UV treatment, growth media was replaced with 1M PBS to prevent absorption of UV radiation by serum proteins, and cells were incubated in growth media for 24h post-UV before processing for TUNEL assay, cell proliferation assays, or immunofluorescence. Data showed a temporal increase in proliferation of HGF-1 cells under the influence of CsA. The 200ng/ml dose was more effective in causing over-proliferation. UV treatment for 10min resulted in significant reduction in cell numbers, as evidenced by counts and proliferation assays. Our study is a first step to further evaluate UV-mediated apoptosis as a mechanism to control certain forms of GO.



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The Meckel Collections (Die Meckelschen Sammlungen), Rüdiger Schultka

Publication date: May 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 217
Author(s): Friedrich Paulsen




http://ift.tt/2C0OZKv

Diversion of complement-mediated killing by Bordetella

Publication date: Available online 14 February 2018
Source:Microbes and Infection
Author(s): Anaïs Thiriard, Dominique Raze, Camille Locht
The complement cascade participates in protection against bacterial infection and pathogens, including Bordetella pertussis, have developed complement-evading strategies. Here we discuss current knowledge on B. pertussis complement evasion strategies and the role of antibody-dependent complement-mediated killing in protection against B. pertussis infection pointing out important knowledge gaps for further research to improve current pertussis vaccines.



http://ift.tt/2C0OqQT

Reliability and construct validity of the Ottawa valve collapse scale when assessing external nasal valve collapse

Nasal valve collapse is a common cause of nasal obstruction in otolaryngology practice. Common examination methods, such as the Cottle Maneuver and modified Cottle Maneuver are available. However, these method...

http://ift.tt/2o4V2Ea

Bilateral Piriform sinus fistulas: a case study and review of management options

Piriform sinus fistulas occur due to developmental abnormalities of the third and fourth branchial arches, and almost always occur unilaterally. They generally present as recurrent abscesses in the anterior-in...

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Plant Growth Promoting Bacteria as an Alternative Strategy for Salt Tolerance in Plants: A Review

Publication date: Available online 13 February 2018
Source:Microbiological Research
Author(s): Muhammad Numan, Samina Bashir, Yasmin Khan, Roqayya Mumtaz, Zabta Khan Shinwari, Abdul Latif Khan, Ajmal Khan, Ahmed AL-Harrasi
Approximately 5.2 billion hectare agriculture land are affected by erosion, salinity and soil degradation. Salinity stress has significantly affecting the fertile lands, and therefore possesses a huge impact on the agriculture and economy of a country. Salt stress has severe effects on the growth and development of plants as well as reducing its yield. Plants are inherently equipped with stress tolerance ability to responds the specific type of stress. Plants retained specific mechanisms for salt stress mitigation, such as hormonal stimulation, ion exchange, antioxidant enzymes and activation of signaling cascades on their metabolic and genetic frontiers that sooth the stressed condition. Additional to the plant inherent mechanisms, certain plant growth promoting bacteria (PGPB) also have specialized mechanism that play key role for salt stress tolerance and plant growth promotion. These bacteria triggers plants to produce different plant growth hormones like auxin, cytokinine and gibberelline as well as volatile organic compounds. These bacteria also produces growth regulators like siderophore, which fix nitrogen, solubilize organic and inorganic phosphate. Considering the importance of PGPB in compensation of salt tolerance in plants, the present study has reviewed the different aspect and mechanism of bacteria that play key role in promoting plants growth and yield. It can be concluded that PGPB can be used as a cost effective and economical tool for salinity tolerance and growth promotion in plants.

Graphical abstract

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Transcriptional and epigenetic regulation of innate-like T lymphocyte development

Publication date: April 2018
Source:Current Opinion in Immunology, Volume 51
Author(s): Mihalis Verykokakis, Barbara L Kee
Invariant Natural Killer T (iNKT) cells are a heterogeneous innate T cell population that recognizes lipid antigens. Despite the monospecific nature of their T cell receptor, iNKT cells differentiate into stable sublineages during thymic development, before foreign antigen encounter. How iNKT cell subsets acquire and maintain their functional programs is a central question in innate lymphocyte biology. Global transcriptional and epigenetic profiling of iNKT subsets has provided insights into the internal wiring of these subsets that defines their identity. Comparison of the iNKT transcriptional programs with those of other adaptive and innate lymphocyte lineages revealed common core regulatory circuits that may dictate effector functions. In this review, we summarize recent advances on the molecular mechanisms involved in iNKT cell development.



http://ift.tt/2srV7aE

Chemical sensing in development and function of intestinal lymphocytes

Publication date: February 2018
Source:Current Opinion in Immunology, Volume 50
Author(s): Luisa Cervantes-Barragan, Marco Colonna
The immune system of the intestinal tract has the challenging task of recognizing and eliminating intestinal pathogens while maintaining tolerance to dietary and commensal antigens; therefore, it must be able to sense environmental cues within the intestine and mount suitable responses dictated by their pathogenic or nonpathogenic nature. The aryl hydrocarbon receptor (AHR) was originally characterized as a chemical sensor of the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [12]. More recently, AHR has emerged as a major chemical sensor expressed in many intestinal immune cells that enables them to distinguish nutritional and microbial cues and is, therefore, important for development, maintenance and function of the intestinal immune system. In this review, we will highlight recent advances in our knowledge of the role of AHR signaling in intestinal innate lymphoid cells (ILC), T cells and B cells.



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Rethinking Phagocytes: Clues from the Retina and Testes

Publication date: Available online 14 February 2018
Source:Trends in Cell Biology
Author(s): Kristen K. Penberthy, Jeffrey J. Lysiak, Kodi S. Ravichandran
Specialized phagocytes are a newly appreciated classification of phagocyte that currently encompasses Sertoli cells (SCs) of the testes and the retinal pigment epithelial cells (RPE) of the retina. While these cells support very different tissues, they have a striking degree of similarity both as phagocytes and in ways that go beyond cell clearance. The clearance of apoptotic germ cells, cell debris, and used photoreceptor outer segments are critical functions of these cells, and the unique nature of their clearance events make specialized phagocytes uniquely suited for studying the larger implications of cell clearance in vivo. The shared functions of specialized phagocytes could provide novel insights into how phagocytosis impacts tissue homeostasis and immune modulation. In this review, we examine the remarkable similarities between SCs and RPE as specialized phagocytes and the physiological effects of cell clearance within a tissue.



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CYP27A1 acts on the pre-vitamin D3 photoproduct, lumisterol, producing biologically active hydroxy-metabolites

Publication date: Available online 13 February 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Robert C. Tuckey, Wei Li, Dejian Ma, Chloe Y.S. Cheng, Katie M. Wang, Tae-Kang Kim, Saowanee Jeayeng, Andrzej T. Slominski
Prolonged exposure of the skin to UV radiation causes previtamin D3, the initial photoproduct formed by opening of the B ring of 7-dehydrocholesterol, to undergo a second photochemical reaction where the B-ring is reformed giving lumisterol3 (L3), a stereoisomer of 7-dehydrocholesterol. L3 was believed to be an inactive photoproduct of excessive UV radiation whose formation prevents excessive vitamin D production. Recently, we reported that L3 is present in serum and that CYP11A1 can act on L3 producing monohydroxy- and dihydroxy-metabolites which inhibit skin cell proliferation similarly to 1α,25-dihydroxyvitamin D3. In this study we tested the ability of human CYP27A1 to hydroxylate L3. L3 was metabolized by purified CYP27A1 to 3 major products identified as 25-hydroxyL3, (25R)-27-hydroxyL3 and (25S)-27-hydroxyL3, by NMR. These three products were also seen when mouse liver mitochondria containing CYP27A1 were incubated with L3. The requirement for CYP27A1 for their formation by mitochondria was confirmed by the inhibition of their synthesis by 5β-cholestane-3α,7α,12α-triol, an intermediate in bile acid synthesis which serves as an efficient competitive substrate for CYP27A1. CYP27A1 displayed a high kcat for the metabolism of L3 (76 mol product/min/mol CYP27A1) and a catalytic efficiency (kcat/Km) that was 260-fold higher than that for vitamin D3. The CYP27A1-derived hydroxy-derivatives inhibited the proliferation of cultured human melanoma cells and colony formation with IC50 values in the nM range. Thus, L3 is metabolized efficiently by CYP27A1 with hydroxylation at C25 or C27 producing metabolites potent in their ability to inhibit melanoma cell proliferation, supporting that L3 is a prohormone which can be activated by CYP-dependent hydroxylations.



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